Rare Diseases

This transcript has been edited for clarity.

Fatima Cardoso, MD: Today we will be discussing breast cancer in male patients. To join me in this discussion, I have Sharon Giordano and Oliver Bogler. I will ask, to start, that we briefly introduce ourselves.

I’m Fatima Cardoso. I’m a medical oncologist based in Lisbon, Portugal. I have had a special interest in this topic for a couple of years. Sharon?

Sharon H. Giordano, MD, MPH, FASCO: I’m Sharon Giordano. I practice at the University of Texas MD Anderson Cancer Center. I’m also a medical oncologist and treat most of the male breast cancer patients that are seen here.

Oliver Bogler, PhD: I’m Oliver Bogler. I’m a cancer biologist by background and an 11-year survivor of breast cancer. Dr. Giordano was my oncologist during the active phase of my treatment. It’s great to be here with you.

Special considerations surrounding male patients

• Dr. Cardoso: Sharon, when you are treating breast cancer in a male patient, what specific considerations do you have?
• Dr. Giordano: As we all know, breast cancer in men is a rare disease. It makes up about 1 in 1,000 cases of breast cancer. I think that one of the major challenges in treating the disease is we just don’t have the same to support our treatments as we do for women.

Often, what we need to do and what we end up doing is extrapolating as much as possible from clinical trials that were conducted in female patients with breast cancer. I think that’s one of the major challenges we face in treating the disease. There have been international efforts to try to put together standardized treatment approaches.

For example, ASCO has created guidelines for the management of male breast cancer. NCCN also has a special page on considerations for treatment of men with breast cancer. I would encourage people to look at those resources if questions do come up on the topic.

Dr. Cardoso: Perhaps we can also mention that the latest clinical trials fortunately have been allowing for male patients to be included, which is very important so that we can start having some data on the new drugs. I think that’s also relevant.

Dr. Giordano: That’s a great point because, historically, most of the trials explicitly excluded men. I don’t know if it was intentional or they just wrote the trials saying “women with breast cancer,” because that’s what most people thought of. I think it’s a great effort by the FDA and by investigators to make sure now that men are included in the trials. That will help build our evidence base.

Dr. Cardoso: Oliver, 11 years ago, you faced the diagnosis and you went through this. Can you speak a little bit about this challenge of going through what is considered a rare disease, but also a disease that is very much associated with the female gender traditionally?

Dr. Bogler: Gladly. For me, it was particularly odd because my wife, at the time that I was diagnosed, was a 5-year survivor of breast cancer. It took me some time to even think that the lump I felt might be the same disease. That seemed very unlikely, statistically, and also odd.

I have to say that I was protected from much of the fish-out-of-water experience that many men have because I both worked and was treated at MD Anderson, where Dr Giordano has a large practice, so my colleagues and my friends were not surprised that a man could get this disease.

Many of the patients I met had that experience, difficulty convincing their primary care physician or even their first-line oncologist that this could be the case. I just want to connect to what you both said, which is that 10 years ago, inclusion of men in clinical trials was not standard. It is a fantastic development to see that because unless we include men, we won’t learn about that type of breast cancer.

Dr. Cardoso: Even if only a few are entering each trial, at least it allows us to see if the drug behaves the same way or if there is any strange behavior of the drug in a male patient. It’s already one step forward. You were going to mention something, Sharon?

Dr. Giordano: I was going to say that, anecdotally, I’ve heard the experience that Oliver referred to, of many men feeling not so much uncomfortable with the diagnosis – although that does happen – but not having an obvious fit within the health care system.

For example, going to get their mammogram as part of their diagnostic workup and whoever might be taking them back saying, “Oh, no, this is Mrs. Jones, not Mr.,” and trying to argue with them that it’s not really meant for them. I had a patient – and this guy had a great sense of humor – who had a biopsy done and the instructions were to place this pink, floral ice pack inside your bra.

Even the materials that we have are gender specific. I think those things all together can certainly contribute to a man feeling like a fish out of water.

Dr. Cardoso: Actually, I fought in my institution because they wanted to call the Breast and Gynecology Unit the Women’s Unit. I said that there is no way you can call it the Women’s Unit because we have male patients. There are small things that we can do in our institutions to try to decrease the stigma and to make it less awkward for a man to be in a waiting room that says Women’s Clinic or something similar to that.

The importance of a support system

Dr. Cardoso: I wanted Oliver, perhaps, to mention experiences that you may have heard from other men. Some men do not feel that comfortable speaking about the disease. Also, some of them do not feel comfortable after treatment to go to the beach, to show the scar, and to show what happens after you have radiation.

Some men actually take it quite heavily, psychologically speaking. Have you encountered some of these men?

Dr. Bogler: Definitely. I think it leads to men not accessing the support opportunities – their family, their friends, or the support groups – and staying away from those because of this feeling of not wanting to share about it. That can be damaging. Cancer treatment is usually a tough road for most people, and the long-term consequences of hormone therapy – most men have hormone-driven disease – can be significant. I agree with you.

I participated in the male breast cancer SCAR Project by David Jay, a famous photographer. One of the high points of my life has been appearing in The New York Times topless, right after my radiation treatment, showing my scar. There are quite a few of us out there who’ve done that.

I’ll just mention in passing the Male Breast Cancer Global Alliance, which is a patient support supergroup, if you will. We’ve got a symposium coming up in November. That’s a great place for men who are early in the stage of their disease, or at any stage, to connect to others who are facing this issue.

Dr. Cardoso: They can also find specific information. This is a really good website where you can find information. One of the most important topics that I’ve heard from my patients is, “I never thought that I could have this disease. I never heard that men could have breast cancer as well.” Information is very crucial.

I believe that if you are well informed, you will also be less scared of the disease. Sources of reliable information are really crucial for patients. Since you mentioned the SCAR Project, we have a similar project here in Portugal that really called attention to the disease. It was very visual and really interesting.
 

Discussions during and after treatment

Dr. Cardoso: I wanted to say something, and I don’t know if both of you would agree. I think only recently surgeons have started to pay attention to the way they operate on men with breast cancer, and even in considering techniques of breast conservation and oncoplastic surgery. I had the feeling, looking at those photos, that some years ago, it wouldn’t have mattered how they do with the mastectomy scar just because it was a man. This was biased, right?

Just because it was a man, there was no need to pay attention to the aesthetic outcome. That is wrong, in my perspective. I’m very happy to see that now there are surgeons considering other types of breast surgery to conserve as much as possible the aesthetic outcome.

Dr. Bogler: I have to say that I was offered reconstruction at MD Anderson. I declined it. It wasn’t that big a part of my body image. When I raised this issue at home, my kids, who were quite young at the time, just suggested, “Well, Dad, why don’t you just wear a swim shirt?” They came up with a very practical solution for this issue.

I agree with you that it should be an option. I was also offered a nipple tattoo. I have yet to take that up, but maybe one day.

Dr. Cardoso: I’m not sure that we need to go into reconstruction. It also depends on whether a man has gynecomastia, if it’s going to be very asymmetric. There are other techniques to do, and depending on the size of the tumor, we can also do breast conservation, which we have done here in a couple of patients.

It’s quite an interesting approach where, for example, a skin-sparing mastectomy would be less aggressive, let’s say. Sharon?

Dr. Giordano: I completely agree. I’ve noticed increasing attention to the issue over the years that I’ve been in practice. I do think that it’s more front-and-center when the surgeons are having discussions with the patients now.

Also, although it’s still a minority, some do choose to have reconstructive surgery; some have more extensive surgeries, and some maybe have nipple reconstruction or a nipple tattoo. In a few men, like you mentioned, who are somewhat asymmetric, it actually can make a difference even when they’re dressed.

For many men, it’s more that they want to take off their shirt to play basketball or go swimming, and to decrease the feeling of awkwardness or like they have to make an explanation for why they have a nipple missing and a scar across their chest.
 

Biological aspects of male patients

Dr. Cardoso: Let’s switch gears now to the management, and before that, the biology. Oliver, with your other hat of biology, speak a little bit on what we know so far – whether it is exactly the same disease or there are biological specific characteristics of breast cancer in men.

Dr. Bogler: I should preface this by saying that I spent my career studying brain tumors. That was clearly a mistake.

Dr. Cardoso: It starts with a B. ...

Dr. Bogler: It starts with a B, but it’s the wrong part of the body. The reality is that we don’t really know that much fundamental biology yet, though the picture is changing and it has changed in recent years. Part of the reason is we don’t have many of the tools that we’ve had for the female disease for many years, particularly laboratory models.

On the genetic and transcriptomics front, there has been some really good activity. There was a comprehensive systematic review by Professor Val Speirs from the University of Aberdeen earlier this year that summarized much of the recent data. It showed that there are a handful of molecular hallmarks of the male disease, compared with the female disease, that are worth exploring.

Interestingly enough, one of them is the androgen receptor. It does beg the question of whether hormone-driven disease might not show up quite differently in males and females, where the hormone picture is a little different. I think there’s increasing evidence that there’s information out there to go after.

I will say that I was treated by Dr. Giordano and her colleagues very much like a woman would have been with my disease, and actually, very similarly to my wife. I’ve done well with it, so I would say, in most cases, the current standard of care is very effective but it falls a little short of personalized medicine, particularly when it comes to the hormone component.

Dr. Cardoso: Sharon?

Dr. Giordano: I would add that when I think about it as a clinician, although there’s a large amount of overlap and many similarities, when we’re treating men with breast cancer, almost all of the men have hormone receptor–positive disease, which I think Oliver mentioned earlier. We’re really thinking about endocrine therapy as one of the mainstays of treatment.

Obviously, as he also mentioned, it’s a different biologic background of hormones in a male vs. a female patient. There’s reason to think that some of those treatments could differ. In general, the subtypes are a little bit different. We see very, very few cases of triple-negative breast cancer in men. I think I’ve seen only one or two in my career. The ones I remember were probably radiation induced. They were cancer survivors who’d had chest-wall radiation for previous diseases. Those patients are very uncommon.

We also tend to see that the histology patterns are a little bit different. We tend to see more ductal cancers in men than we do in women as a relative proportion.

One thing that I always try to remember is that the risk for BRCA mutations or underlying germline genetic mutations is higher in men than in women. Just having a diagnosis of male breast cancer is an indication to consider genetic testing or meet with a genetic counselor to look for a BRCA1 or BRCA2 mutation.

Now, most men will not have that. Only roughly 10% of male patients, or maybe a little less, will have a BRCA2 mutation; for BRCA1, it’s more like only 1% or 2%. They’re not that common. Certainly, male breast cancer is recognized as being associated with the BRCA mutations.

Dr. Cardoso: If I have to give a take-home message in terms of biology, it would be that if there is a diagnosis of hormone receptor–negative or HER2-positive disease in a male patient, I would ask for a confirmation of the diagnosis. It’s not that it cannot exist, but it’s so rare that it’s worthwhile to confirm.

You mentioned that triple-negative disease is less than 1%, at about 0.5%, and HER2-positive disease is about 9%-10%. I think it will be very important to keep this in mind and confirm the biology if you have a different diagnosis than ER-positive, HER2-negative. Unfortunately, I received some cases where this was not done, and in fact, it ended up being a technical problem. People can receive the wrong treatment based on that.

Dr. Giordano: I’ve also seen that happen when it’s a metastasis to the breast rather than a primary breast cancer. I completely agree. That’s an excellent point. 

Management approaches

Dr. Cardoso: Let’s go now to management and focus on early breast cancer first. Sharon, what are your main take-home messages for a professional who doesn’t see this very often? What does someone need to remember when they manage a male patient who has early breast cancer?

Dr. Giordano: In general, in terms of chemotherapy, we essentially use the same guidelines as we do for women. Most of the male patients will have tumors that are hormone receptor positive. For endocrine therapy, we typically rely on tamoxifen as the standard of care for adjuvant endocrine treatment for breast cancer.

There are some data suggesting that there can be some efficacy of aromatase inhibitors as single agents. In general, and extrapolated from some population-based registry data, the outcomes for men treated with single-agent aromatase inhibitors don’t tend to be as good as for those treated with tamoxifen.

I know that these are not randomized data so there are all the caveats of that, but the best information we have suggests that tamoxifen appears to likely be more effective. Typically, we stay with tamoxifen. If, for some reason, a man cannot tolerate tamoxifen or has a contraindication, then we could use a GnRH agonist along with an aromatase inhibitor.

Dr. Cardoso: I would like to mention that, because it’s ER-positive, HER2-negative disease most of the time, there will be the question as to whether we can use genomic tests. I think it is important that people know that we have much less data regarding the use of Oncotype DX, MammaPrint, or any of the genomic tests in male patients.

We have some data on the distribution of, for example, Oncotype DX or MammaPrint scores. Whether we can use these tests for the decision of chemotherapy, we don’t have much data on that. I’ve seen many people making exactly the same decisions as with female patients, but that’s not really based on very strong evidence.

Dr. Giordano: It’s hard to know what to do with that. There are prognostic data on Oncotype, so the higher-risk tumors do seem to have a worse outcome than the lower-score tumors. You’re right, though; I don’t think we have any predictive information to really show that the Oncotype DX score predicts benefit to chemotherapy.

Having said that, I will sometimes order the test in my practice. If somebody comes back with a score of 5 or a very low-risk score, I will use that in my decision-making.

Dr. Cardoso: There is something we didn’t exactly mention in the diagnosis that may be important. We discussed most men not knowing that they can have breast cancer, and Oliver, you mentioned that sometimes the first-line physicians can think that very often. Usually, we have late diagnosis and that means a higher tumor burden.

Sometimes we have to go to chemotherapy because of locally advanced or very positive axillas and not really because of the biology. That’s one of the reasons to go for chemotherapy in this setting, right?

Dr. Bogler: Yes. I remember that conversation with you, Dr. Giordano. I asked you whether I should do one of these tests. You said, “Don’t worry about it. At stage III, you’re going to have chemo anyway.”

Dr. Cardoso: The problem of these rare diagnoses is the not thinking about it, even from the health professional side, and then having the diagnosis quite late that will demand chemotherapy use.

To clarify to everybody, in terms of distinguishing luminal A–like, luminal B–like, and what that implies in a male patient, we really don’t know if it’s the same as in a female. There have been some very interesting studies from our Nordic country colleagues showing that maybe the subtyping is different. There is likely a male-specific subtype that does not exist in female breast cancer and that probably behaves differently. We still have a large amount of research to do to understand that.

Is there anything else you would like to mention about early breast cancer management?

Dr. Bogler: One of the things that’s probably underexplored is adherence to tamoxifen therapy in men. I do know anecdotally that this is the discussion among men because of the impact on quality of life. I do worry that sometimes men perhaps make the wrong choice, and I think that’s an opportunity for more research. Again, if there were alternative therapies that were perhaps a little less impactful on things like libido, that might be an advance in the field.

Dr. Cardoso: We have been seeing more studies on the issue of quality of life. Noncompliance is also an issue in female patients. We have to acknowledge that. Not everybody is able to keep taking the treatments. Interestingly, when there is a relapse and people had stopped taking the tamoxifen, most of them say, “I stopped because I had not understood exactly how important it is.”

We come back to the importance of explaining that it is the most crucial treatment for this subtype of breast cancer. Again, information is really key.

Sometimes I also use the argument with my patients that the alternative is even worse because if you use an aromatase inhibitor, and you have to use an LHRH agonist, then the implications for your sexual life are even worse. That’s how I try to convince them to stay on tamoxifen.

Let’s finalize with a couple of words on metastatic breast cancer in male patients. Sharon, I’ll start with you again. Is there any difference in the management if you have a patient with metastatic, ER-positive, HER2-negative disease? How do you treat? How do you sequence the available therapies? Is it different from the female patient?

Dr. Giordano: I’d say that, big picture, it’s quite similar. Again, most of the men have hormone receptor–positive disease, so really, the mainstay of treatment and the first treatments are going to be endocrine therapies. We’ll sequence through the endocrine therapies like we do in women. When using aromatase inhibitors, I typically would add a GnRH agonist to that, and I have had that be a very successful therapy, along now with the CDK inhibitors that are also approved.

I don’t think the studies of CDK inhibitors included male patients, but at least palbociclib actually was approved in the United States, based on some real-world evidence of its efficacy. Anecdotally, again, in my clinical practice, that tends to be a really powerful combination of leuprolide, an aromatase inhibitor, and a CDK inhibitor.

I think there’s less information about drugs like fulvestrant, whether that would benefit from combination with a GnRH agonist or whether those should be given as single agents. We just don’t really know. We have a few case series out there.

Similar to the early breast cancer setting, I think it’s really important to remember to check for BRCA1 and BRCA2 mutations. PARP inhibitors could be a part of the treatment plan if those underlying germline mutations are found. Generally, we’re following a similar sequence of endocrine therapies and then, eventually, chemotherapy.

Dr. Cardoso: Maybe, Oliver, you’re also seeing that one consistent finding in the biology study is the importance of the AKT/PI3K/mTOR pathway in male patients with breast cancer, because we now have at least two classes of agents to tackle this pathway. Again, anecdotally – we’re not talking about trials – I’ve been seeing quite interesting responses, for example, to everolimus combined with endocrine therapy.

We have a little less experience with the PI3K inhibitor, but that’s just because of accessibility to the drug. I think this combination is also something to keep in mind that can be quite effective in these patients.

Dr. Bogler: I agree. Those findings are exciting in the context of dealing with something as difficult as metastatic breast cancer. It’s good to know that there’s some information coming and opportunities and options, hopefully, down the road for men facing that problem.

Dr. Cardoso: Sharon, although small numbers, in these cases where there is HER2-positive disease, you would also use the new anti-HER2 agents and more or less the same sequence, right?

Dr. Giordano: Absolutely. It’s not particularly data driven, but yes, I would. If it’s a HER2-positive tumor, I would use the same HER2-targeted therapies that are used for women with breast cancer.

Working toward a balance in patient care

Dr. Cardoso: I would like to add something for all of us to be united in the fight. I don’t know if it happens in the U.S., but in many countries, access to these new agents for male patients is very difficult because of the approval and the labeling. This is why I’m always fighting with those who are proposing that the labeling, again, says “women with breast cancer.”

It is really important that we keep on lobbying and pushing for the labeling to say “patients with breast cancer” so that nobody can withhold access to these new therapies because of gender. In the U.S., maybe you don’t have this problem. There are many European countries where men cannot access, for example, fulvestrant because it has been approved for women with breast cancer.

Dr. Giordano: Thankfully, I have not faced that issue very often. I’ve had occasional issues with getting GnRH agonists approved. Generally, in the U.S., if I provide, for example, the NCCN guideline recommendations, most insurers will cover it. I think it’s often just lack of knowledge.

Dr. Cardoso: It’s something to keep working hard on because for the old drugs that were approved with the wording that still said “women,” we have to keep fighting for accessibility.

I think we had a really nice discussion. I’m going to give you an opportunity for any last words that you want to say on this topic. Perhaps we’ll start with you, Sharon, and we’ll leave the very last word to Oliver.

Dr. Giordano: I would just emphasize the importance of doing research in this area. Hopefully, we will be able to get clinical trials. There are reasons to think that endocrine therapies may behave differently in men and women. We need to continue to work together as a community to collect the data so that we can ultimately improve the outcomes for our patients.

Dr. Bogler: I would echo what you just said, Dr. Giordano. I would like to express my gratitude to both of you. Dr. Giordano, you have a huge practice of men at MD Anderson. You took care of me and many other people I know.

Dr. Cardoso, you are a pioneer of a big registry trial that I am privileged to be working on, trying to gather data on men. You’re both pioneers in this field of working on behalf of people like me. I’m just very grateful for what you do.

Dr. Giordano: Thank you.

Dr. Cardoso: Thank you both for accepting this invitation. We hope that everybody takes more interest in this field. Who knows? Maybe we can find enough funds to run a specific trial for male patients with breast cancer.

Dr. Cardoso is director of the breast unit at Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon. Dr. Giordano is professor of breast medical oncology and chair of health services research at the University of Texas MD Anderson Cancer Center, Houston. Dr. Bogler is a cancer biologist at the Randolph (Vt.) Center. Dr. Cardoso reported conflicts of interest with numerous pharmaceutical companies; Dr. Giordano and Dr. Bogler reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Fatima Cardoso, MD: Today we will be discussing breast cancer in male patients. To join me in this discussion, I have Sharon Giordano and Oliver Bogler. I will ask, to start, that we briefly introduce ourselves.

I’m Fatima Cardoso. I’m a medical oncologist based in Lisbon, Portugal. I have had a special interest in this topic for a couple of years. Sharon?

Sharon H. Giordano, MD, MPH, FASCO: I’m Sharon Giordano. I practice at the University of Texas MD Anderson Cancer Center. I’m also a medical oncologist and treat most of the male breast cancer patients that are seen here.

Oliver Bogler, PhD: I’m Oliver Bogler. I’m a cancer biologist by background and an 11-year survivor of breast cancer. Dr. Giordano was my oncologist during the active phase of my treatment. It’s great to be here with you.

Special considerations surrounding male patients

• Dr. Cardoso: Sharon, when you are treating breast cancer in a male patient, what specific considerations do you have?
• Dr. Giordano: As we all know, breast cancer in men is a rare disease. It makes up about 1 in 1,000 cases of breast cancer. I think that one of the major challenges in treating the disease is we just don’t have the same to support our treatments as we do for women.

Often, what we need to do and what we end up doing is extrapolating as much as possible from clinical trials that were conducted in female patients with breast cancer. I think that’s one of the major challenges we face in treating the disease. There have been international efforts to try to put together standardized treatment approaches.

For example, ASCO has created guidelines for the management of male breast cancer. NCCN also has a special page on considerations for treatment of men with breast cancer. I would encourage people to look at those resources if questions do come up on the topic.

Dr. Cardoso: Perhaps we can also mention that the latest clinical trials fortunately have been allowing for male patients to be included, which is very important so that we can start having some data on the new drugs. I think that’s also relevant.

Dr. Giordano: That’s a great point because, historically, most of the trials explicitly excluded men. I don’t know if it was intentional or they just wrote the trials saying “women with breast cancer,” because that’s what most people thought of. I think it’s a great effort by the FDA and by investigators to make sure now that men are included in the trials. That will help build our evidence base.

Dr. Cardoso: Oliver, 11 years ago, you faced the diagnosis and you went through this. Can you speak a little bit about this challenge of going through what is considered a rare disease, but also a disease that is very much associated with the female gender traditionally?

Dr. Bogler: Gladly. For me, it was particularly odd because my wife, at the time that I was diagnosed, was a 5-year survivor of breast cancer. It took me some time to even think that the lump I felt might be the same disease. That seemed very unlikely, statistically, and also odd.

I have to say that I was protected from much of the fish-out-of-water experience that many men have because I both worked and was treated at MD Anderson, where Dr Giordano has a large practice, so my colleagues and my friends were not surprised that a man could get this disease.

Many of the patients I met had that experience, difficulty convincing their primary care physician or even their first-line oncologist that this could be the case. I just want to connect to what you both said, which is that 10 years ago, inclusion of men in clinical trials was not standard. It is a fantastic development to see that because unless we include men, we won’t learn about that type of breast cancer.

Dr. Cardoso: Even if only a few are entering each trial, at least it allows us to see if the drug behaves the same way or if there is any strange behavior of the drug in a male patient. It’s already one step forward. You were going to mention something, Sharon?

Dr. Giordano: I was going to say that, anecdotally, I’ve heard the experience that Oliver referred to, of many men feeling not so much uncomfortable with the diagnosis – although that does happen – but not having an obvious fit within the health care system.

For example, going to get their mammogram as part of their diagnostic workup and whoever might be taking them back saying, “Oh, no, this is Mrs. Jones, not Mr.,” and trying to argue with them that it’s not really meant for them. I had a patient – and this guy had a great sense of humor – who had a biopsy done and the instructions were to place this pink, floral ice pack inside your bra.

Even the materials that we have are gender specific. I think those things all together can certainly contribute to a man feeling like a fish out of water.

Dr. Cardoso: Actually, I fought in my institution because they wanted to call the Breast and Gynecology Unit the Women’s Unit. I said that there is no way you can call it the Women’s Unit because we have male patients. There are small things that we can do in our institutions to try to decrease the stigma and to make it less awkward for a man to be in a waiting room that says Women’s Clinic or something similar to that.

The importance of a support system

Dr. Cardoso: I wanted Oliver, perhaps, to mention experiences that you may have heard from other men. Some men do not feel that comfortable speaking about the disease. Also, some of them do not feel comfortable after treatment to go to the beach, to show the scar, and to show what happens after you have radiation.

Some men actually take it quite heavily, psychologically speaking. Have you encountered some of these men?

Dr. Bogler: Definitely. I think it leads to men not accessing the support opportunities – their family, their friends, or the support groups – and staying away from those because of this feeling of not wanting to share about it. That can be damaging. Cancer treatment is usually a tough road for most people, and the long-term consequences of hormone therapy – most men have hormone-driven disease – can be significant. I agree with you.

I participated in the male breast cancer SCAR Project by David Jay, a famous photographer. One of the high points of my life has been appearing in The New York Times topless, right after my radiation treatment, showing my scar. There are quite a few of us out there who’ve done that.

I’ll just mention in passing the Male Breast Cancer Global Alliance, which is a patient support supergroup, if you will. We’ve got a symposium coming up in November. That’s a great place for men who are early in the stage of their disease, or at any stage, to connect to others who are facing this issue.

Dr. Cardoso: They can also find specific information. This is a really good website where you can find information. One of the most important topics that I’ve heard from my patients is, “I never thought that I could have this disease. I never heard that men could have breast cancer as well.” Information is very crucial.

I believe that if you are well informed, you will also be less scared of the disease. Sources of reliable information are really crucial for patients. Since you mentioned the SCAR Project, we have a similar project here in Portugal that really called attention to the disease. It was very visual and really interesting.
 

Discussions during and after treatment

Dr. Cardoso: I wanted to say something, and I don’t know if both of you would agree. I think only recently surgeons have started to pay attention to the way they operate on men with breast cancer, and even in considering techniques of breast conservation and oncoplastic surgery. I had the feeling, looking at those photos, that some years ago, it wouldn’t have mattered how they do with the mastectomy scar just because it was a man. This was biased, right?

Just because it was a man, there was no need to pay attention to the aesthetic outcome. That is wrong, in my perspective. I’m very happy to see that now there are surgeons considering other types of breast surgery to conserve as much as possible the aesthetic outcome.

Dr. Bogler: I have to say that I was offered reconstruction at MD Anderson. I declined it. It wasn’t that big a part of my body image. When I raised this issue at home, my kids, who were quite young at the time, just suggested, “Well, Dad, why don’t you just wear a swim shirt?” They came up with a very practical solution for this issue.

I agree with you that it should be an option. I was also offered a nipple tattoo. I have yet to take that up, but maybe one day.

Dr. Cardoso: I’m not sure that we need to go into reconstruction. It also depends on whether a man has gynecomastia, if it’s going to be very asymmetric. There are other techniques to do, and depending on the size of the tumor, we can also do breast conservation, which we have done here in a couple of patients.

It’s quite an interesting approach where, for example, a skin-sparing mastectomy would be less aggressive, let’s say. Sharon?

Dr. Giordano: I completely agree. I’ve noticed increasing attention to the issue over the years that I’ve been in practice. I do think that it’s more front-and-center when the surgeons are having discussions with the patients now.

Also, although it’s still a minority, some do choose to have reconstructive surgery; some have more extensive surgeries, and some maybe have nipple reconstruction or a nipple tattoo. In a few men, like you mentioned, who are somewhat asymmetric, it actually can make a difference even when they’re dressed.

For many men, it’s more that they want to take off their shirt to play basketball or go swimming, and to decrease the feeling of awkwardness or like they have to make an explanation for why they have a nipple missing and a scar across their chest.
 

Biological aspects of male patients

Dr. Cardoso: Let’s switch gears now to the management, and before that, the biology. Oliver, with your other hat of biology, speak a little bit on what we know so far – whether it is exactly the same disease or there are biological specific characteristics of breast cancer in men.

Dr. Bogler: I should preface this by saying that I spent my career studying brain tumors. That was clearly a mistake.

Dr. Cardoso: It starts with a B. ...

Dr. Bogler: It starts with a B, but it’s the wrong part of the body. The reality is that we don’t really know that much fundamental biology yet, though the picture is changing and it has changed in recent years. Part of the reason is we don’t have many of the tools that we’ve had for the female disease for many years, particularly laboratory models.

On the genetic and transcriptomics front, there has been some really good activity. There was a comprehensive systematic review by Professor Val Speirs from the University of Aberdeen earlier this year that summarized much of the recent data. It showed that there are a handful of molecular hallmarks of the male disease, compared with the female disease, that are worth exploring.

Interestingly enough, one of them is the androgen receptor. It does beg the question of whether hormone-driven disease might not show up quite differently in males and females, where the hormone picture is a little different. I think there’s increasing evidence that there’s information out there to go after.

I will say that I was treated by Dr. Giordano and her colleagues very much like a woman would have been with my disease, and actually, very similarly to my wife. I’ve done well with it, so I would say, in most cases, the current standard of care is very effective but it falls a little short of personalized medicine, particularly when it comes to the hormone component.

Dr. Cardoso: Sharon?

Dr. Giordano: I would add that when I think about it as a clinician, although there’s a large amount of overlap and many similarities, when we’re treating men with breast cancer, almost all of the men have hormone receptor–positive disease, which I think Oliver mentioned earlier. We’re really thinking about endocrine therapy as one of the mainstays of treatment.

Obviously, as he also mentioned, it’s a different biologic background of hormones in a male vs. a female patient. There’s reason to think that some of those treatments could differ. In general, the subtypes are a little bit different. We see very, very few cases of triple-negative breast cancer in men. I think I’ve seen only one or two in my career. The ones I remember were probably radiation induced. They were cancer survivors who’d had chest-wall radiation for previous diseases. Those patients are very uncommon.

We also tend to see that the histology patterns are a little bit different. We tend to see more ductal cancers in men than we do in women as a relative proportion.

One thing that I always try to remember is that the risk for BRCA mutations or underlying germline genetic mutations is higher in men than in women. Just having a diagnosis of male breast cancer is an indication to consider genetic testing or meet with a genetic counselor to look for a BRCA1 or BRCA2 mutation.

Now, most men will not have that. Only roughly 10% of male patients, or maybe a little less, will have a BRCA2 mutation; for BRCA1, it’s more like only 1% or 2%. They’re not that common. Certainly, male breast cancer is recognized as being associated with the BRCA mutations.

Dr. Cardoso: If I have to give a take-home message in terms of biology, it would be that if there is a diagnosis of hormone receptor–negative or HER2-positive disease in a male patient, I would ask for a confirmation of the diagnosis. It’s not that it cannot exist, but it’s so rare that it’s worthwhile to confirm.

You mentioned that triple-negative disease is less than 1%, at about 0.5%, and HER2-positive disease is about 9%-10%. I think it will be very important to keep this in mind and confirm the biology if you have a different diagnosis than ER-positive, HER2-negative. Unfortunately, I received some cases where this was not done, and in fact, it ended up being a technical problem. People can receive the wrong treatment based on that.

Dr. Giordano: I’ve also seen that happen when it’s a metastasis to the breast rather than a primary breast cancer. I completely agree. That’s an excellent point. 

Management approaches

Dr. Cardoso: Let’s go now to management and focus on early breast cancer first. Sharon, what are your main take-home messages for a professional who doesn’t see this very often? What does someone need to remember when they manage a male patient who has early breast cancer?

Dr. Giordano: In general, in terms of chemotherapy, we essentially use the same guidelines as we do for women. Most of the male patients will have tumors that are hormone receptor positive. For endocrine therapy, we typically rely on tamoxifen as the standard of care for adjuvant endocrine treatment for breast cancer.

There are some data suggesting that there can be some efficacy of aromatase inhibitors as single agents. In general, and extrapolated from some population-based registry data, the outcomes for men treated with single-agent aromatase inhibitors don’t tend to be as good as for those treated with tamoxifen.

I know that these are not randomized data so there are all the caveats of that, but the best information we have suggests that tamoxifen appears to likely be more effective. Typically, we stay with tamoxifen. If, for some reason, a man cannot tolerate tamoxifen or has a contraindication, then we could use a GnRH agonist along with an aromatase inhibitor.

Dr. Cardoso: I would like to mention that, because it’s ER-positive, HER2-negative disease most of the time, there will be the question as to whether we can use genomic tests. I think it is important that people know that we have much less data regarding the use of Oncotype DX, MammaPrint, or any of the genomic tests in male patients.

We have some data on the distribution of, for example, Oncotype DX or MammaPrint scores. Whether we can use these tests for the decision of chemotherapy, we don’t have much data on that. I’ve seen many people making exactly the same decisions as with female patients, but that’s not really based on very strong evidence.

Dr. Giordano: It’s hard to know what to do with that. There are prognostic data on Oncotype, so the higher-risk tumors do seem to have a worse outcome than the lower-score tumors. You’re right, though; I don’t think we have any predictive information to really show that the Oncotype DX score predicts benefit to chemotherapy.

Having said that, I will sometimes order the test in my practice. If somebody comes back with a score of 5 or a very low-risk score, I will use that in my decision-making.

Dr. Cardoso: There is something we didn’t exactly mention in the diagnosis that may be important. We discussed most men not knowing that they can have breast cancer, and Oliver, you mentioned that sometimes the first-line physicians can think that very often. Usually, we have late diagnosis and that means a higher tumor burden.

Sometimes we have to go to chemotherapy because of locally advanced or very positive axillas and not really because of the biology. That’s one of the reasons to go for chemotherapy in this setting, right?

Dr. Bogler: Yes. I remember that conversation with you, Dr. Giordano. I asked you whether I should do one of these tests. You said, “Don’t worry about it. At stage III, you’re going to have chemo anyway.”

Dr. Cardoso: The problem of these rare diagnoses is the not thinking about it, even from the health professional side, and then having the diagnosis quite late that will demand chemotherapy use.

To clarify to everybody, in terms of distinguishing luminal A–like, luminal B–like, and what that implies in a male patient, we really don’t know if it’s the same as in a female. There have been some very interesting studies from our Nordic country colleagues showing that maybe the subtyping is different. There is likely a male-specific subtype that does not exist in female breast cancer and that probably behaves differently. We still have a large amount of research to do to understand that.

Is there anything else you would like to mention about early breast cancer management?

Dr. Bogler: One of the things that’s probably underexplored is adherence to tamoxifen therapy in men. I do know anecdotally that this is the discussion among men because of the impact on quality of life. I do worry that sometimes men perhaps make the wrong choice, and I think that’s an opportunity for more research. Again, if there were alternative therapies that were perhaps a little less impactful on things like libido, that might be an advance in the field.

Dr. Cardoso: We have been seeing more studies on the issue of quality of life. Noncompliance is also an issue in female patients. We have to acknowledge that. Not everybody is able to keep taking the treatments. Interestingly, when there is a relapse and people had stopped taking the tamoxifen, most of them say, “I stopped because I had not understood exactly how important it is.”

We come back to the importance of explaining that it is the most crucial treatment for this subtype of breast cancer. Again, information is really key.

Sometimes I also use the argument with my patients that the alternative is even worse because if you use an aromatase inhibitor, and you have to use an LHRH agonist, then the implications for your sexual life are even worse. That’s how I try to convince them to stay on tamoxifen.

Let’s finalize with a couple of words on metastatic breast cancer in male patients. Sharon, I’ll start with you again. Is there any difference in the management if you have a patient with metastatic, ER-positive, HER2-negative disease? How do you treat? How do you sequence the available therapies? Is it different from the female patient?

Dr. Giordano: I’d say that, big picture, it’s quite similar. Again, most of the men have hormone receptor–positive disease, so really, the mainstay of treatment and the first treatments are going to be endocrine therapies. We’ll sequence through the endocrine therapies like we do in women. When using aromatase inhibitors, I typically would add a GnRH agonist to that, and I have had that be a very successful therapy, along now with the CDK inhibitors that are also approved.

I don’t think the studies of CDK inhibitors included male patients, but at least palbociclib actually was approved in the United States, based on some real-world evidence of its efficacy. Anecdotally, again, in my clinical practice, that tends to be a really powerful combination of leuprolide, an aromatase inhibitor, and a CDK inhibitor.

I think there’s less information about drugs like fulvestrant, whether that would benefit from combination with a GnRH agonist or whether those should be given as single agents. We just don’t really know. We have a few case series out there.

Similar to the early breast cancer setting, I think it’s really important to remember to check for BRCA1 and BRCA2 mutations. PARP inhibitors could be a part of the treatment plan if those underlying germline mutations are found. Generally, we’re following a similar sequence of endocrine therapies and then, eventually, chemotherapy.

Dr. Cardoso: Maybe, Oliver, you’re also seeing that one consistent finding in the biology study is the importance of the AKT/PI3K/mTOR pathway in male patients with breast cancer, because we now have at least two classes of agents to tackle this pathway. Again, anecdotally – we’re not talking about trials – I’ve been seeing quite interesting responses, for example, to everolimus combined with endocrine therapy.

We have a little less experience with the PI3K inhibitor, but that’s just because of accessibility to the drug. I think this combination is also something to keep in mind that can be quite effective in these patients.

Dr. Bogler: I agree. Those findings are exciting in the context of dealing with something as difficult as metastatic breast cancer. It’s good to know that there’s some information coming and opportunities and options, hopefully, down the road for men facing that problem.

Dr. Cardoso: Sharon, although small numbers, in these cases where there is HER2-positive disease, you would also use the new anti-HER2 agents and more or less the same sequence, right?

Dr. Giordano: Absolutely. It’s not particularly data driven, but yes, I would. If it’s a HER2-positive tumor, I would use the same HER2-targeted therapies that are used for women with breast cancer.

Working toward a balance in patient care

Dr. Cardoso: I would like to add something for all of us to be united in the fight. I don’t know if it happens in the U.S., but in many countries, access to these new agents for male patients is very difficult because of the approval and the labeling. This is why I’m always fighting with those who are proposing that the labeling, again, says “women with breast cancer.”

It is really important that we keep on lobbying and pushing for the labeling to say “patients with breast cancer” so that nobody can withhold access to these new therapies because of gender. In the U.S., maybe you don’t have this problem. There are many European countries where men cannot access, for example, fulvestrant because it has been approved for women with breast cancer.

Dr. Giordano: Thankfully, I have not faced that issue very often. I’ve had occasional issues with getting GnRH agonists approved. Generally, in the U.S., if I provide, for example, the NCCN guideline recommendations, most insurers will cover it. I think it’s often just lack of knowledge.

Dr. Cardoso: It’s something to keep working hard on because for the old drugs that were approved with the wording that still said “women,” we have to keep fighting for accessibility.

I think we had a really nice discussion. I’m going to give you an opportunity for any last words that you want to say on this topic. Perhaps we’ll start with you, Sharon, and we’ll leave the very last word to Oliver.

Dr. Giordano: I would just emphasize the importance of doing research in this area. Hopefully, we will be able to get clinical trials. There are reasons to think that endocrine therapies may behave differently in men and women. We need to continue to work together as a community to collect the data so that we can ultimately improve the outcomes for our patients.

Dr. Bogler: I would echo what you just said, Dr. Giordano. I would like to express my gratitude to both of you. Dr. Giordano, you have a huge practice of men at MD Anderson. You took care of me and many other people I know.

Dr. Cardoso, you are a pioneer of a big registry trial that I am privileged to be working on, trying to gather data on men. You’re both pioneers in this field of working on behalf of people like me. I’m just very grateful for what you do.

Dr. Giordano: Thank you.

Dr. Cardoso: Thank you both for accepting this invitation. We hope that everybody takes more interest in this field. Who knows? Maybe we can find enough funds to run a specific trial for male patients with breast cancer.

Dr. Cardoso is director of the breast unit at Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon. Dr. Giordano is professor of breast medical oncology and chair of health services research at the University of Texas MD Anderson Cancer Center, Houston. Dr. Bogler is a cancer biologist at the Randolph (Vt.) Center. Dr. Cardoso reported conflicts of interest with numerous pharmaceutical companies; Dr. Giordano and Dr. Bogler reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Fatima Cardoso, MD: Today we will be discussing breast cancer in male patients. To join me in this discussion, I have Sharon Giordano and Oliver Bogler. I will ask, to start, that we briefly introduce ourselves.

I’m Fatima Cardoso. I’m a medical oncologist based in Lisbon, Portugal. I have had a special interest in this topic for a couple of years. Sharon?

Sharon H. Giordano, MD, MPH, FASCO: I’m Sharon Giordano. I practice at the University of Texas MD Anderson Cancer Center. I’m also a medical oncologist and treat most of the male breast cancer patients that are seen here.

Oliver Bogler, PhD: I’m Oliver Bogler. I’m a cancer biologist by background and an 11-year survivor of breast cancer. Dr. Giordano was my oncologist during the active phase of my treatment. It’s great to be here with you.

Special considerations surrounding male patients

• Dr. Cardoso: Sharon, when you are treating breast cancer in a male patient, what specific considerations do you have?
• Dr. Giordano: As we all know, breast cancer in men is a rare disease. It makes up about 1 in 1,000 cases of breast cancer. I think that one of the major challenges in treating the disease is we just don’t have the same to support our treatments as we do for women.

Often, what we need to do and what we end up doing is extrapolating as much as possible from clinical trials that were conducted in female patients with breast cancer. I think that’s one of the major challenges we face in treating the disease. There have been international efforts to try to put together standardized treatment approaches.

For example, ASCO has created guidelines for the management of male breast cancer. NCCN also has a special page on considerations for treatment of men with breast cancer. I would encourage people to look at those resources if questions do come up on the topic.

Dr. Cardoso: Perhaps we can also mention that the latest clinical trials fortunately have been allowing for male patients to be included, which is very important so that we can start having some data on the new drugs. I think that’s also relevant.

Dr. Giordano: That’s a great point because, historically, most of the trials explicitly excluded men. I don’t know if it was intentional or they just wrote the trials saying “women with breast cancer,” because that’s what most people thought of. I think it’s a great effort by the FDA and by investigators to make sure now that men are included in the trials. That will help build our evidence base.

Dr. Cardoso: Oliver, 11 years ago, you faced the diagnosis and you went through this. Can you speak a little bit about this challenge of going through what is considered a rare disease, but also a disease that is very much associated with the female gender traditionally?

Dr. Bogler: Gladly. For me, it was particularly odd because my wife, at the time that I was diagnosed, was a 5-year survivor of breast cancer. It took me some time to even think that the lump I felt might be the same disease. That seemed very unlikely, statistically, and also odd.

I have to say that I was protected from much of the fish-out-of-water experience that many men have because I both worked and was treated at MD Anderson, where Dr Giordano has a large practice, so my colleagues and my friends were not surprised that a man could get this disease.

Many of the patients I met had that experience, difficulty convincing their primary care physician or even their first-line oncologist that this could be the case. I just want to connect to what you both said, which is that 10 years ago, inclusion of men in clinical trials was not standard. It is a fantastic development to see that because unless we include men, we won’t learn about that type of breast cancer.

Dr. Cardoso: Even if only a few are entering each trial, at least it allows us to see if the drug behaves the same way or if there is any strange behavior of the drug in a male patient. It’s already one step forward. You were going to mention something, Sharon?

Dr. Giordano: I was going to say that, anecdotally, I’ve heard the experience that Oliver referred to, of many men feeling not so much uncomfortable with the diagnosis – although that does happen – but not having an obvious fit within the health care system.

For example, going to get their mammogram as part of their diagnostic workup and whoever might be taking them back saying, “Oh, no, this is Mrs. Jones, not Mr.,” and trying to argue with them that it’s not really meant for them. I had a patient – and this guy had a great sense of humor – who had a biopsy done and the instructions were to place this pink, floral ice pack inside your bra.

Even the materials that we have are gender specific. I think those things all together can certainly contribute to a man feeling like a fish out of water.

Dr. Cardoso: Actually, I fought in my institution because they wanted to call the Breast and Gynecology Unit the Women’s Unit. I said that there is no way you can call it the Women’s Unit because we have male patients. There are small things that we can do in our institutions to try to decrease the stigma and to make it less awkward for a man to be in a waiting room that says Women’s Clinic or something similar to that.

The importance of a support system

Dr. Cardoso: I wanted Oliver, perhaps, to mention experiences that you may have heard from other men. Some men do not feel that comfortable speaking about the disease. Also, some of them do not feel comfortable after treatment to go to the beach, to show the scar, and to show what happens after you have radiation.

Some men actually take it quite heavily, psychologically speaking. Have you encountered some of these men?

Dr. Bogler: Definitely. I think it leads to men not accessing the support opportunities – their family, their friends, or the support groups – and staying away from those because of this feeling of not wanting to share about it. That can be damaging. Cancer treatment is usually a tough road for most people, and the long-term consequences of hormone therapy – most men have hormone-driven disease – can be significant. I agree with you.

I participated in the male breast cancer SCAR Project by David Jay, a famous photographer. One of the high points of my life has been appearing in The New York Times topless, right after my radiation treatment, showing my scar. There are quite a few of us out there who’ve done that.

I’ll just mention in passing the Male Breast Cancer Global Alliance, which is a patient support supergroup, if you will. We’ve got a symposium coming up in November. That’s a great place for men who are early in the stage of their disease, or at any stage, to connect to others who are facing this issue.

Dr. Cardoso: They can also find specific information. This is a really good website where you can find information. One of the most important topics that I’ve heard from my patients is, “I never thought that I could have this disease. I never heard that men could have breast cancer as well.” Information is very crucial.

I believe that if you are well informed, you will also be less scared of the disease. Sources of reliable information are really crucial for patients. Since you mentioned the SCAR Project, we have a similar project here in Portugal that really called attention to the disease. It was very visual and really interesting.
 

Discussions during and after treatment

Dr. Cardoso: I wanted to say something, and I don’t know if both of you would agree. I think only recently surgeons have started to pay attention to the way they operate on men with breast cancer, and even in considering techniques of breast conservation and oncoplastic surgery. I had the feeling, looking at those photos, that some years ago, it wouldn’t have mattered how they do with the mastectomy scar just because it was a man. This was biased, right?

Just because it was a man, there was no need to pay attention to the aesthetic outcome. That is wrong, in my perspective. I’m very happy to see that now there are surgeons considering other types of breast surgery to conserve as much as possible the aesthetic outcome.

Dr. Bogler: I have to say that I was offered reconstruction at MD Anderson. I declined it. It wasn’t that big a part of my body image. When I raised this issue at home, my kids, who were quite young at the time, just suggested, “Well, Dad, why don’t you just wear a swim shirt?” They came up with a very practical solution for this issue.

I agree with you that it should be an option. I was also offered a nipple tattoo. I have yet to take that up, but maybe one day.

Dr. Cardoso: I’m not sure that we need to go into reconstruction. It also depends on whether a man has gynecomastia, if it’s going to be very asymmetric. There are other techniques to do, and depending on the size of the tumor, we can also do breast conservation, which we have done here in a couple of patients.

It’s quite an interesting approach where, for example, a skin-sparing mastectomy would be less aggressive, let’s say. Sharon?

Dr. Giordano: I completely agree. I’ve noticed increasing attention to the issue over the years that I’ve been in practice. I do think that it’s more front-and-center when the surgeons are having discussions with the patients now.

Also, although it’s still a minority, some do choose to have reconstructive surgery; some have more extensive surgeries, and some maybe have nipple reconstruction or a nipple tattoo. In a few men, like you mentioned, who are somewhat asymmetric, it actually can make a difference even when they’re dressed.

For many men, it’s more that they want to take off their shirt to play basketball or go swimming, and to decrease the feeling of awkwardness or like they have to make an explanation for why they have a nipple missing and a scar across their chest.
 

Biological aspects of male patients

Dr. Cardoso: Let’s switch gears now to the management, and before that, the biology. Oliver, with your other hat of biology, speak a little bit on what we know so far – whether it is exactly the same disease or there are biological specific characteristics of breast cancer in men.

Dr. Bogler: I should preface this by saying that I spent my career studying brain tumors. That was clearly a mistake.

Dr. Cardoso: It starts with a B. ...

Dr. Bogler: It starts with a B, but it’s the wrong part of the body. The reality is that we don’t really know that much fundamental biology yet, though the picture is changing and it has changed in recent years. Part of the reason is we don’t have many of the tools that we’ve had for the female disease for many years, particularly laboratory models.

On the genetic and transcriptomics front, there has been some really good activity. There was a comprehensive systematic review by Professor Val Speirs from the University of Aberdeen earlier this year that summarized much of the recent data. It showed that there are a handful of molecular hallmarks of the male disease, compared with the female disease, that are worth exploring.

Interestingly enough, one of them is the androgen receptor. It does beg the question of whether hormone-driven disease might not show up quite differently in males and females, where the hormone picture is a little different. I think there’s increasing evidence that there’s information out there to go after.

I will say that I was treated by Dr. Giordano and her colleagues very much like a woman would have been with my disease, and actually, very similarly to my wife. I’ve done well with it, so I would say, in most cases, the current standard of care is very effective but it falls a little short of personalized medicine, particularly when it comes to the hormone component.

Dr. Cardoso: Sharon?

Dr. Giordano: I would add that when I think about it as a clinician, although there’s a large amount of overlap and many similarities, when we’re treating men with breast cancer, almost all of the men have hormone receptor–positive disease, which I think Oliver mentioned earlier. We’re really thinking about endocrine therapy as one of the mainstays of treatment.

Obviously, as he also mentioned, it’s a different biologic background of hormones in a male vs. a female patient. There’s reason to think that some of those treatments could differ. In general, the subtypes are a little bit different. We see very, very few cases of triple-negative breast cancer in men. I think I’ve seen only one or two in my career. The ones I remember were probably radiation induced. They were cancer survivors who’d had chest-wall radiation for previous diseases. Those patients are very uncommon.

We also tend to see that the histology patterns are a little bit different. We tend to see more ductal cancers in men than we do in women as a relative proportion.

One thing that I always try to remember is that the risk for BRCA mutations or underlying germline genetic mutations is higher in men than in women. Just having a diagnosis of male breast cancer is an indication to consider genetic testing or meet with a genetic counselor to look for a BRCA1 or BRCA2 mutation.

Now, most men will not have that. Only roughly 10% of male patients, or maybe a little less, will have a BRCA2 mutation; for BRCA1, it’s more like only 1% or 2%. They’re not that common. Certainly, male breast cancer is recognized as being associated with the BRCA mutations.

Dr. Cardoso: If I have to give a take-home message in terms of biology, it would be that if there is a diagnosis of hormone receptor–negative or HER2-positive disease in a male patient, I would ask for a confirmation of the diagnosis. It’s not that it cannot exist, but it’s so rare that it’s worthwhile to confirm.

You mentioned that triple-negative disease is less than 1%, at about 0.5%, and HER2-positive disease is about 9%-10%. I think it will be very important to keep this in mind and confirm the biology if you have a different diagnosis than ER-positive, HER2-negative. Unfortunately, I received some cases where this was not done, and in fact, it ended up being a technical problem. People can receive the wrong treatment based on that.

Dr. Giordano: I’ve also seen that happen when it’s a metastasis to the breast rather than a primary breast cancer. I completely agree. That’s an excellent point. 

Management approaches

Dr. Cardoso: Let’s go now to management and focus on early breast cancer first. Sharon, what are your main take-home messages for a professional who doesn’t see this very often? What does someone need to remember when they manage a male patient who has early breast cancer?

Dr. Giordano: In general, in terms of chemotherapy, we essentially use the same guidelines as we do for women. Most of the male patients will have tumors that are hormone receptor positive. For endocrine therapy, we typically rely on tamoxifen as the standard of care for adjuvant endocrine treatment for breast cancer.

There are some data suggesting that there can be some efficacy of aromatase inhibitors as single agents. In general, and extrapolated from some population-based registry data, the outcomes for men treated with single-agent aromatase inhibitors don’t tend to be as good as for those treated with tamoxifen.

I know that these are not randomized data so there are all the caveats of that, but the best information we have suggests that tamoxifen appears to likely be more effective. Typically, we stay with tamoxifen. If, for some reason, a man cannot tolerate tamoxifen or has a contraindication, then we could use a GnRH agonist along with an aromatase inhibitor.

Dr. Cardoso: I would like to mention that, because it’s ER-positive, HER2-negative disease most of the time, there will be the question as to whether we can use genomic tests. I think it is important that people know that we have much less data regarding the use of Oncotype DX, MammaPrint, or any of the genomic tests in male patients.

We have some data on the distribution of, for example, Oncotype DX or MammaPrint scores. Whether we can use these tests for the decision of chemotherapy, we don’t have much data on that. I’ve seen many people making exactly the same decisions as with female patients, but that’s not really based on very strong evidence.

Dr. Giordano: It’s hard to know what to do with that. There are prognostic data on Oncotype, so the higher-risk tumors do seem to have a worse outcome than the lower-score tumors. You’re right, though; I don’t think we have any predictive information to really show that the Oncotype DX score predicts benefit to chemotherapy.

Having said that, I will sometimes order the test in my practice. If somebody comes back with a score of 5 or a very low-risk score, I will use that in my decision-making.

Dr. Cardoso: There is something we didn’t exactly mention in the diagnosis that may be important. We discussed most men not knowing that they can have breast cancer, and Oliver, you mentioned that sometimes the first-line physicians can think that very often. Usually, we have late diagnosis and that means a higher tumor burden.

Sometimes we have to go to chemotherapy because of locally advanced or very positive axillas and not really because of the biology. That’s one of the reasons to go for chemotherapy in this setting, right?

Dr. Bogler: Yes. I remember that conversation with you, Dr. Giordano. I asked you whether I should do one of these tests. You said, “Don’t worry about it. At stage III, you’re going to have chemo anyway.”

Dr. Cardoso: The problem of these rare diagnoses is the not thinking about it, even from the health professional side, and then having the diagnosis quite late that will demand chemotherapy use.

To clarify to everybody, in terms of distinguishing luminal A–like, luminal B–like, and what that implies in a male patient, we really don’t know if it’s the same as in a female. There have been some very interesting studies from our Nordic country colleagues showing that maybe the subtyping is different. There is likely a male-specific subtype that does not exist in female breast cancer and that probably behaves differently. We still have a large amount of research to do to understand that.

Is there anything else you would like to mention about early breast cancer management?

Dr. Bogler: One of the things that’s probably underexplored is adherence to tamoxifen therapy in men. I do know anecdotally that this is the discussion among men because of the impact on quality of life. I do worry that sometimes men perhaps make the wrong choice, and I think that’s an opportunity for more research. Again, if there were alternative therapies that were perhaps a little less impactful on things like libido, that might be an advance in the field.

Dr. Cardoso: We have been seeing more studies on the issue of quality of life. Noncompliance is also an issue in female patients. We have to acknowledge that. Not everybody is able to keep taking the treatments. Interestingly, when there is a relapse and people had stopped taking the tamoxifen, most of them say, “I stopped because I had not understood exactly how important it is.”

We come back to the importance of explaining that it is the most crucial treatment for this subtype of breast cancer. Again, information is really key.

Sometimes I also use the argument with my patients that the alternative is even worse because if you use an aromatase inhibitor, and you have to use an LHRH agonist, then the implications for your sexual life are even worse. That’s how I try to convince them to stay on tamoxifen.

Let’s finalize with a couple of words on metastatic breast cancer in male patients. Sharon, I’ll start with you again. Is there any difference in the management if you have a patient with metastatic, ER-positive, HER2-negative disease? How do you treat? How do you sequence the available therapies? Is it different from the female patient?

Dr. Giordano: I’d say that, big picture, it’s quite similar. Again, most of the men have hormone receptor–positive disease, so really, the mainstay of treatment and the first treatments are going to be endocrine therapies. We’ll sequence through the endocrine therapies like we do in women. When using aromatase inhibitors, I typically would add a GnRH agonist to that, and I have had that be a very successful therapy, along now with the CDK inhibitors that are also approved.

I don’t think the studies of CDK inhibitors included male patients, but at least palbociclib actually was approved in the United States, based on some real-world evidence of its efficacy. Anecdotally, again, in my clinical practice, that tends to be a really powerful combination of leuprolide, an aromatase inhibitor, and a CDK inhibitor.

I think there’s less information about drugs like fulvestrant, whether that would benefit from combination with a GnRH agonist or whether those should be given as single agents. We just don’t really know. We have a few case series out there.

Similar to the early breast cancer setting, I think it’s really important to remember to check for BRCA1 and BRCA2 mutations. PARP inhibitors could be a part of the treatment plan if those underlying germline mutations are found. Generally, we’re following a similar sequence of endocrine therapies and then, eventually, chemotherapy.

Dr. Cardoso: Maybe, Oliver, you’re also seeing that one consistent finding in the biology study is the importance of the AKT/PI3K/mTOR pathway in male patients with breast cancer, because we now have at least two classes of agents to tackle this pathway. Again, anecdotally – we’re not talking about trials – I’ve been seeing quite interesting responses, for example, to everolimus combined with endocrine therapy.

We have a little less experience with the PI3K inhibitor, but that’s just because of accessibility to the drug. I think this combination is also something to keep in mind that can be quite effective in these patients.

Dr. Bogler: I agree. Those findings are exciting in the context of dealing with something as difficult as metastatic breast cancer. It’s good to know that there’s some information coming and opportunities and options, hopefully, down the road for men facing that problem.

Dr. Cardoso: Sharon, although small numbers, in these cases where there is HER2-positive disease, you would also use the new anti-HER2 agents and more or less the same sequence, right?

Dr. Giordano: Absolutely. It’s not particularly data driven, but yes, I would. If it’s a HER2-positive tumor, I would use the same HER2-targeted therapies that are used for women with breast cancer.

Working toward a balance in patient care

Dr. Cardoso: I would like to add something for all of us to be united in the fight. I don’t know if it happens in the U.S., but in many countries, access to these new agents for male patients is very difficult because of the approval and the labeling. This is why I’m always fighting with those who are proposing that the labeling, again, says “women with breast cancer.”

It is really important that we keep on lobbying and pushing for the labeling to say “patients with breast cancer” so that nobody can withhold access to these new therapies because of gender. In the U.S., maybe you don’t have this problem. There are many European countries where men cannot access, for example, fulvestrant because it has been approved for women with breast cancer.

Dr. Giordano: Thankfully, I have not faced that issue very often. I’ve had occasional issues with getting GnRH agonists approved. Generally, in the U.S., if I provide, for example, the NCCN guideline recommendations, most insurers will cover it. I think it’s often just lack of knowledge.

Dr. Cardoso: It’s something to keep working hard on because for the old drugs that were approved with the wording that still said “women,” we have to keep fighting for accessibility.

I think we had a really nice discussion. I’m going to give you an opportunity for any last words that you want to say on this topic. Perhaps we’ll start with you, Sharon, and we’ll leave the very last word to Oliver.

Dr. Giordano: I would just emphasize the importance of doing research in this area. Hopefully, we will be able to get clinical trials. There are reasons to think that endocrine therapies may behave differently in men and women. We need to continue to work together as a community to collect the data so that we can ultimately improve the outcomes for our patients.

Dr. Bogler: I would echo what you just said, Dr. Giordano. I would like to express my gratitude to both of you. Dr. Giordano, you have a huge practice of men at MD Anderson. You took care of me and many other people I know.

Dr. Cardoso, you are a pioneer of a big registry trial that I am privileged to be working on, trying to gather data on men. You’re both pioneers in this field of working on behalf of people like me. I’m just very grateful for what you do.

Dr. Giordano: Thank you.

Dr. Cardoso: Thank you both for accepting this invitation. We hope that everybody takes more interest in this field. Who knows? Maybe we can find enough funds to run a specific trial for male patients with breast cancer.

Dr. Cardoso is director of the breast unit at Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon. Dr. Giordano is professor of breast medical oncology and chair of health services research at the University of Texas MD Anderson Cancer Center, Houston. Dr. Bogler is a cancer biologist at the Randolph (Vt.) Center. Dr. Cardoso reported conflicts of interest with numerous pharmaceutical companies; Dr. Giordano and Dr. Bogler reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.

Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
 

Shutting down the disease process

When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”

GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”

Shared mechanism

Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.

Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.² When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”

The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.³

Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.⁴ Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.

However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.

“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”

Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.

Key clues that distinguish A-CIDP from GBS include:

• A high level of cerebrospinal fluid protein.

• Very slow nerve conduction.

• Early muscle wasting (rare in GBS).

Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.

After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.⁵ Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.⁶

Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.⁶All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”

Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.⁷

“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”

Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.

“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
 

Recap of diagnosis and treatment

For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.

IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.

However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.⁸ Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
 

COVID-19 and GBS triggers

Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.

The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.

Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.⁹ “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.

GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”

The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.

The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
 

GBS: ‘Adverse event of interest’

A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”

Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”

COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.¹⁰ As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.

Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.¹¹ Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.

The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.¹² In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11

The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”

The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”

It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.

Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
 

References

1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.

2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.

3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.

4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.

5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.

6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.

7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.

9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.

10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.

11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.

12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
 

Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.

Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
 

Shutting down the disease process

When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”

GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”

Shared mechanism

Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.

Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.² When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”

The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.³

Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.⁴ Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.

However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.

“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”

Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.

Key clues that distinguish A-CIDP from GBS include:

• A high level of cerebrospinal fluid protein.

• Very slow nerve conduction.

• Early muscle wasting (rare in GBS).

Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.

After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.⁵ Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.⁶

Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.⁶All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”

Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.⁷

“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”

Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.

“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
 

Recap of diagnosis and treatment

For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.

IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.

However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.⁸ Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
 

COVID-19 and GBS triggers

Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.

The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.

Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.⁹ “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.

GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”

The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.

The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
 

GBS: ‘Adverse event of interest’

A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”

Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”

COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.¹⁰ As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.

Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.¹¹ Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.

The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.¹² In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11

The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”

The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”

It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.

Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
 

References

1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.

2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.

3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.

4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.

5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.

6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.

7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.

9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.

10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.

11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.

12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
 

Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.

Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
 

Shutting down the disease process

When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”

GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”

Shared mechanism

Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.

Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.² When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”

The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.³

Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.⁴ Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.

However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.

“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”

Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.

Key clues that distinguish A-CIDP from GBS include:

• A high level of cerebrospinal fluid protein.

• Very slow nerve conduction.

• Early muscle wasting (rare in GBS).

Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.

After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.⁵ Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.⁶

Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.⁶All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”

Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.⁷

“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”

Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.

“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
 

Recap of diagnosis and treatment

For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.

IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.

However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.⁸ Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
 

COVID-19 and GBS triggers

Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.

The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.

Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.⁹ “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.

GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”

The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.

The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
 

GBS: ‘Adverse event of interest’

A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”

Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”

COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.¹⁰ As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.

Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.¹¹ Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.

The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.¹² In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11

The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”

The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”

It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.

Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
 

References

1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.

2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.

3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.

4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.

5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.

6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.

7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.

9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.

10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.

11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.

12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
 

Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.

What do neurologists need to know to ensure that their Fabry disease patients receive a timely diagnosis and then optimal treatment? Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
 

What is Fabry disease?

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.

Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.

Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.

Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.

“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”

How do patients with Fabry disease typically present?

“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.

“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.

Who oversees the care of patients with Fabry disease?

“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.

At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.

“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.

What recent research and advances should neurologists be aware of?

Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.

“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.

“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”

Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”

“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”

Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.

“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”

Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”

On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.

Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.

“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”

“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”

Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
 

How might these advances affect the trajectory of Fabry disease?

“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.

“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”

Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
 

Concluding remarks

In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:

Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”

Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”

Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”

Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”

Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
 

Additional recommended reading

Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.

Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.

Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.

Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.

Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.

Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
 

References

1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.

2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.

3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.

4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC

Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.

What do neurologists need to know to ensure that their Fabry disease patients receive a timely diagnosis and then optimal treatment? Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
 

What is Fabry disease?

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.

Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.

Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.

Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.

“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”

How do patients with Fabry disease typically present?

“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.

“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.

Who oversees the care of patients with Fabry disease?

“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.

At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.

“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.

What recent research and advances should neurologists be aware of?

Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.

“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.

“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”

Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”

“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”

Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.

“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”

Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”

On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.

Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.

“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”

“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”

Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
 

How might these advances affect the trajectory of Fabry disease?

“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.

“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”

Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
 

Concluding remarks

In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:

Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”

Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”

Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”

Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”

Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
 

Additional recommended reading

Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.

Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.

Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.

Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.

Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.

Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
 

References

1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.

2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.

3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.

4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC

Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.

What do neurologists need to know to ensure that their Fabry disease patients receive a timely diagnosis and then optimal treatment? Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
 

What is Fabry disease?

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.

Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.

Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.

Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.

“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”

How do patients with Fabry disease typically present?

“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.

“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.

Who oversees the care of patients with Fabry disease?

“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.

At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.

“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.

What recent research and advances should neurologists be aware of?

Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.

“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.

“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”

Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”

“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”

Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.

“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”

Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”

On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.

Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.

“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”

“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”

Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
 

How might these advances affect the trajectory of Fabry disease?

“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.

“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”

Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
 

Concluding remarks

In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:

Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”

Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”

Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”

Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”

Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
 

Additional recommended reading

Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.

Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.

Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.

Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.

Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.

Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
 

References

1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.

2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.

3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.

4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC

It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.¹

FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.

Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.²There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.

Making the diagnosis

Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)

In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.

MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.³ The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.

They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.

“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”

Pathophysiological basis of FA

The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.⁴

The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.

Treatment options have been limited

Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),⁵ which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.⁶ Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.

“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”

In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.

The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.

Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).

In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.⁷Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.

Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
 

The FA therapeutic pipeline

According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.

Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.⁸Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,⁹ or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.

CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.¹⁰Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.¹¹

Gene therapy: Promising

Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.

Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.

Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.

Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.

Future directions

Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.¹³

They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”

The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.

“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”

David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.

References

1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.

2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.

3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.

4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.

5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.

6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.

7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897

8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.

9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.

10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.

11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.

12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.

13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264

It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.¹

FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.

Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.²There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.

Making the diagnosis

Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)

In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.

MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.³ The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.

They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.

“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”

Pathophysiological basis of FA

The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.⁴

The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.

Treatment options have been limited

Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),⁵ which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.⁶ Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.

“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”

In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.

The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.

Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).

In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.⁷Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.

Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
 

The FA therapeutic pipeline

According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.

Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.⁸Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,⁹ or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.

CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.¹⁰Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.¹¹

Gene therapy: Promising

Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.

Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.

Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.

Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.

Future directions

Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.¹³

They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”

The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.

“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”

David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.

References

1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.

2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.

3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.

4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.

5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.

6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.

7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897

8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.

9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.

10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.

11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.

12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.

13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264

It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.¹

FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.

Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.²There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.

Making the diagnosis

Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)

In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.

MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.³ The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.

They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.

“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”

Pathophysiological basis of FA

The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.⁴

The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.

Treatment options have been limited

Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),⁵ which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.⁶ Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.

“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”

In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.

The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.

Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).

In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.⁷Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.

Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
 

The FA therapeutic pipeline

According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.

Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.⁸Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,⁹ or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.

CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.¹⁰Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.¹¹

Gene therapy: Promising

Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.

Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.

Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.

Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.

Future directions

Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.¹³

They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”

The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.

“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”

David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.

References

1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.

2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.

3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.

4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.

5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.

6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.

7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897

8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.

9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.

10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.

11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.

12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.

13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264

The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
 

What is Huntington’s disease?

Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.

Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.

Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.

Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:

Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.¹ Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.

Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.

Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.

The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.

“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”
 

Tackling a tricky protein

Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.

Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.

“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.

Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.

“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”

Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”

Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.² A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.²

Other strategies have yielded disappointing or mixed results:

A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.³ Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.

Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.⁴

In neither case was excess protein-lowering thought to be the cause of safety problems.

DNA repair emerges as a promising target

Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.

Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.

The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.⁵ As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.

DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.

In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.

After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.

In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.⁶ “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.

At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.⁷ (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.

“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.

Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.

“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”

Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.

Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”

Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.
 

References

1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-.

2. Wave Life Sciences. Defining a new era of oligonucleotides. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select.

3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf.

4. UniQure. Second Quarter 2022 Financial Results. https://uniqure.gcs-web.com/node/10856/pdf.

5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.

6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. doi: 10.1016/S1474-4422(17)30161-8.

7. CHDI Foundation. Postcard from Dubrovnik 2023. https://chdifoundation.org/postcard-from-dubrovnik-2023/.

The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
 

What is Huntington’s disease?

Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.

Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.

Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.

Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:

Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.¹ Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.

Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.

Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.

The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.

“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”
 

Tackling a tricky protein

Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.

Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.

“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.

Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.

“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”

Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”

Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.² A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.²

Other strategies have yielded disappointing or mixed results:

A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.³ Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.

Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.⁴

In neither case was excess protein-lowering thought to be the cause of safety problems.

DNA repair emerges as a promising target

Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.

Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.

The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.⁵ As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.

DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.

In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.

After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.

In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.⁶ “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.

At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.⁷ (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.

“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.

Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.

“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”

Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.

Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”

Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.
 

References

1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-.

2. Wave Life Sciences. Defining a new era of oligonucleotides. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select.

3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf.

4. UniQure. Second Quarter 2022 Financial Results. https://uniqure.gcs-web.com/node/10856/pdf.

5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.

6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. doi: 10.1016/S1474-4422(17)30161-8.

7. CHDI Foundation. Postcard from Dubrovnik 2023. https://chdifoundation.org/postcard-from-dubrovnik-2023/.

The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
 

What is Huntington’s disease?

Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.

Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.

Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.

Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:

Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.¹ Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.

Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.

Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.

The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.

“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”
 

Tackling a tricky protein

Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.

Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.

“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.

Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.

“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”

Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”

Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.² A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.²

Other strategies have yielded disappointing or mixed results:

A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.³ Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.

Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.⁴

In neither case was excess protein-lowering thought to be the cause of safety problems.

DNA repair emerges as a promising target

Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.

Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.

The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.⁵ As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.

DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.

In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.

After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.

In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.⁶ “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.

At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.⁷ (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.

“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.

Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.

“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”

Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.

Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”

Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.
 

References

1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-.

2. Wave Life Sciences. Defining a new era of oligonucleotides. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select.

3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf.

4. UniQure. Second Quarter 2022 Financial Results. https://uniqure.gcs-web.com/node/10856/pdf.

5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.

6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. doi: 10.1016/S1474-4422(17)30161-8.

7. CHDI Foundation. Postcard from Dubrovnik 2023. https://chdifoundation.org/postcard-from-dubrovnik-2023/.

In 1976, Abbey S. Meyers, a mother from Connecticut, finally got a diagnosis for her son. He had been displaying “very bizarre symptoms,” Ms. Meyers said in an interview with IndoUSRare,¹ but, eventually, at 8 years of age, he was given a diagnosis of Tourette syndrome.

“They tried some medicine to try to get him to sit still, but the drugs didn’t work – or if they did, they put him to sleep,” she recounted. “The teachers would be angry that he fell asleep in the classroom.”

Ms. Meyers consulted the late Arthur K. Shapiro, MD, at what was then named the Mount Sinai School of Medicine in New York. Dr. Shapiro was conducting a small clinical trial of pimozide, a drug under investigation for schizophrenia, for its utility in children with Tourette syndrome.

“The drug worked like magic,” Ms. Meyers reported. Her son’s symptoms were substantially reduced, without sedation. He was followed by Dr. Shapiro every 3 months, at which point he would receive a 90-day refill.

However, when her son turned 10 years of age, Dr. Shapiro was no longer able to provide refills: The Food and Drug Administration (FDA) had turned down the drug manufacturer’s application for approval of pimozide for a schizophrenia indication. The company opted not to pursue further development of the drug because it was not deemed profitable.²

Pimozide became unavailable in the United States. The fact that the drug was so promising for Tourette syndrome did not warrant further investment because Tourette syndrome affected a relatively small number of people.

“I was just devastated,” Ms. Meyers reported.
 

Springing into advocacy

Ms. Meyers, who was working with the Tourette Syndrome Association at the time (now the Tourette Association of America), contacted people from other rare disease organizations, including the National Huntington’s Disease Association (today the Huntington’s Disease Society of America) and the Paget Foundation (today part of the Bone Health and Osteoporosis Foundation). Those organizations were experiencing similar problems with drug companies that wouldn’t engage in research and development of drugs for patients who had a rare disorder.

“We realized we had to work together to get something done to solve this problem,” Ms. Meyers said.

The sense of urgency over this roadblock increased when another patient who was taking pimozide tried to get a supply of the drug from Canada and was blocked from doing so by customs officials at the airport because the drug was not FDA approved. Working with that patient’s mother, Ms. Meyers contacted U.S. Representative Henry A. Waxman (D-Calif.), who was chair of the Subcommittee on Health and the Environment of the House Energy & Commerce Committee.

Ms. Meyers thought that Congress needed Rep. Waxman’s support if it was going to get involved with this problem. “So, we got Henry Waxman and his staff familiar with the orphan drug problem.”
 

ODA: Breakthrough legislation

The impetus for the Orphan Drug Act (ODA) started in 1979 with an FDA task force report calling for measures to address what was labeled the “orphan drug problem.”³

In 1982, Rep. Waxman convened a hearing and invited several pharmaceutical companies to attend. They declined the invitation. Ms. Meyers testified at the hearing, which was covered by the Los Angeles Times, giving the issue notoriety.

The issue was also addressed in the popular television series Quincy, M.E. Episodes depicted challenges facing a patient with Tourette syndrome and a patient with myoclonus. Series star Jack Klugman testified before Congress about the need for legislation regarding the development of drugs targeting the treatment of rare diseases.⁴

Rep. Waxman became the bill’s primary House sponsor. The ODA was approved by the House of Representatives on Dec. 14, 1982.

The combined efforts of the advocacy coalition ultimately culminated in the original ODA being signed into law by President Ronald Reagan on Jan. 4, 1983. The ODA incentivized pharmaceutical companies to allot more resources toward research on and development and distribution of therapeutics for people with a rare disease who had, until that point, been “orphaned,” so to speak, by the medical and scientific community.⁵

What is it to be a ‘rare disorder’ or an ‘orphan drug’?

The ODA defines a rare disorder as either a condition that affects fewer than 200,000 people or a condition that affects more than 200,000 people but for which there is no reasonable expectation that a pharmaceutical company will recoup the cost of developing a drug by selling it.⁵

Gregory Twachtman/MDedge News

NORD is born

The creation of NORD was initiated by the same group of advocates who lobbied tirelessly for passage of the ODA – including Ms. Meyers, who served as president of the organization for many years. Heidi Ross, MPH, NORD’s vice president of policy and regulatory affairs, called these advocates “trailblazers.”

NORD

NORD

Spotlight: Patient care and research

Edward Neilan, MD, PhD, recently joined NORD as chief medical and scientific officer. As a pediatrician, medical geneticist, and molecular biologist, Dr. Neilan became acquainted with NORD as far back as medical school and his residency, when he used a book called the NORD Guide to Rare Disorders to help him explain certain diseases to patients and families.¹⁰ “I had a favorable view of NORD because of how useful the book was,” he said.

Natural history research

NORD’s research department awards seed grants to academic investigators who are researching rare disorders and has built an online patient registry platform that helps other, disease-specific patient advocacy organizations conduct natural history studies.

Dr. Neilan said that the registry program was motivated by input from the FDA indicating that companies were sometimes trying to develop drugs to treat a rare disease before fully understanding the natural history of that disease.

“There was a perceived lack of enough natural history data,” Dr. Neilan explained, “so how could the effectiveness of the drug be measured? What would be a meaningful improvement?” NORD assists in making these rare disease foundations more “research ready” so that enough will be known about the disease for drug development “to have a greater chance of success.”

“There’s a lot of promise on the horizon with gene therapy, and the new platforms may accelerate the production of these therapies,” Ms. Kowalski said.

Registries are customized to each disease and foundation by experts, patients, and families involved with that particular disease and foundation. For example: An ongoing study on the NORD platform is a study of metachromatic leukodystrophy (MLD), an autosomal-recessive lysosomal disorder that results in a buildup of sulfatides, a major lipid group in serum, which lead to destruction of the myelin sheath and progressive demyelination of the nervous system.¹³

“[MLD] is a tragic disorder that can first present in late infancy and may progress rapidly over 6 months or so to the point that children lose much of their neurological functioning,” Dr. Neilan said.

The FDA funded NORD to run the HOME study,^14,15 in which families can participate without visiting a research site in person. This was particularly valuable during the COVID-19 pandemic, when many studies were “forced to shift gears and see how much data could be collected if patients were afraid to come to the hospital or not allowed to go to a hospital for nonemergency visits,” Dr. Neilan said.

The HOME study was designed before the onset of the COVID-19 pandemic to reduce the burden on patients of participating in research. The trial became a trend-setter in the shift to what are known as decentralized trials, in which research can be conducted through video, using a tablet that NORD mails to the family.

“This is obviously much more convenient for families who no longer have to travel long distances to the few sites in the country – which are often hundreds or even thousands of miles away – that are studying the condition,” Dr. Neilan said. The decentralized trial model is being used with other conditions, as well.

“There are infantile, juvenile, and adult-onset forms of MLD, and the limited therapeutic options may involve bone-marrow transplant, which may be at least partially effective, as donor-derived bone marrow–derived cells can provide enzymes to protect the brain,” said Dr. Neilan. Gene therapy for MLD has also been developed and is approved in Europe, but not in the United States. “MLD is typical of conditions that often start early in childhood and are progressive, so that, sometimes, by the time the parent realizes that there’s a problem, too much damage has been done to the brain for much repair to take place. Prevention of further damage is easier than reversing an ongoing disease process, so early treatment is important.” That’s why the number of movements to expand newborn screening for various conditions, to identify them before symptoms develop, is increasing.

“That’s another area where NORD has historically been active – in encouraging newborn screening,” Dr. Neilan said.
 

Evolution of the ODA

Since 1983, “a number of amendments ... made the original [ODA] stronger or refined it in various ways,” said Mr. Saltonstall. NORD continues to “very carefully watch any attempts to change it, alter it, move it, take pieces away from it, or – some people say – to make it ‘better.’ To us, it’s a very important law.”

Orphan Drug Credit (ODC). Ms. Ross elaborated: “In recent years, Congress has considered significant changes to the Orphan Drug Credit, which is one of several critical incentives established by the ODA.” When established in 1983, the ODC provided sponsors of a drug with a 50% tax credit for qualified clinical testing expenses associated with developing an orphan drug.

“Unfortunately, despite fierce opposition from NORD and our army of membership organizations and grassroots advocates,” Ms. Ross said, “the Tax Cuts and Jobs Act of 2017 reduced the ODC from 50% to 25%. Given the significant amount of time it takes to conduct research and development into rare diseases, we still don’t have a good sense as to the impact of the ODC being reduced to 25%.”

However, efforts to further limit the availability of the ODC during debate around the Build Back Better framework in 2021 were ultimately defeated. That defeat was, in part, a result of NORD’s rare disease community’s advocacy,¹⁶ when no changes to the ODC were included in the Inflation Reduction Act.

Patient Assistance Program. In 1987, NORD’s multifaceted patient assistance program (serving today under the umbrella name RareCare17) was founded to help patients obtain lifesaving or life-sustaining medication that they could not otherwise afford, Ms. Ross said. This was based on an unmet need for patients living and struggling with a rare disease who didn’t have access to the care and treatment they needed. “There was no other foundation equipped to do this at the time. NORD came forward to develop the first program of its kind.”

The program provides medication, financial assistance with insurance premiums and copays, diagnostic testing assistance, and travel assistance for clinical trials or consultation with disease specialists. According to Ms. Ross, “today, NORD’s patient assistance program provides, on average, $30 million to $40 million in patient assistance annually to eligible patients and families.”

Pharmaceutical companies do contribute to the patient assistance program. “However, they’re in the dark as to how the money is allocated,” said Mr. Saltonstall. “For example, a given company might donate money for patients with a particular disease but won’t know if patients who have that disease will necessarily receive funds to use toward that company’s drug. The patient might receive assistance to take a drug made by a different company – a competitor.”

There are approximately 14 foundations around the country that have worked within the constraints of the Department of Health & Human Services Office of Inspector General, which established rules about how foundations must operate. Under the broader umbrella of NORD, these foundations also help pay coinsurance costs or provide drugs at no cost to patients who meet financial criteria.
 

An enduring movement

Despite the successes brought about by the ODA, the search for new rare disorder treatments is far from over. We know of more than 7,000 rare diseases; scientists discover more every year. Fewer than 5% of rare disorders have an FDA-approved treatment.

Similar to advancements made in other diseases, progress in rare disease care and treatments will continue to require an all-in approach to solve what is a looming and massive public health challenge.

As NORD founder Abbey S. Meyers wrote in her 2016 book, Orphan Drugs: A Global Crusade: “It was all of us working together that built an impregnable movement demanding a solution. In the end, with the help of government and a touch of Hollywood, the forces opposing us could not win.”

References

1. Rare Disease Day 2023 at IndoUSrare – Fireside Chat with Dr. Abbey S. Meyers. 2023 Mar 3. Indo US Organization for Rare Diseases. https://www.youtube.com/watch?v=fGTWUcQJPlU.

2. Mikami K. Soc Hist Med. 2019;32(3):609-30. doi: 10.1093/shm/hkx098.

3. National Organization for Rare Disorders. The Orphan Drug Act Turns 40: NORD Celebrates Its Impact on Rare Diseases. 2023 Jan 4. https://rarediseases.org/the-orphan-drug-act-turns-40-nord-celebrates-its-impact-on-rare-diseases. 4. Swann J. The story behind the Orphan Drug Act. US Food and Drug Administration. 2018 Feb 23. https://www.fda.gov/industry/fdas-rare-disease-day/story-behind-orphan-drug-act.

5. Roberts A-D and Wadhwa R. Orphan drug approval laws, in StatPearls (Internet). StatPearls Publishing. 2023 Jun 5. www.ncbi.nlm.nih.gov/books/NBK572052/#.

6. National Organization for Rare Disorders. Rare disease database. https://rarediseases.org/rare-diseases/.

7. National Organization for Rare Disorders. Rare disease video library. 2023 Jan 19. https://rarediseases.org/video-library/.

8. National Center for Advancing Translational Sciences. Rare disease research and resources. 2023 May 16. Accessed Sep. 17., 2023. https://ncats.nih.gov/rare-diseases.

9. Food and Drug Administration. Rare diseases team. 2023 Aug 29. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/rare-diseases-team.

10. National Organization for Rare Disorders. “NORD Guide to Rare Disorders,” 3rd edition. Philadelphia: Lippincott Williams & Wilkins, 2002.

11. National Organization for Rare Disorders. Cockayne syndrome. 2022 Jun 7. https://rarediseases.org/rare-diseases/cockayne-syndrome/.

12. National Organization for Rare Disorders. NORD Rare Disease Centers of Excellence. 2023 Jun 28. https://rarediseases.org/rare-disease-centers-of-excellence/.

13. National Organization for Rare Disorders. Metachromatic leukodystrophy. 2022 Mar 22. https://rarediseases.org/rare-diseases/metachromatic-leukodystrophy/#complete-report.

14. National Organization for Rare Disorders. The Natural History of Metachromatic Leukodystrophy Study. 2023 Feb 23. https://rarediseases.org/mld-home-study/.

15. The Natural History of Metachromatic Leukodystrophy Study (HOME Study). 2023 Jun 13. https://clinicaltrials.gov/study/NCT04628364?.

16. National Organization for Rare Disorders, Saltonstall PL. Letter to US Congress House Committee on Ways and Means. 2021 Sep 13. https://rarediseases.org/wp-content/uploads/2022/04/NORD_ODTC-Letter_FINAL.pdf.

17. National Organization for Rare Disorders. RareCare®: NORD’s patient assistance programs. 2022 Nov 1. https://rarediseases.org/wp-content/uploads/2022/04/NORD_ODTC-Letter_FINAL.pdf.

In 1976, Abbey S. Meyers, a mother from Connecticut, finally got a diagnosis for her son. He had been displaying “very bizarre symptoms,” Ms. Meyers said in an interview with IndoUSRare,¹ but, eventually, at 8 years of age, he was given a diagnosis of Tourette syndrome.

“They tried some medicine to try to get him to sit still, but the drugs didn’t work – or if they did, they put him to sleep,” she recounted. “The teachers would be angry that he fell asleep in the classroom.”

Ms. Meyers consulted the late Arthur K. Shapiro, MD, at what was then named the Mount Sinai School of Medicine in New York. Dr. Shapiro was conducting a small clinical trial of pimozide, a drug under investigation for schizophrenia, for its utility in children with Tourette syndrome.

“The drug worked like magic,” Ms. Meyers reported. Her son’s symptoms were substantially reduced, without sedation. He was followed by Dr. Shapiro every 3 months, at which point he would receive a 90-day refill.

However, when her son turned 10 years of age, Dr. Shapiro was no longer able to provide refills: The Food and Drug Administration (FDA) had turned down the drug manufacturer’s application for approval of pimozide for a schizophrenia indication. The company opted not to pursue further development of the drug because it was not deemed profitable.²

Pimozide became unavailable in the United States. The fact that the drug was so promising for Tourette syndrome did not warrant further investment because Tourette syndrome affected a relatively small number of people.

“I was just devastated,” Ms. Meyers reported.
 

Springing into advocacy

Ms. Meyers, who was working with the Tourette Syndrome Association at the time (now the Tourette Association of America), contacted people from other rare disease organizations, including the National Huntington’s Disease Association (today the Huntington’s Disease Society of America) and the Paget Foundation (today part of the Bone Health and Osteoporosis Foundation). Those organizations were experiencing similar problems with drug companies that wouldn’t engage in research and development of drugs for patients who had a rare disorder.

“We realized we had to work together to get something done to solve this problem,” Ms. Meyers said.

The sense of urgency over this roadblock increased when another patient who was taking pimozide tried to get a supply of the drug from Canada and was blocked from doing so by customs officials at the airport because the drug was not FDA approved. Working with that patient’s mother, Ms. Meyers contacted U.S. Representative Henry A. Waxman (D-Calif.), who was chair of the Subcommittee on Health and the Environment of the House Energy & Commerce Committee.

Ms. Meyers thought that Congress needed Rep. Waxman’s support if it was going to get involved with this problem. “So, we got Henry Waxman and his staff familiar with the orphan drug problem.”
 

ODA: Breakthrough legislation

The impetus for the Orphan Drug Act (ODA) started in 1979 with an FDA task force report calling for measures to address what was labeled the “orphan drug problem.”³

In 1982, Rep. Waxman convened a hearing and invited several pharmaceutical companies to attend. They declined the invitation. Ms. Meyers testified at the hearing, which was covered by the Los Angeles Times, giving the issue notoriety.

The issue was also addressed in the popular television series Quincy, M.E. Episodes depicted challenges facing a patient with Tourette syndrome and a patient with myoclonus. Series star Jack Klugman testified before Congress about the need for legislation regarding the development of drugs targeting the treatment of rare diseases.⁴

Rep. Waxman became the bill’s primary House sponsor. The ODA was approved by the House of Representatives on Dec. 14, 1982.

The combined efforts of the advocacy coalition ultimately culminated in the original ODA being signed into law by President Ronald Reagan on Jan. 4, 1983. The ODA incentivized pharmaceutical companies to allot more resources toward research on and development and distribution of therapeutics for people with a rare disease who had, until that point, been “orphaned,” so to speak, by the medical and scientific community.⁵

What is it to be a ‘rare disorder’ or an ‘orphan drug’?

The ODA defines a rare disorder as either a condition that affects fewer than 200,000 people or a condition that affects more than 200,000 people but for which there is no reasonable expectation that a pharmaceutical company will recoup the cost of developing a drug by selling it.⁵

Gregory Twachtman/MDedge News

NORD is born

The creation of NORD was initiated by the same group of advocates who lobbied tirelessly for passage of the ODA – including Ms. Meyers, who served as president of the organization for many years. Heidi Ross, MPH, NORD’s vice president of policy and regulatory affairs, called these advocates “trailblazers.”

NORD

NORD

Spotlight: Patient care and research

Edward Neilan, MD, PhD, recently joined NORD as chief medical and scientific officer. As a pediatrician, medical geneticist, and molecular biologist, Dr. Neilan became acquainted with NORD as far back as medical school and his residency, when he used a book called the NORD Guide to Rare Disorders to help him explain certain diseases to patients and families.¹⁰ “I had a favorable view of NORD because of how useful the book was,” he said.

Natural history research

NORD’s research department awards seed grants to academic investigators who are researching rare disorders and has built an online patient registry platform that helps other, disease-specific patient advocacy organizations conduct natural history studies.

Dr. Neilan said that the registry program was motivated by input from the FDA indicating that companies were sometimes trying to develop drugs to treat a rare disease before fully understanding the natural history of that disease.

“There was a perceived lack of enough natural history data,” Dr. Neilan explained, “so how could the effectiveness of the drug be measured? What would be a meaningful improvement?” NORD assists in making these rare disease foundations more “research ready” so that enough will be known about the disease for drug development “to have a greater chance of success.”

“There’s a lot of promise on the horizon with gene therapy, and the new platforms may accelerate the production of these therapies,” Ms. Kowalski said.

Registries are customized to each disease and foundation by experts, patients, and families involved with that particular disease and foundation. For example: An ongoing study on the NORD platform is a study of metachromatic leukodystrophy (MLD), an autosomal-recessive lysosomal disorder that results in a buildup of sulfatides, a major lipid group in serum, which lead to destruction of the myelin sheath and progressive demyelination of the nervous system.¹³

“[MLD] is a tragic disorder that can first present in late infancy and may progress rapidly over 6 months or so to the point that children lose much of their neurological functioning,” Dr. Neilan said.

The FDA funded NORD to run the HOME study,^14,15 in which families can participate without visiting a research site in person. This was particularly valuable during the COVID-19 pandemic, when many studies were “forced to shift gears and see how much data could be collected if patients were afraid to come to the hospital or not allowed to go to a hospital for nonemergency visits,” Dr. Neilan said.

The HOME study was designed before the onset of the COVID-19 pandemic to reduce the burden on patients of participating in research. The trial became a trend-setter in the shift to what are known as decentralized trials, in which research can be conducted through video, using a tablet that NORD mails to the family.

“This is obviously much more convenient for families who no longer have to travel long distances to the few sites in the country – which are often hundreds or even thousands of miles away – that are studying the condition,” Dr. Neilan said. The decentralized trial model is being used with other conditions, as well.

“There are infantile, juvenile, and adult-onset forms of MLD, and the limited therapeutic options may involve bone-marrow transplant, which may be at least partially effective, as donor-derived bone marrow–derived cells can provide enzymes to protect the brain,” said Dr. Neilan. Gene therapy for MLD has also been developed and is approved in Europe, but not in the United States. “MLD is typical of conditions that often start early in childhood and are progressive, so that, sometimes, by the time the parent realizes that there’s a problem, too much damage has been done to the brain for much repair to take place. Prevention of further damage is easier than reversing an ongoing disease process, so early treatment is important.” That’s why the number of movements to expand newborn screening for various conditions, to identify them before symptoms develop, is increasing.

“That’s another area where NORD has historically been active – in encouraging newborn screening,” Dr. Neilan said.
 

Evolution of the ODA

Since 1983, “a number of amendments ... made the original [ODA] stronger or refined it in various ways,” said Mr. Saltonstall. NORD continues to “very carefully watch any attempts to change it, alter it, move it, take pieces away from it, or – some people say – to make it ‘better.’ To us, it’s a very important law.”

Orphan Drug Credit (ODC). Ms. Ross elaborated: “In recent years, Congress has considered significant changes to the Orphan Drug Credit, which is one of several critical incentives established by the ODA.” When established in 1983, the ODC provided sponsors of a drug with a 50% tax credit for qualified clinical testing expenses associated with developing an orphan drug.

“Unfortunately, despite fierce opposition from NORD and our army of membership organizations and grassroots advocates,” Ms. Ross said, “the Tax Cuts and Jobs Act of 2017 reduced the ODC from 50% to 25%. Given the significant amount of time it takes to conduct research and development into rare diseases, we still don’t have a good sense as to the impact of the ODC being reduced to 25%.”

However, efforts to further limit the availability of the ODC during debate around the Build Back Better framework in 2021 were ultimately defeated. That defeat was, in part, a result of NORD’s rare disease community’s advocacy,¹⁶ when no changes to the ODC were included in the Inflation Reduction Act.

Patient Assistance Program. In 1987, NORD’s multifaceted patient assistance program (serving today under the umbrella name RareCare17) was founded to help patients obtain lifesaving or life-sustaining medication that they could not otherwise afford, Ms. Ross said. This was based on an unmet need for patients living and struggling with a rare disease who didn’t have access to the care and treatment they needed. “There was no other foundation equipped to do this at the time. NORD came forward to develop the first program of its kind.”

The program provides medication, financial assistance with insurance premiums and copays, diagnostic testing assistance, and travel assistance for clinical trials or consultation with disease specialists. According to Ms. Ross, “today, NORD’s patient assistance program provides, on average, $30 million to $40 million in patient assistance annually to eligible patients and families.”

Pharmaceutical companies do contribute to the patient assistance program. “However, they’re in the dark as to how the money is allocated,” said Mr. Saltonstall. “For example, a given company might donate money for patients with a particular disease but won’t know if patients who have that disease will necessarily receive funds to use toward that company’s drug. The patient might receive assistance to take a drug made by a different company – a competitor.”

There are approximately 14 foundations around the country that have worked within the constraints of the Department of Health & Human Services Office of Inspector General, which established rules about how foundations must operate. Under the broader umbrella of NORD, these foundations also help pay coinsurance costs or provide drugs at no cost to patients who meet financial criteria.
 

An enduring movement

Despite the successes brought about by the ODA, the search for new rare disorder treatments is far from over. We know of more than 7,000 rare diseases; scientists discover more every year. Fewer than 5% of rare disorders have an FDA-approved treatment.

Similar to advancements made in other diseases, progress in rare disease care and treatments will continue to require an all-in approach to solve what is a looming and massive public health challenge.

As NORD founder Abbey S. Meyers wrote in her 2016 book, Orphan Drugs: A Global Crusade: “It was all of us working together that built an impregnable movement demanding a solution. In the end, with the help of government and a touch of Hollywood, the forces opposing us could not win.”

References

1. Rare Disease Day 2023 at IndoUSrare – Fireside Chat with Dr. Abbey S. Meyers. 2023 Mar 3. Indo US Organization for Rare Diseases. https://www.youtube.com/watch?v=fGTWUcQJPlU.

2. Mikami K. Soc Hist Med. 2019;32(3):609-30. doi: 10.1093/shm/hkx098.

3. National Organization for Rare Disorders. The Orphan Drug Act Turns 40: NORD Celebrates Its Impact on Rare Diseases. 2023 Jan 4. https://rarediseases.org/the-orphan-drug-act-turns-40-nord-celebrates-its-impact-on-rare-diseases. 4. Swann J. The story behind the Orphan Drug Act. US Food and Drug Administration. 2018 Feb 23. https://www.fda.gov/industry/fdas-rare-disease-day/story-behind-orphan-drug-act.

5. Roberts A-D and Wadhwa R. Orphan drug approval laws, in StatPearls (Internet). StatPearls Publishing. 2023 Jun 5. www.ncbi.nlm.nih.gov/books/NBK572052/#.

6. National Organization for Rare Disorders. Rare disease database. https://rarediseases.org/rare-diseases/.

7. National Organization for Rare Disorders. Rare disease video library. 2023 Jan 19. https://rarediseases.org/video-library/.

8. National Center for Advancing Translational Sciences. Rare disease research and resources. 2023 May 16. Accessed Sep. 17., 2023. https://ncats.nih.gov/rare-diseases.

9. Food and Drug Administration. Rare diseases team. 2023 Aug 29. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/rare-diseases-team.

10. National Organization for Rare Disorders. “NORD Guide to Rare Disorders,” 3rd edition. Philadelphia: Lippincott Williams & Wilkins, 2002.

11. National Organization for Rare Disorders. Cockayne syndrome. 2022 Jun 7. https://rarediseases.org/rare-diseases/cockayne-syndrome/.

12. National Organization for Rare Disorders. NORD Rare Disease Centers of Excellence. 2023 Jun 28. https://rarediseases.org/rare-disease-centers-of-excellence/.

13. National Organization for Rare Disorders. Metachromatic leukodystrophy. 2022 Mar 22. https://rarediseases.org/rare-diseases/metachromatic-leukodystrophy/#complete-report.

14. National Organization for Rare Disorders. The Natural History of Metachromatic Leukodystrophy Study. 2023 Feb 23. https://rarediseases.org/mld-home-study/.

15. The Natural History of Metachromatic Leukodystrophy Study (HOME Study). 2023 Jun 13. https://clinicaltrials.gov/study/NCT04628364?.

16. National Organization for Rare Disorders, Saltonstall PL. Letter to US Congress House Committee on Ways and Means. 2021 Sep 13. https://rarediseases.org/wp-content/uploads/2022/04/NORD_ODTC-Letter_FINAL.pdf.

17. National Organization for Rare Disorders. RareCare®: NORD’s patient assistance programs. 2022 Nov 1. https://rarediseases.org/wp-content/uploads/2022/04/NORD_ODTC-Letter_FINAL.pdf.

In 1976, Abbey S. Meyers, a mother from Connecticut, finally got a diagnosis for her son. He had been displaying “very bizarre symptoms,” Ms. Meyers said in an interview with IndoUSRare,¹ but, eventually, at 8 years of age, he was given a diagnosis of Tourette syndrome.

“They tried some medicine to try to get him to sit still, but the drugs didn’t work – or if they did, they put him to sleep,” she recounted. “The teachers would be angry that he fell asleep in the classroom.”

Ms. Meyers consulted the late Arthur K. Shapiro, MD, at what was then named the Mount Sinai School of Medicine in New York. Dr. Shapiro was conducting a small clinical trial of pimozide, a drug under investigation for schizophrenia, for its utility in children with Tourette syndrome.

“The drug worked like magic,” Ms. Meyers reported. Her son’s symptoms were substantially reduced, without sedation. He was followed by Dr. Shapiro every 3 months, at which point he would receive a 90-day refill.

However, when her son turned 10 years of age, Dr. Shapiro was no longer able to provide refills: The Food and Drug Administration (FDA) had turned down the drug manufacturer’s application for approval of pimozide for a schizophrenia indication. The company opted not to pursue further development of the drug because it was not deemed profitable.²

Pimozide became unavailable in the United States. The fact that the drug was so promising for Tourette syndrome did not warrant further investment because Tourette syndrome affected a relatively small number of people.

“I was just devastated,” Ms. Meyers reported.
 

Springing into advocacy

Ms. Meyers, who was working with the Tourette Syndrome Association at the time (now the Tourette Association of America), contacted people from other rare disease organizations, including the National Huntington’s Disease Association (today the Huntington’s Disease Society of America) and the Paget Foundation (today part of the Bone Health and Osteoporosis Foundation). Those organizations were experiencing similar problems with drug companies that wouldn’t engage in research and development of drugs for patients who had a rare disorder.

“We realized we had to work together to get something done to solve this problem,” Ms. Meyers said.

The sense of urgency over this roadblock increased when another patient who was taking pimozide tried to get a supply of the drug from Canada and was blocked from doing so by customs officials at the airport because the drug was not FDA approved. Working with that patient’s mother, Ms. Meyers contacted U.S. Representative Henry A. Waxman (D-Calif.), who was chair of the Subcommittee on Health and the Environment of the House Energy & Commerce Committee.

Ms. Meyers thought that Congress needed Rep. Waxman’s support if it was going to get involved with this problem. “So, we got Henry Waxman and his staff familiar with the orphan drug problem.”
 

ODA: Breakthrough legislation

The impetus for the Orphan Drug Act (ODA) started in 1979 with an FDA task force report calling for measures to address what was labeled the “orphan drug problem.”³

In 1982, Rep. Waxman convened a hearing and invited several pharmaceutical companies to attend. They declined the invitation. Ms. Meyers testified at the hearing, which was covered by the Los Angeles Times, giving the issue notoriety.

The issue was also addressed in the popular television series Quincy, M.E. Episodes depicted challenges facing a patient with Tourette syndrome and a patient with myoclonus. Series star Jack Klugman testified before Congress about the need for legislation regarding the development of drugs targeting the treatment of rare diseases.⁴

Rep. Waxman became the bill’s primary House sponsor. The ODA was approved by the House of Representatives on Dec. 14, 1982.

The combined efforts of the advocacy coalition ultimately culminated in the original ODA being signed into law by President Ronald Reagan on Jan. 4, 1983. The ODA incentivized pharmaceutical companies to allot more resources toward research on and development and distribution of therapeutics for people with a rare disease who had, until that point, been “orphaned,” so to speak, by the medical and scientific community.⁵

What is it to be a ‘rare disorder’ or an ‘orphan drug’?

The ODA defines a rare disorder as either a condition that affects fewer than 200,000 people or a condition that affects more than 200,000 people but for which there is no reasonable expectation that a pharmaceutical company will recoup the cost of developing a drug by selling it.⁵

Gregory Twachtman/MDedge News

NORD is born

The creation of NORD was initiated by the same group of advocates who lobbied tirelessly for passage of the ODA – including Ms. Meyers, who served as president of the organization for many years. Heidi Ross, MPH, NORD’s vice president of policy and regulatory affairs, called these advocates “trailblazers.”

NORD

NORD

Spotlight: Patient care and research

Edward Neilan, MD, PhD, recently joined NORD as chief medical and scientific officer. As a pediatrician, medical geneticist, and molecular biologist, Dr. Neilan became acquainted with NORD as far back as medical school and his residency, when he used a book called the NORD Guide to Rare Disorders to help him explain certain diseases to patients and families.¹⁰ “I had a favorable view of NORD because of how useful the book was,” he said.

Natural history research

NORD’s research department awards seed grants to academic investigators who are researching rare disorders and has built an online patient registry platform that helps other, disease-specific patient advocacy organizations conduct natural history studies.

Dr. Neilan said that the registry program was motivated by input from the FDA indicating that companies were sometimes trying to develop drugs to treat a rare disease before fully understanding the natural history of that disease.

“There was a perceived lack of enough natural history data,” Dr. Neilan explained, “so how could the effectiveness of the drug be measured? What would be a meaningful improvement?” NORD assists in making these rare disease foundations more “research ready” so that enough will be known about the disease for drug development “to have a greater chance of success.”

“There’s a lot of promise on the horizon with gene therapy, and the new platforms may accelerate the production of these therapies,” Ms. Kowalski said.

Registries are customized to each disease and foundation by experts, patients, and families involved with that particular disease and foundation. For example: An ongoing study on the NORD platform is a study of metachromatic leukodystrophy (MLD), an autosomal-recessive lysosomal disorder that results in a buildup of sulfatides, a major lipid group in serum, which lead to destruction of the myelin sheath and progressive demyelination of the nervous system.¹³

“[MLD] is a tragic disorder that can first present in late infancy and may progress rapidly over 6 months or so to the point that children lose much of their neurological functioning,” Dr. Neilan said.

The FDA funded NORD to run the HOME study,^14,15 in which families can participate without visiting a research site in person. This was particularly valuable during the COVID-19 pandemic, when many studies were “forced to shift gears and see how much data could be collected if patients were afraid to come to the hospital or not allowed to go to a hospital for nonemergency visits,” Dr. Neilan said.

The HOME study was designed before the onset of the COVID-19 pandemic to reduce the burden on patients of participating in research. The trial became a trend-setter in the shift to what are known as decentralized trials, in which research can be conducted through video, using a tablet that NORD mails to the family.

“This is obviously much more convenient for families who no longer have to travel long distances to the few sites in the country – which are often hundreds or even thousands of miles away – that are studying the condition,” Dr. Neilan said. The decentralized trial model is being used with other conditions, as well.

“There are infantile, juvenile, and adult-onset forms of MLD, and the limited therapeutic options may involve bone-marrow transplant, which may be at least partially effective, as donor-derived bone marrow–derived cells can provide enzymes to protect the brain,” said Dr. Neilan. Gene therapy for MLD has also been developed and is approved in Europe, but not in the United States. “MLD is typical of conditions that often start early in childhood and are progressive, so that, sometimes, by the time the parent realizes that there’s a problem, too much damage has been done to the brain for much repair to take place. Prevention of further damage is easier than reversing an ongoing disease process, so early treatment is important.” That’s why the number of movements to expand newborn screening for various conditions, to identify them before symptoms develop, is increasing.

“That’s another area where NORD has historically been active – in encouraging newborn screening,” Dr. Neilan said.
 

Evolution of the ODA

Since 1983, “a number of amendments ... made the original [ODA] stronger or refined it in various ways,” said Mr. Saltonstall. NORD continues to “very carefully watch any attempts to change it, alter it, move it, take pieces away from it, or – some people say – to make it ‘better.’ To us, it’s a very important law.”

Orphan Drug Credit (ODC). Ms. Ross elaborated: “In recent years, Congress has considered significant changes to the Orphan Drug Credit, which is one of several critical incentives established by the ODA.” When established in 1983, the ODC provided sponsors of a drug with a 50% tax credit for qualified clinical testing expenses associated with developing an orphan drug.

“Unfortunately, despite fierce opposition from NORD and our army of membership organizations and grassroots advocates,” Ms. Ross said, “the Tax Cuts and Jobs Act of 2017 reduced the ODC from 50% to 25%. Given the significant amount of time it takes to conduct research and development into rare diseases, we still don’t have a good sense as to the impact of the ODC being reduced to 25%.”

However, efforts to further limit the availability of the ODC during debate around the Build Back Better framework in 2021 were ultimately defeated. That defeat was, in part, a result of NORD’s rare disease community’s advocacy,¹⁶ when no changes to the ODC were included in the Inflation Reduction Act.

Patient Assistance Program. In 1987, NORD’s multifaceted patient assistance program (serving today under the umbrella name RareCare17) was founded to help patients obtain lifesaving or life-sustaining medication that they could not otherwise afford, Ms. Ross said. This was based on an unmet need for patients living and struggling with a rare disease who didn’t have access to the care and treatment they needed. “There was no other foundation equipped to do this at the time. NORD came forward to develop the first program of its kind.”

The program provides medication, financial assistance with insurance premiums and copays, diagnostic testing assistance, and travel assistance for clinical trials or consultation with disease specialists. According to Ms. Ross, “today, NORD’s patient assistance program provides, on average, $30 million to $40 million in patient assistance annually to eligible patients and families.”

Pharmaceutical companies do contribute to the patient assistance program. “However, they’re in the dark as to how the money is allocated,” said Mr. Saltonstall. “For example, a given company might donate money for patients with a particular disease but won’t know if patients who have that disease will necessarily receive funds to use toward that company’s drug. The patient might receive assistance to take a drug made by a different company – a competitor.”

There are approximately 14 foundations around the country that have worked within the constraints of the Department of Health & Human Services Office of Inspector General, which established rules about how foundations must operate. Under the broader umbrella of NORD, these foundations also help pay coinsurance costs or provide drugs at no cost to patients who meet financial criteria.
 

An enduring movement

Despite the successes brought about by the ODA, the search for new rare disorder treatments is far from over. We know of more than 7,000 rare diseases; scientists discover more every year. Fewer than 5% of rare disorders have an FDA-approved treatment.

Similar to advancements made in other diseases, progress in rare disease care and treatments will continue to require an all-in approach to solve what is a looming and massive public health challenge.

As NORD founder Abbey S. Meyers wrote in her 2016 book, Orphan Drugs: A Global Crusade: “It was all of us working together that built an impregnable movement demanding a solution. In the end, with the help of government and a touch of Hollywood, the forces opposing us could not win.”

References

1. Rare Disease Day 2023 at IndoUSrare – Fireside Chat with Dr. Abbey S. Meyers. 2023 Mar 3. Indo US Organization for Rare Diseases. https://www.youtube.com/watch?v=fGTWUcQJPlU.

2. Mikami K. Soc Hist Med. 2019;32(3):609-30. doi: 10.1093/shm/hkx098.

3. National Organization for Rare Disorders. The Orphan Drug Act Turns 40: NORD Celebrates Its Impact on Rare Diseases. 2023 Jan 4. https://rarediseases.org/the-orphan-drug-act-turns-40-nord-celebrates-its-impact-on-rare-diseases. 4. Swann J. The story behind the Orphan Drug Act. US Food and Drug Administration. 2018 Feb 23. https://www.fda.gov/industry/fdas-rare-disease-day/story-behind-orphan-drug-act.

5. Roberts A-D and Wadhwa R. Orphan drug approval laws, in StatPearls (Internet). StatPearls Publishing. 2023 Jun 5. www.ncbi.nlm.nih.gov/books/NBK572052/#.

6. National Organization for Rare Disorders. Rare disease database. https://rarediseases.org/rare-diseases/.

7. National Organization for Rare Disorders. Rare disease video library. 2023 Jan 19. https://rarediseases.org/video-library/.

8. National Center for Advancing Translational Sciences. Rare disease research and resources. 2023 May 16. Accessed Sep. 17., 2023. https://ncats.nih.gov/rare-diseases.

9. Food and Drug Administration. Rare diseases team. 2023 Aug 29. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/rare-diseases-team.

10. National Organization for Rare Disorders. “NORD Guide to Rare Disorders,” 3rd edition. Philadelphia: Lippincott Williams & Wilkins, 2002.

11. National Organization for Rare Disorders. Cockayne syndrome. 2022 Jun 7. https://rarediseases.org/rare-diseases/cockayne-syndrome/.

12. National Organization for Rare Disorders. NORD Rare Disease Centers of Excellence. 2023 Jun 28. https://rarediseases.org/rare-disease-centers-of-excellence/.

13. National Organization for Rare Disorders. Metachromatic leukodystrophy. 2022 Mar 22. https://rarediseases.org/rare-diseases/metachromatic-leukodystrophy/#complete-report.

14. National Organization for Rare Disorders. The Natural History of Metachromatic Leukodystrophy Study. 2023 Feb 23. https://rarediseases.org/mld-home-study/.

15. The Natural History of Metachromatic Leukodystrophy Study (HOME Study). 2023 Jun 13. https://clinicaltrials.gov/study/NCT04628364?.

16. National Organization for Rare Disorders, Saltonstall PL. Letter to US Congress House Committee on Ways and Means. 2021 Sep 13. https://rarediseases.org/wp-content/uploads/2022/04/NORD_ODTC-Letter_FINAL.pdf.

17. National Organization for Rare Disorders. RareCare®: NORD’s patient assistance programs. 2022 Nov 1. https://rarediseases.org/wp-content/uploads/2022/04/NORD_ODTC-Letter_FINAL.pdf.

INTRODUCTIONS

Editor’s note
By Glenn S. Williams
2023 is indeed a noteworthy year. As you will read in this issue, it marks the 40th anniversary of the landmark Orphan Drug Act (ODA) and the formation of the National Organization for Rare Disorders. 2023 also marks the 30th anniversary of Neurology Reviews, the parent publication of the Rare Neurological Disease Special Report.

A note from NORD
By Edward Neilan, MD, PhD
The coalition of rare disease advocates who sparked rare disease advocacy and convinced lawmakers to pass the ODA in 1983 established NORD that same year to provide an ongoing, unified voice for the needs of the rare disease community.

Rare disease roundup
A look back at some of the 2023 rare disease headlines from Neurology Reviews.
 

CLINICAL REVIEWS

The Orphan Drug Act and NORD at their 40th anniversary: Dramatic achievements and ongoing innovation
By Batya Swift Yasgur, MA, MSW
The movement whose face is ODA and NORD continues to build its legacy. Next? Progress in rare disease care will require an all-in approach to solving a looming and massive public health challenge.

Emerging therapies in Duchenne and facioscapulohumeral muscular dystrophy
By Frieda Wiley, PharmD
Newly approved and investigational therapies, and enhanced diagnostics, are sparking optimism about treating MD – especially Duchenne and facioscapulohumeral types.

Has prompt diagnosis of amyotrophic lateral sclerosis become urgent?
By Ted Bosworth
Optimism is high about improving the survival and care of ALS patients. Neurologists who don’t specialize in ALS can add to the positivity by endorsing a role in speedier diagnostic pathways.

A new chapter for research on treating Huntington’s disease
By Jennie Smith
Setbacks in trials of protein-lowering therapies – mostly over their safety – mask a story of rapid advances and a more recently discovered treatment pathway that also offers promise for other diseases.

The dawning age of therapy for Friedreich ataxia
By Neil Osterweil
The first therapy to target the underlying pathology of Friedreich ataxia was approved in 2023. Other drug and genetic therapies are in the pipeline.

Stiff person syndrome: When a rare disorder hits the headlines
By Kate Johnson
Awareness of this disorder is increasing, but clinicians are challenged to apply the proper workup to avoid wrong turns in identifying affected patients.

Advances in testing and therapeutics are improving the lives of patients with Fabry disease
By Lorraine L. Janeczko, MPH
Thanks to robust research efforts, treatment options are expanding and patients are getting their diagnosis earlier – often, when they are presymptomatic and treatment has greater potential for enhancing quality of life.

Guillain-Barré syndrome: Honing treatment strategies
By John Jesitus
Classic subtypes of Guillain-Barré syndrome are varying manifestations of a shared disease process, novel insights into the disease indicate. This understanding is yielding new treatment strategies.

INTRODUCTIONS

Editor’s note
By Glenn S. Williams
2023 is indeed a noteworthy year. As you will read in this issue, it marks the 40th anniversary of the landmark Orphan Drug Act (ODA) and the formation of the National Organization for Rare Disorders. 2023 also marks the 30th anniversary of Neurology Reviews, the parent publication of the Rare Neurological Disease Special Report.

A note from NORD
By Edward Neilan, MD, PhD
The coalition of rare disease advocates who sparked rare disease advocacy and convinced lawmakers to pass the ODA in 1983 established NORD that same year to provide an ongoing, unified voice for the needs of the rare disease community.

Rare disease roundup
A look back at some of the 2023 rare disease headlines from Neurology Reviews.
 

CLINICAL REVIEWS

The Orphan Drug Act and NORD at their 40th anniversary: Dramatic achievements and ongoing innovation
By Batya Swift Yasgur, MA, MSW
The movement whose face is ODA and NORD continues to build its legacy. Next? Progress in rare disease care will require an all-in approach to solving a looming and massive public health challenge.

Emerging therapies in Duchenne and facioscapulohumeral muscular dystrophy
By Frieda Wiley, PharmD
Newly approved and investigational therapies, and enhanced diagnostics, are sparking optimism about treating MD – especially Duchenne and facioscapulohumeral types.

Has prompt diagnosis of amyotrophic lateral sclerosis become urgent?
By Ted Bosworth
Optimism is high about improving the survival and care of ALS patients. Neurologists who don’t specialize in ALS can add to the positivity by endorsing a role in speedier diagnostic pathways.

A new chapter for research on treating Huntington’s disease
By Jennie Smith
Setbacks in trials of protein-lowering therapies – mostly over their safety – mask a story of rapid advances and a more recently discovered treatment pathway that also offers promise for other diseases.

The dawning age of therapy for Friedreich ataxia
By Neil Osterweil
The first therapy to target the underlying pathology of Friedreich ataxia was approved in 2023. Other drug and genetic therapies are in the pipeline.

Stiff person syndrome: When a rare disorder hits the headlines
By Kate Johnson
Awareness of this disorder is increasing, but clinicians are challenged to apply the proper workup to avoid wrong turns in identifying affected patients.

Advances in testing and therapeutics are improving the lives of patients with Fabry disease
By Lorraine L. Janeczko, MPH
Thanks to robust research efforts, treatment options are expanding and patients are getting their diagnosis earlier – often, when they are presymptomatic and treatment has greater potential for enhancing quality of life.

Guillain-Barré syndrome: Honing treatment strategies
By John Jesitus
Classic subtypes of Guillain-Barré syndrome are varying manifestations of a shared disease process, novel insights into the disease indicate. This understanding is yielding new treatment strategies.

INTRODUCTIONS

Editor’s note
By Glenn S. Williams
2023 is indeed a noteworthy year. As you will read in this issue, it marks the 40th anniversary of the landmark Orphan Drug Act (ODA) and the formation of the National Organization for Rare Disorders. 2023 also marks the 30th anniversary of Neurology Reviews, the parent publication of the Rare Neurological Disease Special Report.

A note from NORD
By Edward Neilan, MD, PhD
The coalition of rare disease advocates who sparked rare disease advocacy and convinced lawmakers to pass the ODA in 1983 established NORD that same year to provide an ongoing, unified voice for the needs of the rare disease community.

Rare disease roundup
A look back at some of the 2023 rare disease headlines from Neurology Reviews.
 

CLINICAL REVIEWS

The Orphan Drug Act and NORD at their 40th anniversary: Dramatic achievements and ongoing innovation
By Batya Swift Yasgur, MA, MSW
The movement whose face is ODA and NORD continues to build its legacy. Next? Progress in rare disease care will require an all-in approach to solving a looming and massive public health challenge.

Emerging therapies in Duchenne and facioscapulohumeral muscular dystrophy
By Frieda Wiley, PharmD
Newly approved and investigational therapies, and enhanced diagnostics, are sparking optimism about treating MD – especially Duchenne and facioscapulohumeral types.

Has prompt diagnosis of amyotrophic lateral sclerosis become urgent?
By Ted Bosworth
Optimism is high about improving the survival and care of ALS patients. Neurologists who don’t specialize in ALS can add to the positivity by endorsing a role in speedier diagnostic pathways.

A new chapter for research on treating Huntington’s disease
By Jennie Smith
Setbacks in trials of protein-lowering therapies – mostly over their safety – mask a story of rapid advances and a more recently discovered treatment pathway that also offers promise for other diseases.

The dawning age of therapy for Friedreich ataxia
By Neil Osterweil
The first therapy to target the underlying pathology of Friedreich ataxia was approved in 2023. Other drug and genetic therapies are in the pipeline.

Stiff person syndrome: When a rare disorder hits the headlines
By Kate Johnson
Awareness of this disorder is increasing, but clinicians are challenged to apply the proper workup to avoid wrong turns in identifying affected patients.

Advances in testing and therapeutics are improving the lives of patients with Fabry disease
By Lorraine L. Janeczko, MPH
Thanks to robust research efforts, treatment options are expanding and patients are getting their diagnosis earlier – often, when they are presymptomatic and treatment has greater potential for enhancing quality of life.

Guillain-Barré syndrome: Honing treatment strategies
By John Jesitus
Classic subtypes of Guillain-Barré syndrome are varying manifestations of a shared disease process, novel insights into the disease indicate. This understanding is yielding new treatment strategies.

Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,¹ ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”

After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.² This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.

That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
 

The knotty problem with therapeutic trials for ALS

“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”

The generalist can make a difference in therapeutic success

The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.

Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.

General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”

This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.

Where we stand: Pathophysiology, diagnosis, treatment

Pathophysiology. ALS is characterized by muscle denervation.⁴ In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.^2,5,6

Comprehensive care at specialty centers

Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.

“Tertiary-care centers for ALS serve a critical purpose,”

Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.

Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.

All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.

“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.

Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
 

Looking ahead

There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.

Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.

In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.

“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”

Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
 

References

1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.

2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.

3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.

4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.

5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.

6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.

7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.

8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.

9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.

10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.

Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,¹ ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”

After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.² This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.

That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
 

The knotty problem with therapeutic trials for ALS

“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”

The generalist can make a difference in therapeutic success

The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.

Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.

General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”

This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.

Where we stand: Pathophysiology, diagnosis, treatment

Pathophysiology. ALS is characterized by muscle denervation.⁴ In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.^2,5,6

Comprehensive care at specialty centers

Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.

“Tertiary-care centers for ALS serve a critical purpose,”

Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.

Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.

All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.

“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.

Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
 

Looking ahead

There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.

Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.

In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.

“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”

Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
 

References

1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.

2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.

3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.

4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.

5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.

6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.

7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.

8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.

9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.

10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.

Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,¹ ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”

After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.² This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.

That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
 

The knotty problem with therapeutic trials for ALS

“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”

The generalist can make a difference in therapeutic success

The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.

Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.

General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”

This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.

Where we stand: Pathophysiology, diagnosis, treatment

Pathophysiology. ALS is characterized by muscle denervation.⁴ In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.^2,5,6

Comprehensive care at specialty centers

Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.

“Tertiary-care centers for ALS serve a critical purpose,”

Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.

Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.

All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.

“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.

Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
 

Looking ahead

There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.

Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.

In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.

“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”

Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
 

References

1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.

2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.

3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.

4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.

5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.

6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.

7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.

8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.

9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.

10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.

“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”

DMD: Current and emerging therapies

DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.

FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.

AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.

The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.³ The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.

Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.

Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.

Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:

ENTR-601-44 is another exon 44–skipping therapy in the pipeline.

On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.

Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.

Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.

Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.

“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
 

FSHD: Emerging therapies

The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.¹ An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.⁴ The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.

AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.⁵ The trial began in April 2023; estimated completion date is September 2025.

As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.

“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
 

Neonatal screening and early diagnosis: Imperative for improving outcomes

Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.

DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.

In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.

Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.

“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”

Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
 

DMD therapies carry a hefty price

Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.

Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.^6,7

‘It takes a village’: Comprehensive care requires a multidisciplinary team

Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.

A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.

“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”

“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”

Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.

Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
 

References

1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.

2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.

3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.

4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.

5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.

6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.

7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.

“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”

DMD: Current and emerging therapies

DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.

FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.

AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.

The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.³ The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.

Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.

Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.

Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:

ENTR-601-44 is another exon 44–skipping therapy in the pipeline.

On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.

Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.

Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.

Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.

“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
 

FSHD: Emerging therapies

The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.¹ An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.⁴ The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.

AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.⁵ The trial began in April 2023; estimated completion date is September 2025.

As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.

“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
 

Neonatal screening and early diagnosis: Imperative for improving outcomes

Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.

DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.

In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.

Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.

“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”

Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
 

DMD therapies carry a hefty price

Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.

Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.^6,7

‘It takes a village’: Comprehensive care requires a multidisciplinary team

Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.

A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.

“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”

“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”

Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.

Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
 

References

1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.

2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.

3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.

4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.

5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.

6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.

7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.

“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”

DMD: Current and emerging therapies

DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.

FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.

AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.

The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.³ The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.

Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.

Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.

Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:

ENTR-601-44 is another exon 44–skipping therapy in the pipeline.

On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.

Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.

Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.

Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.

“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
 

FSHD: Emerging therapies

The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.¹ An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.⁴ The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.

AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.⁵ The trial began in April 2023; estimated completion date is September 2025.

As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.

“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
 

Neonatal screening and early diagnosis: Imperative for improving outcomes

Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.

DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.

In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.

Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.

“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”

Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
 

DMD therapies carry a hefty price

Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.

Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.^6,7

‘It takes a village’: Comprehensive care requires a multidisciplinary team

Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.

A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.

“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”

“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”

Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.

Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
 

References

1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.

2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.

3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.

4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.

5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.

6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.

7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.

TOPLINE:

Noninvasive three-dimensional (3D) stereophotogrammetry may be a valuable adjunctive tool to detect progression of craniofacial morphea (CM) over time.

METHODOLOGY:

• Existing tools that detect disease progression in patients with CM are limited.
• In a prospective cohort study, researchers evaluated the use of 3-D stereophotogrammetry, a noninvasive, radiation-free imaging modality, to detect disease progression in 27 consecutive patients with CM seen at Boston Children’s Hospital and Brigham and Women’s Hospital from April 1, 2019, to March 1, 2023.
• After clinical and 3-D stereophotogrammetry assessments were performed at 2- to 12-month intervals, the 3-D images were rated by an expert (a board-certified plastic craniofacial surgeon) and a nonexpert (a board-certified dermatologist) as demonstrating progression or no progression.
• Kappa coefficients were used to calculate inter-rater reliability.

TAKEAWAY:

• Most of the study participants (73%) were female, their median age was 14 years (range, 5-40 years), and each underwent 3-D stereophotogrammetry imaging at least two times spaced a median of 3 months apart.
• On the basis of clinical assessments during the 48-month study period, 10 patients (37%) experienced progression of their disease.
• 3-D stereophotogrammetry not only corroborated clinical impressions of disease progression with strong inter-rater reliability (kappa = 0.80; 95% confidence interval, 0.61-0.99), but it also detected occult progression of asymmetry not noted on clinical examination in three additional patients.
• In subgroup analyses, assessment of 3-D images demonstrated substantial to near-perfect inter-rater reliability in patients with Fitzpatrick skin types IV-VI.

IN PRACTICE:

“Further work is necessary to validate this measure in a larger cohort and to guide its incorporation into medical decision-making for patients with CM,” the researchers wrote.

SOURCE:

Katharina S. Shaw, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, led the research. The study was published online in JAMA Dermatology.

LIMITATIONS:

The sample was small, and a criterion standard for assessing CM was lacking.

DISCLOSURES:

The researchers reported having no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Noninvasive three-dimensional (3D) stereophotogrammetry may be a valuable adjunctive tool to detect progression of craniofacial morphea (CM) over time.

METHODOLOGY:

• Existing tools that detect disease progression in patients with CM are limited.
• In a prospective cohort study, researchers evaluated the use of 3-D stereophotogrammetry, a noninvasive, radiation-free imaging modality, to detect disease progression in 27 consecutive patients with CM seen at Boston Children’s Hospital and Brigham and Women’s Hospital from April 1, 2019, to March 1, 2023.
• After clinical and 3-D stereophotogrammetry assessments were performed at 2- to 12-month intervals, the 3-D images were rated by an expert (a board-certified plastic craniofacial surgeon) and a nonexpert (a board-certified dermatologist) as demonstrating progression or no progression.
• Kappa coefficients were used to calculate inter-rater reliability.

TAKEAWAY:

• Most of the study participants (73%) were female, their median age was 14 years (range, 5-40 years), and each underwent 3-D stereophotogrammetry imaging at least two times spaced a median of 3 months apart.
• On the basis of clinical assessments during the 48-month study period, 10 patients (37%) experienced progression of their disease.
• 3-D stereophotogrammetry not only corroborated clinical impressions of disease progression with strong inter-rater reliability (kappa = 0.80; 95% confidence interval, 0.61-0.99), but it also detected occult progression of asymmetry not noted on clinical examination in three additional patients.
• In subgroup analyses, assessment of 3-D images demonstrated substantial to near-perfect inter-rater reliability in patients with Fitzpatrick skin types IV-VI.

IN PRACTICE:

“Further work is necessary to validate this measure in a larger cohort and to guide its incorporation into medical decision-making for patients with CM,” the researchers wrote.

SOURCE:

Katharina S. Shaw, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, led the research. The study was published online in JAMA Dermatology.

LIMITATIONS:

The sample was small, and a criterion standard for assessing CM was lacking.

DISCLOSURES:

The researchers reported having no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Noninvasive three-dimensional (3D) stereophotogrammetry may be a valuable adjunctive tool to detect progression of craniofacial morphea (CM) over time.

METHODOLOGY:

• Existing tools that detect disease progression in patients with CM are limited.
• In a prospective cohort study, researchers evaluated the use of 3-D stereophotogrammetry, a noninvasive, radiation-free imaging modality, to detect disease progression in 27 consecutive patients with CM seen at Boston Children’s Hospital and Brigham and Women’s Hospital from April 1, 2019, to March 1, 2023.
• After clinical and 3-D stereophotogrammetry assessments were performed at 2- to 12-month intervals, the 3-D images were rated by an expert (a board-certified plastic craniofacial surgeon) and a nonexpert (a board-certified dermatologist) as demonstrating progression or no progression.
• Kappa coefficients were used to calculate inter-rater reliability.

TAKEAWAY:

• Most of the study participants (73%) were female, their median age was 14 years (range, 5-40 years), and each underwent 3-D stereophotogrammetry imaging at least two times spaced a median of 3 months apart.
• On the basis of clinical assessments during the 48-month study period, 10 patients (37%) experienced progression of their disease.
• 3-D stereophotogrammetry not only corroborated clinical impressions of disease progression with strong inter-rater reliability (kappa = 0.80; 95% confidence interval, 0.61-0.99), but it also detected occult progression of asymmetry not noted on clinical examination in three additional patients.
• In subgroup analyses, assessment of 3-D images demonstrated substantial to near-perfect inter-rater reliability in patients with Fitzpatrick skin types IV-VI.

IN PRACTICE:

“Further work is necessary to validate this measure in a larger cohort and to guide its incorporation into medical decision-making for patients with CM,” the researchers wrote.

SOURCE:

Katharina S. Shaw, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, led the research. The study was published online in JAMA Dermatology.

LIMITATIONS:

The sample was small, and a criterion standard for assessing CM was lacking.

DISCLOSURES:

The researchers reported having no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.