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‘Hidden’ cognitive impairments in DMD may worsen outcomes
A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.
“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.
Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.
A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
A tool for continuous cognitive assessment
The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.
Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.
She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.
Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.
She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.
Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.
She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.
Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
Overcoming a significant barrier
The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.
Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”
Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.
A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.
“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.
Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.
A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
A tool for continuous cognitive assessment
The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.
Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.
She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.
Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.
She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.
Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.
She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.
Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
Overcoming a significant barrier
The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.
Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”
Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.
A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.
“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.
Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.
A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
A tool for continuous cognitive assessment
The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.
Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.
She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.
Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.
She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.
Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.
She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.
Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
Overcoming a significant barrier
The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.
Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”
Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.
FROM AANEM 2023
First new treatment in 30 years for rare disease is effective, tolerable, convenient
PHOENIX –
“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.
Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.
The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Filling an unmet need
A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.
Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.
“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.
Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.
The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.
For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.
They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.
Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.
Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.
The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).
Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.
Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.
In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.
The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.
“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.
Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
Promising data
Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”
The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”
Dr. Gable agreed that new options are important to address an unmet need in CIDP.
“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.
“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”
Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.
“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”
The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.
A version of this article first appeared on Medscape.com.
PHOENIX –
“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.
Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.
The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Filling an unmet need
A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.
Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.
“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.
Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.
The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.
For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.
They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.
Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.
Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.
The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).
Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.
Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.
In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.
The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.
“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.
Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
Promising data
Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”
The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”
Dr. Gable agreed that new options are important to address an unmet need in CIDP.
“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.
“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”
Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.
“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”
The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.
A version of this article first appeared on Medscape.com.
PHOENIX –
“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.
Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.
The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Filling an unmet need
A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.
Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.
“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.
Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.
The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.
For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.
They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.
Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.
Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.
The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).
Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.
Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.
In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.
The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.
“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.
Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
Promising data
Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”
The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”
Dr. Gable agreed that new options are important to address an unmet need in CIDP.
“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.
“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”
Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.
“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”
The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.
A version of this article first appeared on Medscape.com.
AT AANEM 2023
Duchenne muscular dystrophy gene therapy safe, effective at 4 years
PHOENIX – compared with untreated patients who showed significant decline over the same time period, new research shows.
“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.
The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
Severe type of DMD
Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.
SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.
In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.
The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.
For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.
All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.
At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.
The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.
Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.
No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.
Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).
Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).
Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.
Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.
The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.
Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
Increased function, long-term stability
Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.
“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.
“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.
A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.
In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments.
“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”
She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”
The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.
A version of this article first appeared on Medscape.com.
PHOENIX – compared with untreated patients who showed significant decline over the same time period, new research shows.
“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.
The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
Severe type of DMD
Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.
SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.
In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.
The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.
For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.
All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.
At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.
The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.
Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.
No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.
Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).
Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).
Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.
Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.
The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.
Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
Increased function, long-term stability
Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.
“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.
“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.
A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.
In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments.
“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”
She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”
The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.
A version of this article first appeared on Medscape.com.
PHOENIX – compared with untreated patients who showed significant decline over the same time period, new research shows.
“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.
The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
Severe type of DMD
Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.
SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.
In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.
The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.
For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.
All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.
At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.
The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.
Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.
No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.
Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).
Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).
Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.
Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.
The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.
Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
Increased function, long-term stability
Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.
“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.
“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.
A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.
In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments.
“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”
She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”
The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.
A version of this article first appeared on Medscape.com.
AT AANEM 2023
In myasthenia gravis, antibodies pass open-label tests
PHOENIX – . The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.
The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.
At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.
In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.
Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.
After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.
The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.
“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
A reduction in steroid use?
During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.
As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.
Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
Clinical improvements seen
In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.
MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.
Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.
In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.
The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.
MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.
PHOENIX – . The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.
The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.
At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.
In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.
Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.
After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.
The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.
“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
A reduction in steroid use?
During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.
As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.
Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
Clinical improvements seen
In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.
MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.
Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.
In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.
The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.
MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.
PHOENIX – . The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.
The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.
At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.
In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.
Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.
After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.
The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.
“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
A reduction in steroid use?
During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.
As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.
Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
Clinical improvements seen
In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.
MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.
Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.
In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.
The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.
MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.
AT AANEM 2023
More phase 3 data support use of nemolizumab for prurigo nodularis
reported at the annual Congress of the European Academy of Dermatology and Venereology.
In the OLYMPIA 1 study, clinically significant improvements in both itch and skin lesions were seen after 16 weeks of treatment with nemolizumab compared with placebo (P < .0001).
Indeed, among the 286 patients who participated in the trial (190 on nemolizumab and 96 on placebo), 58.4% of those treated with nemolizumab and 16.7% of those who received placebo had an improvement of 4 points or more in the weekly average peak pruritus numeric rating scale (PP-NRS) at week 16 (P < .0001).
Skin lesions were assessed using an investigators general assessment (IGA) score, where IGA success was defined as a score of 0/1 indicating clear or almost clear skin or where there had been at least a 2-point change from baseline values. Over a quarter (26.3%) of nemolizumab-treated patients met these criteria versus 7.3% for those on placebo (P = .0001).
“These results confirm the results of the OLYMPIA 2 study, the other phase 3 study, and now I hope you understand why we are so excited,” lead investigator Sonja Ständer, MD, of the Center for Chronic Pruritus at University Hospital Münster, Germany, said at the meeting, where she presented the data.
The OLYMPIA 2 study included 274 patients and the results showed a weekly average PP-NRS score improvement of 56.3% vs. 20.9% for placebo and IGA success in 37.7% and 11% of patients, respectively, at 16 weeks.
First-in-class therapy
“We know how difficult it is to treat patients; they are refractory to treatment, frustrated, and this really impacts them regarding their quality of life,” said Dr. Ständer. New options are needed to help patients, and nemolizumab, a first-in-class interleukin-31 (IL-31) receptor alpha antagonist, is one treatment that may answer this call.
Prurigo nodularis is a chronic neuroimmune skin condition characterized by severe itch and multiple nodular skin lesions, Dr. Ständer explained. She added that there is evidence that IL-31 has a key role to play in the development of itch, and in differentiation of keratinocytes, type 2 and type 17 immune responses, and fibrosis associated with the condition.
The OLYMPIA 1 and 2 trials are part of a large developmental program that includes two ongoing trials. One is assessing the durability of response over 24 weeks in 40 patients and the other is a long-term extension trial involving 450 patients from the OLYMPIA 1 and 2 trials.
Inclusion criteria and additional results
For inclusion in the study, adults with prurigo nodularis for at least 6 months had to have 20 or more nodules on the body with a bilateral distribution, an IGA score of 3 or more, and an average PP-NRS of 7 or higher. The latter “was really a high bar for them to qualify for the trial,” said Dr. Ständer.
After an initial 4-week screening period, patients were randomly assigned to 24 weeks of treatment with nemolizumab or placebo given as a subcutaneous injection every 4 weeks. An 8-week “off-treatment” period followed.
The nemolizumab dose was based on the patient’s body weight, with patients weighing less than 90 kg (198 pounds) getting a loading dose of 60 mg followed by further doses of 30 mg; while patients weighing 90 kg or more receiving 50 mg of nemolizumab.
Dr. Ständer reported that nemolizumab met all of the trials’ secondary endpoints; this included at least a 4-point improvement in sleep disturbance. She noted that changes in itch and subsequent sleep disturbance occurred early, at 4 weeks of treatment – after just one injection of nemolizumab.
The response rates seen in the moderate to severe prurigo nodularis population studies are quite unique when compared with conventional therapies, Dr. Ständer maintained. “We’ve never seen something like this before.”
No safety concerns
No significant difference in tolerability was seen between the nemolizumab and placebo groups, Dr. Ständer observed. Any adverse event occurred in 71.7% and 65.3% of patients, respectively, and serious adverse events in 8.6% and 10.5%.
There was a similar rate of adverse events leading to discontinuation, respectively (4.8% vs. 4.2%).
Headache was seen more frequently among those on nemolizumab than those on placebo (7.0% vs. 2.1%), and there was a higher number of eczema cases among those on nemolizumab (5.3% vs. 1.1%). The latter is somewhat paradoxical because nemolizumab is also being studied as a treatment for atopic dermatitis, with good results seen in phase 3 trials. Asked about this finding after her presentation, Dr. Ständer said “we are following up on that to know exactly what is going on; this is a side effect of nemolizumab that is seen also with other biologics.”
JAK inhibitor trial for PN, CPUO
Nemolizumab is not the only promising new approach to treating prurigo nodularis. During a separate late-breaking news session at the meeting, Shawn Kwatra, MD, director of the Johns Hopkins Itch Center in Baltimore, presented “dramatic” data from a “proof-of-concept” phase 2 study with the Janus kinase (JAK) inhibitor abrocitinib (Cibinqo), which is approved for atopic dermatitis in the United States and Europe.
The investigator-initiated trial took a different approach from most other trials, Dr. Kwatra said. The starting point was to look at studying multiple rather than single dermatologic diseases that were perhaps being left a little by the wayside but may share some common ground. Those two diseases were prurigo nodularis and chronic pruritus of unknown origin (CPUO).
“They’re actually very analogous conditions in the way we treat, so I thought those would be a good pair,” Dr. Kwatra said, noting that there were several studies that made him think that JAK inhibition “would be an interesting concept to try.”
On that basis, 10 women with prurigo nodularis (mean age, 58 years) and two women and eight men with CPUO (mean age, 70 years) were recruited and all were treated with abrocitinib at a once-daily oral dose of 200 mg for 12 weeks.
“They all had really intense itch,” before treatment, Dr. Kwatra said. The mean baseline PP-NRS was 9.2 and 8.2 in the prurigo nodularis and CPUO groups, respectively. By the end of treatment, however, “the improvement in itch was pretty dramatic,” especially for prurigo nodularis, he said.
At 12 weeks, the PP-NRS score had fallen to 2.0 in the prurigo nodularis group, equating to a significant 78% change from baseline (P < .001). And, in the CPUO group, the 12-week PP-NRS score was 3.8, nearly a 54% drop from baseline (P = .01).
Sleep disturbance was improved for both conditions, and in the patients with prurigo nodularis, there were improvements in skin lesions. Looking at the patients who responded to treatment, Dr. Kwatra noted that “if you responded, you respond fast, and you respond almost entirely.”
Additional findings from cutaneous transcriptome analysis showed that JAK inhibition with abrocitinib was modulating Th1-, Th2-, Th17-, and Th22-mediated pathways in both groups of patients.
The overall frequency of adverse events was low, and no serious adverse events occurred.
Commenting on the potential use of abrocitinib in managing patients with PN and CPUO, Tiago dos Reis Matos, MD, PhD, MSc, Amsterdam University Medical Centers, told this news organization that JAK1 inhibitors “are showing promising results in treating several diseases.”
Dr. Matos, who was not involved in the study, added that JAK inhibition was “of special interest in prurigo nodularis and chronic pruritus, since these are some of the most difficult diseases to treat with limited therapeutic options.”
Dr. Kwatra observed: “Obviously, we need further development. But we also have clues here about how to design phase 3 trials.”
Galderma funded the OLYMPIA 1 and 2 studies. Dr. Ständer was an investigator for the trial and reported serving as a consultant, speaker, or investigator for multiple pharmaceutical companies, including Galderma.
Johns Hopkins University supported the abrocitinib study with funding from Pfizer. Dr. Kwatra is an advisory board member or consultant to several pharmaceutical companies and is an investigator for Galderma, Incyte, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
reported at the annual Congress of the European Academy of Dermatology and Venereology.
In the OLYMPIA 1 study, clinically significant improvements in both itch and skin lesions were seen after 16 weeks of treatment with nemolizumab compared with placebo (P < .0001).
Indeed, among the 286 patients who participated in the trial (190 on nemolizumab and 96 on placebo), 58.4% of those treated with nemolizumab and 16.7% of those who received placebo had an improvement of 4 points or more in the weekly average peak pruritus numeric rating scale (PP-NRS) at week 16 (P < .0001).
Skin lesions were assessed using an investigators general assessment (IGA) score, where IGA success was defined as a score of 0/1 indicating clear or almost clear skin or where there had been at least a 2-point change from baseline values. Over a quarter (26.3%) of nemolizumab-treated patients met these criteria versus 7.3% for those on placebo (P = .0001).
“These results confirm the results of the OLYMPIA 2 study, the other phase 3 study, and now I hope you understand why we are so excited,” lead investigator Sonja Ständer, MD, of the Center for Chronic Pruritus at University Hospital Münster, Germany, said at the meeting, where she presented the data.
The OLYMPIA 2 study included 274 patients and the results showed a weekly average PP-NRS score improvement of 56.3% vs. 20.9% for placebo and IGA success in 37.7% and 11% of patients, respectively, at 16 weeks.
First-in-class therapy
“We know how difficult it is to treat patients; they are refractory to treatment, frustrated, and this really impacts them regarding their quality of life,” said Dr. Ständer. New options are needed to help patients, and nemolizumab, a first-in-class interleukin-31 (IL-31) receptor alpha antagonist, is one treatment that may answer this call.
Prurigo nodularis is a chronic neuroimmune skin condition characterized by severe itch and multiple nodular skin lesions, Dr. Ständer explained. She added that there is evidence that IL-31 has a key role to play in the development of itch, and in differentiation of keratinocytes, type 2 and type 17 immune responses, and fibrosis associated with the condition.
The OLYMPIA 1 and 2 trials are part of a large developmental program that includes two ongoing trials. One is assessing the durability of response over 24 weeks in 40 patients and the other is a long-term extension trial involving 450 patients from the OLYMPIA 1 and 2 trials.
Inclusion criteria and additional results
For inclusion in the study, adults with prurigo nodularis for at least 6 months had to have 20 or more nodules on the body with a bilateral distribution, an IGA score of 3 or more, and an average PP-NRS of 7 or higher. The latter “was really a high bar for them to qualify for the trial,” said Dr. Ständer.
After an initial 4-week screening period, patients were randomly assigned to 24 weeks of treatment with nemolizumab or placebo given as a subcutaneous injection every 4 weeks. An 8-week “off-treatment” period followed.
The nemolizumab dose was based on the patient’s body weight, with patients weighing less than 90 kg (198 pounds) getting a loading dose of 60 mg followed by further doses of 30 mg; while patients weighing 90 kg or more receiving 50 mg of nemolizumab.
Dr. Ständer reported that nemolizumab met all of the trials’ secondary endpoints; this included at least a 4-point improvement in sleep disturbance. She noted that changes in itch and subsequent sleep disturbance occurred early, at 4 weeks of treatment – after just one injection of nemolizumab.
The response rates seen in the moderate to severe prurigo nodularis population studies are quite unique when compared with conventional therapies, Dr. Ständer maintained. “We’ve never seen something like this before.”
No safety concerns
No significant difference in tolerability was seen between the nemolizumab and placebo groups, Dr. Ständer observed. Any adverse event occurred in 71.7% and 65.3% of patients, respectively, and serious adverse events in 8.6% and 10.5%.
There was a similar rate of adverse events leading to discontinuation, respectively (4.8% vs. 4.2%).
Headache was seen more frequently among those on nemolizumab than those on placebo (7.0% vs. 2.1%), and there was a higher number of eczema cases among those on nemolizumab (5.3% vs. 1.1%). The latter is somewhat paradoxical because nemolizumab is also being studied as a treatment for atopic dermatitis, with good results seen in phase 3 trials. Asked about this finding after her presentation, Dr. Ständer said “we are following up on that to know exactly what is going on; this is a side effect of nemolizumab that is seen also with other biologics.”
JAK inhibitor trial for PN, CPUO
Nemolizumab is not the only promising new approach to treating prurigo nodularis. During a separate late-breaking news session at the meeting, Shawn Kwatra, MD, director of the Johns Hopkins Itch Center in Baltimore, presented “dramatic” data from a “proof-of-concept” phase 2 study with the Janus kinase (JAK) inhibitor abrocitinib (Cibinqo), which is approved for atopic dermatitis in the United States and Europe.
The investigator-initiated trial took a different approach from most other trials, Dr. Kwatra said. The starting point was to look at studying multiple rather than single dermatologic diseases that were perhaps being left a little by the wayside but may share some common ground. Those two diseases were prurigo nodularis and chronic pruritus of unknown origin (CPUO).
“They’re actually very analogous conditions in the way we treat, so I thought those would be a good pair,” Dr. Kwatra said, noting that there were several studies that made him think that JAK inhibition “would be an interesting concept to try.”
On that basis, 10 women with prurigo nodularis (mean age, 58 years) and two women and eight men with CPUO (mean age, 70 years) were recruited and all were treated with abrocitinib at a once-daily oral dose of 200 mg for 12 weeks.
“They all had really intense itch,” before treatment, Dr. Kwatra said. The mean baseline PP-NRS was 9.2 and 8.2 in the prurigo nodularis and CPUO groups, respectively. By the end of treatment, however, “the improvement in itch was pretty dramatic,” especially for prurigo nodularis, he said.
At 12 weeks, the PP-NRS score had fallen to 2.0 in the prurigo nodularis group, equating to a significant 78% change from baseline (P < .001). And, in the CPUO group, the 12-week PP-NRS score was 3.8, nearly a 54% drop from baseline (P = .01).
Sleep disturbance was improved for both conditions, and in the patients with prurigo nodularis, there were improvements in skin lesions. Looking at the patients who responded to treatment, Dr. Kwatra noted that “if you responded, you respond fast, and you respond almost entirely.”
Additional findings from cutaneous transcriptome analysis showed that JAK inhibition with abrocitinib was modulating Th1-, Th2-, Th17-, and Th22-mediated pathways in both groups of patients.
The overall frequency of adverse events was low, and no serious adverse events occurred.
Commenting on the potential use of abrocitinib in managing patients with PN and CPUO, Tiago dos Reis Matos, MD, PhD, MSc, Amsterdam University Medical Centers, told this news organization that JAK1 inhibitors “are showing promising results in treating several diseases.”
Dr. Matos, who was not involved in the study, added that JAK inhibition was “of special interest in prurigo nodularis and chronic pruritus, since these are some of the most difficult diseases to treat with limited therapeutic options.”
Dr. Kwatra observed: “Obviously, we need further development. But we also have clues here about how to design phase 3 trials.”
Galderma funded the OLYMPIA 1 and 2 studies. Dr. Ständer was an investigator for the trial and reported serving as a consultant, speaker, or investigator for multiple pharmaceutical companies, including Galderma.
Johns Hopkins University supported the abrocitinib study with funding from Pfizer. Dr. Kwatra is an advisory board member or consultant to several pharmaceutical companies and is an investigator for Galderma, Incyte, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
reported at the annual Congress of the European Academy of Dermatology and Venereology.
In the OLYMPIA 1 study, clinically significant improvements in both itch and skin lesions were seen after 16 weeks of treatment with nemolizumab compared with placebo (P < .0001).
Indeed, among the 286 patients who participated in the trial (190 on nemolizumab and 96 on placebo), 58.4% of those treated with nemolizumab and 16.7% of those who received placebo had an improvement of 4 points or more in the weekly average peak pruritus numeric rating scale (PP-NRS) at week 16 (P < .0001).
Skin lesions were assessed using an investigators general assessment (IGA) score, where IGA success was defined as a score of 0/1 indicating clear or almost clear skin or where there had been at least a 2-point change from baseline values. Over a quarter (26.3%) of nemolizumab-treated patients met these criteria versus 7.3% for those on placebo (P = .0001).
“These results confirm the results of the OLYMPIA 2 study, the other phase 3 study, and now I hope you understand why we are so excited,” lead investigator Sonja Ständer, MD, of the Center for Chronic Pruritus at University Hospital Münster, Germany, said at the meeting, where she presented the data.
The OLYMPIA 2 study included 274 patients and the results showed a weekly average PP-NRS score improvement of 56.3% vs. 20.9% for placebo and IGA success in 37.7% and 11% of patients, respectively, at 16 weeks.
First-in-class therapy
“We know how difficult it is to treat patients; they are refractory to treatment, frustrated, and this really impacts them regarding their quality of life,” said Dr. Ständer. New options are needed to help patients, and nemolizumab, a first-in-class interleukin-31 (IL-31) receptor alpha antagonist, is one treatment that may answer this call.
Prurigo nodularis is a chronic neuroimmune skin condition characterized by severe itch and multiple nodular skin lesions, Dr. Ständer explained. She added that there is evidence that IL-31 has a key role to play in the development of itch, and in differentiation of keratinocytes, type 2 and type 17 immune responses, and fibrosis associated with the condition.
The OLYMPIA 1 and 2 trials are part of a large developmental program that includes two ongoing trials. One is assessing the durability of response over 24 weeks in 40 patients and the other is a long-term extension trial involving 450 patients from the OLYMPIA 1 and 2 trials.
Inclusion criteria and additional results
For inclusion in the study, adults with prurigo nodularis for at least 6 months had to have 20 or more nodules on the body with a bilateral distribution, an IGA score of 3 or more, and an average PP-NRS of 7 or higher. The latter “was really a high bar for them to qualify for the trial,” said Dr. Ständer.
After an initial 4-week screening period, patients were randomly assigned to 24 weeks of treatment with nemolizumab or placebo given as a subcutaneous injection every 4 weeks. An 8-week “off-treatment” period followed.
The nemolizumab dose was based on the patient’s body weight, with patients weighing less than 90 kg (198 pounds) getting a loading dose of 60 mg followed by further doses of 30 mg; while patients weighing 90 kg or more receiving 50 mg of nemolizumab.
Dr. Ständer reported that nemolizumab met all of the trials’ secondary endpoints; this included at least a 4-point improvement in sleep disturbance. She noted that changes in itch and subsequent sleep disturbance occurred early, at 4 weeks of treatment – after just one injection of nemolizumab.
The response rates seen in the moderate to severe prurigo nodularis population studies are quite unique when compared with conventional therapies, Dr. Ständer maintained. “We’ve never seen something like this before.”
No safety concerns
No significant difference in tolerability was seen between the nemolizumab and placebo groups, Dr. Ständer observed. Any adverse event occurred in 71.7% and 65.3% of patients, respectively, and serious adverse events in 8.6% and 10.5%.
There was a similar rate of adverse events leading to discontinuation, respectively (4.8% vs. 4.2%).
Headache was seen more frequently among those on nemolizumab than those on placebo (7.0% vs. 2.1%), and there was a higher number of eczema cases among those on nemolizumab (5.3% vs. 1.1%). The latter is somewhat paradoxical because nemolizumab is also being studied as a treatment for atopic dermatitis, with good results seen in phase 3 trials. Asked about this finding after her presentation, Dr. Ständer said “we are following up on that to know exactly what is going on; this is a side effect of nemolizumab that is seen also with other biologics.”
JAK inhibitor trial for PN, CPUO
Nemolizumab is not the only promising new approach to treating prurigo nodularis. During a separate late-breaking news session at the meeting, Shawn Kwatra, MD, director of the Johns Hopkins Itch Center in Baltimore, presented “dramatic” data from a “proof-of-concept” phase 2 study with the Janus kinase (JAK) inhibitor abrocitinib (Cibinqo), which is approved for atopic dermatitis in the United States and Europe.
The investigator-initiated trial took a different approach from most other trials, Dr. Kwatra said. The starting point was to look at studying multiple rather than single dermatologic diseases that were perhaps being left a little by the wayside but may share some common ground. Those two diseases were prurigo nodularis and chronic pruritus of unknown origin (CPUO).
“They’re actually very analogous conditions in the way we treat, so I thought those would be a good pair,” Dr. Kwatra said, noting that there were several studies that made him think that JAK inhibition “would be an interesting concept to try.”
On that basis, 10 women with prurigo nodularis (mean age, 58 years) and two women and eight men with CPUO (mean age, 70 years) were recruited and all were treated with abrocitinib at a once-daily oral dose of 200 mg for 12 weeks.
“They all had really intense itch,” before treatment, Dr. Kwatra said. The mean baseline PP-NRS was 9.2 and 8.2 in the prurigo nodularis and CPUO groups, respectively. By the end of treatment, however, “the improvement in itch was pretty dramatic,” especially for prurigo nodularis, he said.
At 12 weeks, the PP-NRS score had fallen to 2.0 in the prurigo nodularis group, equating to a significant 78% change from baseline (P < .001). And, in the CPUO group, the 12-week PP-NRS score was 3.8, nearly a 54% drop from baseline (P = .01).
Sleep disturbance was improved for both conditions, and in the patients with prurigo nodularis, there were improvements in skin lesions. Looking at the patients who responded to treatment, Dr. Kwatra noted that “if you responded, you respond fast, and you respond almost entirely.”
Additional findings from cutaneous transcriptome analysis showed that JAK inhibition with abrocitinib was modulating Th1-, Th2-, Th17-, and Th22-mediated pathways in both groups of patients.
The overall frequency of adverse events was low, and no serious adverse events occurred.
Commenting on the potential use of abrocitinib in managing patients with PN and CPUO, Tiago dos Reis Matos, MD, PhD, MSc, Amsterdam University Medical Centers, told this news organization that JAK1 inhibitors “are showing promising results in treating several diseases.”
Dr. Matos, who was not involved in the study, added that JAK inhibition was “of special interest in prurigo nodularis and chronic pruritus, since these are some of the most difficult diseases to treat with limited therapeutic options.”
Dr. Kwatra observed: “Obviously, we need further development. But we also have clues here about how to design phase 3 trials.”
Galderma funded the OLYMPIA 1 and 2 studies. Dr. Ständer was an investigator for the trial and reported serving as a consultant, speaker, or investigator for multiple pharmaceutical companies, including Galderma.
Johns Hopkins University supported the abrocitinib study with funding from Pfizer. Dr. Kwatra is an advisory board member or consultant to several pharmaceutical companies and is an investigator for Galderma, Incyte, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
FROM THE EADV CONGRESS
Birch bark–derived treatment reduces daily dressings in patients with epidermolysis bullosa
Additional when compared with a control gel.
In a final, post hoc analysis to come from the trial, 15 of 45 (33%) patients treated with Oleogel-S10 versus 5 of 48 (10.4%) treated with the control gel were reported as no longer needing daily dressing changes at 45 days of follow-up.
Moreover, the effect was sustained, with similar percentages of patients no longer requiring daily dressing changes at 60 days (34% vs. 13%, respectively) and 90 days (36% vs. 11%) of follow-up.
The mean reduction in daily dressing changes was 1.36 for Oleogel-S10 and 0.41 for the control gel (P = .005).
“Patients who, in the beginning, had daily dressing changes had almost three fewer dressing changes every 2 weeks if they were treated with Oleogel-S10,” Dimitra Kiritsi, MD, PhD, of the department of dermatology at the University of Freiburg (Germany), reported at the annual congress of the European Academy of Dermatology and Venereology. By comparison, patients in the control group had just one fewer daily dressing change in 2 weeks.
“You might say okay, but what does this mean in terms of time?” added Dr. Kiritsi. Using historical data on the time required for whole body care (Orphanet J Rare Dis. 2020 Jan 3. doi: 10.1186/s13023-019-1279-y), it was estimated that treatment with Oleogel-S10 was associated with an overall time-saving per week of 11 hours (6.6 hours for the patient and 4.4 hours for the caregiver) and use of the control gel was associated with an overall time-saving of 4 hours (2.4 hours for the patient and 1.6 hours for the caregiver).
“This is, for our patients, important,” said Dr. Kiritsi, as “it is time that they can spend doing something nice with the family” instead, avoiding the pain and distress associated with frequent dressing changes.
Approved in Europe, not in the United States
Oleogel-S10, classified as an herbal product, contains triterpenes derived from birch bark extract, which have been formulated with sunflower oil to form a gel.
Despite being approved for use in Europe, Oleogel-S10 has not yet been approved to treat EB in the United States. The FDA did not approve Amryt Pharma’s new drug application in February 2022. The application had included data from the EASE trial.
EASE included 223 patients with dystrophic or junctional EB, including 156 children, at 58 sites in 28 countries. As such, this makes it the largest treatment study in this rare genetic disease to date.
The trial had consisted of an initial 90-day, double-blind treatment period, during which time 109 patients had used Oleogel-S10 and 114 had used a control gel. This was followed by a 24-month open-label phase, during which time all remaining patients (n = 205) had used Oleogel-S10 on top of their standard of care.
Dr. Kiritsi summarized the main results of the EASE trial as follows.
- Complete healing of target wounds (primary endpoint) in 41.3% of patients treated with Oleogel-S10 and 28.9% of patients treated with the control gel (P = .013).
- Improved total body wound burden measured by both Epidermolysis Bullosa Disease Activity and Scarring Index and Body Surface Area Percentage scores.
- Reduced frequency of dressing changes (1 less per 2 weeks for Oleogel-S10 versus 0 less per 2 weeks for control gel).
- Improved pain among participants aged 4 years and older while their dressings were being changed.
- Reduced rates of wound infection (0.9% Oleogel-S10 vs. 4.4% control gel).
- Similar rates of treatment-emergent adverse events (24.8% vs. 22.8%, respectively), which were mostly deemed to be mild or moderate.
The EASE study – an important trial for EB
EASE is an important trial for EB, the study’s principal investigator Dédée Murrell, MD, DSc, University of New South Wales, Sydney, has pointed out previously.
“This was the first EB study to meet its primary endpoint and demonstrated a statistically significant acceleration of target wound healing by day 45,” Dr. Murrell said in a press release issued by Amryt Pharma to coincide with the online publication of the trial results.
“In addition, the favorable trends we see with key secondary endpoints such as reduced wound burden, pain, and frequency of dressing changes are considered as being very meaningful for patients,” Dr. Murrell said.
The EASE study was funded by Amryt Research Limited. Dr. Kiritsi reported receiving honoraria or consultation fees from Amryt, RHEACELL GmbH, and Fibrx Derm. She also acknowledged grant or research support from DEBRA International, EB Research Partnership, Fritz-Thyssen Foundation, German Research Foundation, and RHEACELL. Dr. Murrell has ties to Amryt and Amicus and is a co-owner of the patent for topical sirolimus for EB simplex.
A version of this article appeared on Medscape.com.
Additional when compared with a control gel.
In a final, post hoc analysis to come from the trial, 15 of 45 (33%) patients treated with Oleogel-S10 versus 5 of 48 (10.4%) treated with the control gel were reported as no longer needing daily dressing changes at 45 days of follow-up.
Moreover, the effect was sustained, with similar percentages of patients no longer requiring daily dressing changes at 60 days (34% vs. 13%, respectively) and 90 days (36% vs. 11%) of follow-up.
The mean reduction in daily dressing changes was 1.36 for Oleogel-S10 and 0.41 for the control gel (P = .005).
“Patients who, in the beginning, had daily dressing changes had almost three fewer dressing changes every 2 weeks if they were treated with Oleogel-S10,” Dimitra Kiritsi, MD, PhD, of the department of dermatology at the University of Freiburg (Germany), reported at the annual congress of the European Academy of Dermatology and Venereology. By comparison, patients in the control group had just one fewer daily dressing change in 2 weeks.
“You might say okay, but what does this mean in terms of time?” added Dr. Kiritsi. Using historical data on the time required for whole body care (Orphanet J Rare Dis. 2020 Jan 3. doi: 10.1186/s13023-019-1279-y), it was estimated that treatment with Oleogel-S10 was associated with an overall time-saving per week of 11 hours (6.6 hours for the patient and 4.4 hours for the caregiver) and use of the control gel was associated with an overall time-saving of 4 hours (2.4 hours for the patient and 1.6 hours for the caregiver).
“This is, for our patients, important,” said Dr. Kiritsi, as “it is time that they can spend doing something nice with the family” instead, avoiding the pain and distress associated with frequent dressing changes.
Approved in Europe, not in the United States
Oleogel-S10, classified as an herbal product, contains triterpenes derived from birch bark extract, which have been formulated with sunflower oil to form a gel.
Despite being approved for use in Europe, Oleogel-S10 has not yet been approved to treat EB in the United States. The FDA did not approve Amryt Pharma’s new drug application in February 2022. The application had included data from the EASE trial.
EASE included 223 patients with dystrophic or junctional EB, including 156 children, at 58 sites in 28 countries. As such, this makes it the largest treatment study in this rare genetic disease to date.
The trial had consisted of an initial 90-day, double-blind treatment period, during which time 109 patients had used Oleogel-S10 and 114 had used a control gel. This was followed by a 24-month open-label phase, during which time all remaining patients (n = 205) had used Oleogel-S10 on top of their standard of care.
Dr. Kiritsi summarized the main results of the EASE trial as follows.
- Complete healing of target wounds (primary endpoint) in 41.3% of patients treated with Oleogel-S10 and 28.9% of patients treated with the control gel (P = .013).
- Improved total body wound burden measured by both Epidermolysis Bullosa Disease Activity and Scarring Index and Body Surface Area Percentage scores.
- Reduced frequency of dressing changes (1 less per 2 weeks for Oleogel-S10 versus 0 less per 2 weeks for control gel).
- Improved pain among participants aged 4 years and older while their dressings were being changed.
- Reduced rates of wound infection (0.9% Oleogel-S10 vs. 4.4% control gel).
- Similar rates of treatment-emergent adverse events (24.8% vs. 22.8%, respectively), which were mostly deemed to be mild or moderate.
The EASE study – an important trial for EB
EASE is an important trial for EB, the study’s principal investigator Dédée Murrell, MD, DSc, University of New South Wales, Sydney, has pointed out previously.
“This was the first EB study to meet its primary endpoint and demonstrated a statistically significant acceleration of target wound healing by day 45,” Dr. Murrell said in a press release issued by Amryt Pharma to coincide with the online publication of the trial results.
“In addition, the favorable trends we see with key secondary endpoints such as reduced wound burden, pain, and frequency of dressing changes are considered as being very meaningful for patients,” Dr. Murrell said.
The EASE study was funded by Amryt Research Limited. Dr. Kiritsi reported receiving honoraria or consultation fees from Amryt, RHEACELL GmbH, and Fibrx Derm. She also acknowledged grant or research support from DEBRA International, EB Research Partnership, Fritz-Thyssen Foundation, German Research Foundation, and RHEACELL. Dr. Murrell has ties to Amryt and Amicus and is a co-owner of the patent for topical sirolimus for EB simplex.
A version of this article appeared on Medscape.com.
Additional when compared with a control gel.
In a final, post hoc analysis to come from the trial, 15 of 45 (33%) patients treated with Oleogel-S10 versus 5 of 48 (10.4%) treated with the control gel were reported as no longer needing daily dressing changes at 45 days of follow-up.
Moreover, the effect was sustained, with similar percentages of patients no longer requiring daily dressing changes at 60 days (34% vs. 13%, respectively) and 90 days (36% vs. 11%) of follow-up.
The mean reduction in daily dressing changes was 1.36 for Oleogel-S10 and 0.41 for the control gel (P = .005).
“Patients who, in the beginning, had daily dressing changes had almost three fewer dressing changes every 2 weeks if they were treated with Oleogel-S10,” Dimitra Kiritsi, MD, PhD, of the department of dermatology at the University of Freiburg (Germany), reported at the annual congress of the European Academy of Dermatology and Venereology. By comparison, patients in the control group had just one fewer daily dressing change in 2 weeks.
“You might say okay, but what does this mean in terms of time?” added Dr. Kiritsi. Using historical data on the time required for whole body care (Orphanet J Rare Dis. 2020 Jan 3. doi: 10.1186/s13023-019-1279-y), it was estimated that treatment with Oleogel-S10 was associated with an overall time-saving per week of 11 hours (6.6 hours for the patient and 4.4 hours for the caregiver) and use of the control gel was associated with an overall time-saving of 4 hours (2.4 hours for the patient and 1.6 hours for the caregiver).
“This is, for our patients, important,” said Dr. Kiritsi, as “it is time that they can spend doing something nice with the family” instead, avoiding the pain and distress associated with frequent dressing changes.
Approved in Europe, not in the United States
Oleogel-S10, classified as an herbal product, contains triterpenes derived from birch bark extract, which have been formulated with sunflower oil to form a gel.
Despite being approved for use in Europe, Oleogel-S10 has not yet been approved to treat EB in the United States. The FDA did not approve Amryt Pharma’s new drug application in February 2022. The application had included data from the EASE trial.
EASE included 223 patients with dystrophic or junctional EB, including 156 children, at 58 sites in 28 countries. As such, this makes it the largest treatment study in this rare genetic disease to date.
The trial had consisted of an initial 90-day, double-blind treatment period, during which time 109 patients had used Oleogel-S10 and 114 had used a control gel. This was followed by a 24-month open-label phase, during which time all remaining patients (n = 205) had used Oleogel-S10 on top of their standard of care.
Dr. Kiritsi summarized the main results of the EASE trial as follows.
- Complete healing of target wounds (primary endpoint) in 41.3% of patients treated with Oleogel-S10 and 28.9% of patients treated with the control gel (P = .013).
- Improved total body wound burden measured by both Epidermolysis Bullosa Disease Activity and Scarring Index and Body Surface Area Percentage scores.
- Reduced frequency of dressing changes (1 less per 2 weeks for Oleogel-S10 versus 0 less per 2 weeks for control gel).
- Improved pain among participants aged 4 years and older while their dressings were being changed.
- Reduced rates of wound infection (0.9% Oleogel-S10 vs. 4.4% control gel).
- Similar rates of treatment-emergent adverse events (24.8% vs. 22.8%, respectively), which were mostly deemed to be mild or moderate.
The EASE study – an important trial for EB
EASE is an important trial for EB, the study’s principal investigator Dédée Murrell, MD, DSc, University of New South Wales, Sydney, has pointed out previously.
“This was the first EB study to meet its primary endpoint and demonstrated a statistically significant acceleration of target wound healing by day 45,” Dr. Murrell said in a press release issued by Amryt Pharma to coincide with the online publication of the trial results.
“In addition, the favorable trends we see with key secondary endpoints such as reduced wound burden, pain, and frequency of dressing changes are considered as being very meaningful for patients,” Dr. Murrell said.
The EASE study was funded by Amryt Research Limited. Dr. Kiritsi reported receiving honoraria or consultation fees from Amryt, RHEACELL GmbH, and Fibrx Derm. She also acknowledged grant or research support from DEBRA International, EB Research Partnership, Fritz-Thyssen Foundation, German Research Foundation, and RHEACELL. Dr. Murrell has ties to Amryt and Amicus and is a co-owner of the patent for topical sirolimus for EB simplex.
A version of this article appeared on Medscape.com.
FROM THE EADV CONGRESS
FDA OKs first ustekinumab biosimilar
The U.S. Food and Drug Administration has approved ustekinumab-auub (Wezlana) as a biosimilar to ustekinumab (Stelara) for the treatment of multiple inflammatory conditions. This is the first approval for a ustekinumab biosimilar in the United States.
Ustekinumab-auub was also granted an interchangeability designation, meaning that, depending on state law, a pharmacist may substitute the biosimilar for the reference product without consulting the prescribing provider.
“Today’s approval exemplifies the FDA’s longstanding commitment to support a competitive marketplace for biological products,” Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval can empower patients by helping to increase access to safe, effective, and high-quality medications at potentially lower cost.”
Ustekinumab, manufactured by Johnson & Johnson, targets interleukin-12 and IL-23 and was first approved in 2009. Ustekinumab-auub was developed by Amgen.
Ustekinumab-auub is approved for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, active psoriatic arthritis, moderate to severely active Crohn’s disease, and moderate to severely active ulcerative colitis. It is also approved for pediatric patients aged 6 years and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and active psoriatic arthritis.
The approval was based on “comprehensive review of scientific evidence,” including “comparisons of the products on an analytical level using an extensive battery of chemical and biological tests and biological assays that confirmed similarity in the structural and functional features of Wezlana and Stelara (including those known to impact safety and efficacy), and comparative human pharmacokinetic data, clinical immunogenicity data, and other clinical safety and effectiveness data,” the FDA said.
Some common side effects of ustekinumab-auub include nasopharyngitis, upper respiratory tract infection, headache, fatigue, and nausea. The most severe side effect of the biosimilar, as with the reference drug ustekinumab, is infection.
The product launch of ustekinumab-auub will be delayed as a part of a settlement of Johnson & Johnson’s lawsuit against Amgen, according to Reuters. The details of the settlement are confidential, but it was stated that the biosimilar would be available by Jan. 1, 2025.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved ustekinumab-auub (Wezlana) as a biosimilar to ustekinumab (Stelara) for the treatment of multiple inflammatory conditions. This is the first approval for a ustekinumab biosimilar in the United States.
Ustekinumab-auub was also granted an interchangeability designation, meaning that, depending on state law, a pharmacist may substitute the biosimilar for the reference product without consulting the prescribing provider.
“Today’s approval exemplifies the FDA’s longstanding commitment to support a competitive marketplace for biological products,” Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval can empower patients by helping to increase access to safe, effective, and high-quality medications at potentially lower cost.”
Ustekinumab, manufactured by Johnson & Johnson, targets interleukin-12 and IL-23 and was first approved in 2009. Ustekinumab-auub was developed by Amgen.
Ustekinumab-auub is approved for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, active psoriatic arthritis, moderate to severely active Crohn’s disease, and moderate to severely active ulcerative colitis. It is also approved for pediatric patients aged 6 years and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and active psoriatic arthritis.
The approval was based on “comprehensive review of scientific evidence,” including “comparisons of the products on an analytical level using an extensive battery of chemical and biological tests and biological assays that confirmed similarity in the structural and functional features of Wezlana and Stelara (including those known to impact safety and efficacy), and comparative human pharmacokinetic data, clinical immunogenicity data, and other clinical safety and effectiveness data,” the FDA said.
Some common side effects of ustekinumab-auub include nasopharyngitis, upper respiratory tract infection, headache, fatigue, and nausea. The most severe side effect of the biosimilar, as with the reference drug ustekinumab, is infection.
The product launch of ustekinumab-auub will be delayed as a part of a settlement of Johnson & Johnson’s lawsuit against Amgen, according to Reuters. The details of the settlement are confidential, but it was stated that the biosimilar would be available by Jan. 1, 2025.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved ustekinumab-auub (Wezlana) as a biosimilar to ustekinumab (Stelara) for the treatment of multiple inflammatory conditions. This is the first approval for a ustekinumab biosimilar in the United States.
Ustekinumab-auub was also granted an interchangeability designation, meaning that, depending on state law, a pharmacist may substitute the biosimilar for the reference product without consulting the prescribing provider.
“Today’s approval exemplifies the FDA’s longstanding commitment to support a competitive marketplace for biological products,” Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval can empower patients by helping to increase access to safe, effective, and high-quality medications at potentially lower cost.”
Ustekinumab, manufactured by Johnson & Johnson, targets interleukin-12 and IL-23 and was first approved in 2009. Ustekinumab-auub was developed by Amgen.
Ustekinumab-auub is approved for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, active psoriatic arthritis, moderate to severely active Crohn’s disease, and moderate to severely active ulcerative colitis. It is also approved for pediatric patients aged 6 years and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and active psoriatic arthritis.
The approval was based on “comprehensive review of scientific evidence,” including “comparisons of the products on an analytical level using an extensive battery of chemical and biological tests and biological assays that confirmed similarity in the structural and functional features of Wezlana and Stelara (including those known to impact safety and efficacy), and comparative human pharmacokinetic data, clinical immunogenicity data, and other clinical safety and effectiveness data,” the FDA said.
Some common side effects of ustekinumab-auub include nasopharyngitis, upper respiratory tract infection, headache, fatigue, and nausea. The most severe side effect of the biosimilar, as with the reference drug ustekinumab, is infection.
The product launch of ustekinumab-auub will be delayed as a part of a settlement of Johnson & Johnson’s lawsuit against Amgen, according to Reuters. The details of the settlement are confidential, but it was stated that the biosimilar would be available by Jan. 1, 2025.
A version of this article first appeared on Medscape.com.
FDA okays drug for Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) in patients as young as age 2 years, the company has announced Vamorolone is a structurally unique steroidal anti-inflammatory drug that potently inhibits proinflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor.
“Corticosteroids have been a first line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others,” Sharon Hesterlee, PhD, chief research officer for the Muscular Dystrophy Association, said in a statement.
The approval of vamorolone “provides people living with Duchenne, and their families, a powerful tool to treat the disease, while limiting some negative side effects associated with corticosteroids,” Dr. Hesterlee added.
The approval was based on data from the phase 2b VISION-DMD study, supplemented with safety information collected from three open-label studies.
Vamorolone was administered at doses ranging from 2-6 mg/kg/d for a period of up to 48 months.
Vamorolone demonstrated efficacy similar to that of traditional corticosteroids, with data suggesting a reduction in adverse events – notably related to bone health, growth trajectory, and behavior.
Vamorolone had received orphan drug status for DMD, as well as fast track and rare pediatric disease designations. It will be made available in the United States by Catalyst Pharmaceuticals.
A version of this article first appeared on Medscape.com .
Duchenne muscular dystrophy (DMD) in patients as young as age 2 years, the company has announced Vamorolone is a structurally unique steroidal anti-inflammatory drug that potently inhibits proinflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor.
“Corticosteroids have been a first line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others,” Sharon Hesterlee, PhD, chief research officer for the Muscular Dystrophy Association, said in a statement.
The approval of vamorolone “provides people living with Duchenne, and their families, a powerful tool to treat the disease, while limiting some negative side effects associated with corticosteroids,” Dr. Hesterlee added.
The approval was based on data from the phase 2b VISION-DMD study, supplemented with safety information collected from three open-label studies.
Vamorolone was administered at doses ranging from 2-6 mg/kg/d for a period of up to 48 months.
Vamorolone demonstrated efficacy similar to that of traditional corticosteroids, with data suggesting a reduction in adverse events – notably related to bone health, growth trajectory, and behavior.
Vamorolone had received orphan drug status for DMD, as well as fast track and rare pediatric disease designations. It will be made available in the United States by Catalyst Pharmaceuticals.
A version of this article first appeared on Medscape.com .
Duchenne muscular dystrophy (DMD) in patients as young as age 2 years, the company has announced Vamorolone is a structurally unique steroidal anti-inflammatory drug that potently inhibits proinflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor.
“Corticosteroids have been a first line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others,” Sharon Hesterlee, PhD, chief research officer for the Muscular Dystrophy Association, said in a statement.
The approval of vamorolone “provides people living with Duchenne, and their families, a powerful tool to treat the disease, while limiting some negative side effects associated with corticosteroids,” Dr. Hesterlee added.
The approval was based on data from the phase 2b VISION-DMD study, supplemented with safety information collected from three open-label studies.
Vamorolone was administered at doses ranging from 2-6 mg/kg/d for a period of up to 48 months.
Vamorolone demonstrated efficacy similar to that of traditional corticosteroids, with data suggesting a reduction in adverse events – notably related to bone health, growth trajectory, and behavior.
Vamorolone had received orphan drug status for DMD, as well as fast track and rare pediatric disease designations. It will be made available in the United States by Catalyst Pharmaceuticals.
A version of this article first appeared on Medscape.com .
Male patients with breast cancer: Special considerations and gender-specific concerns
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.
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.
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.
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.
Guillain-Barré syndrome: Honing treatment strategies
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.”
Compared to what was known about GBS in decades past, neurologists now better understand how and where antibodies attack the nerve; how complement then damages the nodes of Ranvier and paranodes; and how an external attack results in sometimes irreparable internal nerve damage. “We’ve got a string, beginning to end, of understanding the disease,” declared Dr. Lunn.
Understanding of differences in the spectrum of pathology of GBS has led to additional diagnostic categories, said Dr. Lunn. Acute inflammatory demyelinating polyradiculoneuropathy, or typical GBS, represents the most common form in affluent Western nations. A motor variant was recognized in the 1980s; in the mid-1990s, Ho and colleagues described a cohort of patients in China who had acute motor axonal neuropathy and acute motor sensory axonal neuropathy1 – two forms that are particularly common throughout Asia and South America.
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.”
Compared to what was known about GBS in decades past, neurologists now better understand how and where antibodies attack the nerve; how complement then damages the nodes of Ranvier and paranodes; and how an external attack results in sometimes irreparable internal nerve damage. “We’ve got a string, beginning to end, of understanding the disease,” declared Dr. Lunn.
Understanding of differences in the spectrum of pathology of GBS has led to additional diagnostic categories, said Dr. Lunn. Acute inflammatory demyelinating polyradiculoneuropathy, or typical GBS, represents the most common form in affluent Western nations. A motor variant was recognized in the 1980s; in the mid-1990s, Ho and colleagues described a cohort of patients in China who had acute motor axonal neuropathy and acute motor sensory axonal neuropathy1 – two forms that are particularly common throughout Asia and South America.
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.”
Compared to what was known about GBS in decades past, neurologists now better understand how and where antibodies attack the nerve; how complement then damages the nodes of Ranvier and paranodes; and how an external attack results in sometimes irreparable internal nerve damage. “We’ve got a string, beginning to end, of understanding the disease,” declared Dr. Lunn.
Understanding of differences in the spectrum of pathology of GBS has led to additional diagnostic categories, said Dr. Lunn. Acute inflammatory demyelinating polyradiculoneuropathy, or typical GBS, represents the most common form in affluent Western nations. A motor variant was recognized in the 1980s; in the mid-1990s, Ho and colleagues described a cohort of patients in China who had acute motor axonal neuropathy and acute motor sensory axonal neuropathy1 – two forms that are particularly common throughout Asia and South America.
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.