MDedge Neurology

Dr. Jones and Dr. Joans are neurologists in town. I don’t know either one particularly well.

I don’t know their backstory, either, but they seem to have some intense competition going on.

Technically all of us neuros in the area compete with each other, but it’s pretty friendly. There are plenty of patients, and we all get along on the occasions we run into each other at the hospital or Costco or a meeting. Occasionally we call to bounce a case off each other. None of us advertise.

But Jones and Joans have kicked it up a notch. One got an EEG machine, the other got an EEG machine. A few weeks later one got a balance testing gadget, then the other got the same thing. One invested in all kinds of fancy devices to detect concussions, and shortly afterward so did the other one. Within a few months each bought their own Doppler equipment and hired an ultrasound tech. One took out a glossy ad in a local magazine, the next month so had the other. Both point out that they’ve been named on different “best doctor” lists. I assume it’s only a matter of time before each invests in their own MRI.

This kind of thing requires a lot of money to support, so both have jumped into the world of medical liens and hired NPs and PAs to increase patient volume.

I’m sure they both make more money than I ever will, and they can have it.

I don’t need that kind of complexity in my life. I have my own EMG/NCV machine, and beyond that I send all the testing (and complicated EMG/NCVs) to other facilities. I don’t want to figure out how to make payments on all those new gadgets, or hire staff to run them, or learn all the new codes I’d need (I do all my own coding, anyway), or decide if the advertising will pay for itself, or deal with liens.

I’m not even sure I want to be that busy. Obviously, I don’t want to be empty, but I also like having some degree of sanity. Time to review tests, type up notes, return calls ... all the things you have to do on the fly between patients, because if you don’t get them done at the office then you have to do them when you get home. Believe me, I already have enough going on there.

I have no desire to advertise that I’m the best neurologist in town (though I believe I’m the best in my building, since there isn’t another one) or to be the busiest, or to be involved in a game of one-upmanship with the nice group down the street.

If Drs. Jones and Joans want to do that, fine. More power to them.

For me, I’ve chosen simplicity in my practice, and prefer it. Like everyone else I want to earn a living, but I also want to to enjoy my job, and non-job, time as best possible.

I’m willing to trade that for money.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Dr. Jones and Dr. Joans are neurologists in town. I don’t know either one particularly well.

I don’t know their backstory, either, but they seem to have some intense competition going on.

Technically all of us neuros in the area compete with each other, but it’s pretty friendly. There are plenty of patients, and we all get along on the occasions we run into each other at the hospital or Costco or a meeting. Occasionally we call to bounce a case off each other. None of us advertise.

But Jones and Joans have kicked it up a notch. One got an EEG machine, the other got an EEG machine. A few weeks later one got a balance testing gadget, then the other got the same thing. One invested in all kinds of fancy devices to detect concussions, and shortly afterward so did the other one. Within a few months each bought their own Doppler equipment and hired an ultrasound tech. One took out a glossy ad in a local magazine, the next month so had the other. Both point out that they’ve been named on different “best doctor” lists. I assume it’s only a matter of time before each invests in their own MRI.

This kind of thing requires a lot of money to support, so both have jumped into the world of medical liens and hired NPs and PAs to increase patient volume.

I’m sure they both make more money than I ever will, and they can have it.

I don’t need that kind of complexity in my life. I have my own EMG/NCV machine, and beyond that I send all the testing (and complicated EMG/NCVs) to other facilities. I don’t want to figure out how to make payments on all those new gadgets, or hire staff to run them, or learn all the new codes I’d need (I do all my own coding, anyway), or decide if the advertising will pay for itself, or deal with liens.

I’m not even sure I want to be that busy. Obviously, I don’t want to be empty, but I also like having some degree of sanity. Time to review tests, type up notes, return calls ... all the things you have to do on the fly between patients, because if you don’t get them done at the office then you have to do them when you get home. Believe me, I already have enough going on there.

I have no desire to advertise that I’m the best neurologist in town (though I believe I’m the best in my building, since there isn’t another one) or to be the busiest, or to be involved in a game of one-upmanship with the nice group down the street.

If Drs. Jones and Joans want to do that, fine. More power to them.

For me, I’ve chosen simplicity in my practice, and prefer it. Like everyone else I want to earn a living, but I also want to to enjoy my job, and non-job, time as best possible.

I’m willing to trade that for money.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Dr. Jones and Dr. Joans are neurologists in town. I don’t know either one particularly well.

I don’t know their backstory, either, but they seem to have some intense competition going on.

Technically all of us neuros in the area compete with each other, but it’s pretty friendly. There are plenty of patients, and we all get along on the occasions we run into each other at the hospital or Costco or a meeting. Occasionally we call to bounce a case off each other. None of us advertise.

But Jones and Joans have kicked it up a notch. One got an EEG machine, the other got an EEG machine. A few weeks later one got a balance testing gadget, then the other got the same thing. One invested in all kinds of fancy devices to detect concussions, and shortly afterward so did the other one. Within a few months each bought their own Doppler equipment and hired an ultrasound tech. One took out a glossy ad in a local magazine, the next month so had the other. Both point out that they’ve been named on different “best doctor” lists. I assume it’s only a matter of time before each invests in their own MRI.

This kind of thing requires a lot of money to support, so both have jumped into the world of medical liens and hired NPs and PAs to increase patient volume.

I’m sure they both make more money than I ever will, and they can have it.

I don’t need that kind of complexity in my life. I have my own EMG/NCV machine, and beyond that I send all the testing (and complicated EMG/NCVs) to other facilities. I don’t want to figure out how to make payments on all those new gadgets, or hire staff to run them, or learn all the new codes I’d need (I do all my own coding, anyway), or decide if the advertising will pay for itself, or deal with liens.

I’m not even sure I want to be that busy. Obviously, I don’t want to be empty, but I also like having some degree of sanity. Time to review tests, type up notes, return calls ... all the things you have to do on the fly between patients, because if you don’t get them done at the office then you have to do them when you get home. Believe me, I already have enough going on there.

I have no desire to advertise that I’m the best neurologist in town (though I believe I’m the best in my building, since there isn’t another one) or to be the busiest, or to be involved in a game of one-upmanship with the nice group down the street.

If Drs. Jones and Joans want to do that, fine. More power to them.

For me, I’ve chosen simplicity in my practice, and prefer it. Like everyone else I want to earn a living, but I also want to to enjoy my job, and non-job, time as best possible.

I’m willing to trade that for money.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

The first therapy targeted at modifying a mutant gene associated with amyotrophic lateral sclerosis (ALS), approved in early 2023, has offered reassurance that the biology of ALS, when known, is targetable. Historically, the disease has been considered a clinical diagnosis, but the progress in identifying molecular mechanisms is permitting ALS to be understood as a biological entity and suggests rationally targeted therapies will be the way forward following the inadequacy of nonselective drugs.

Despite a narrow indication, the only therapy targeted at an ALS-associated gene so far, SOD1 ALS, supports the premise that the biology of ALS can be modified, according to Christina N. Fournier, MD, an associate professor in the Department of Neurology, Emory University, Atlanta, Georgia.

About 15% of ALS Has An Identifiable Genetic Cause

A family history of ALS is present in about 10% of cases. A genetic cause can be identified in approximately 15%. Cases without an identifiable genetic etiology are considered sporadic. So far, the only approved therapy that modifies the function of a gene associated with ALS is tofersen (Qalsody, Biogen), an antisense oligonucleotide. Tofersen inhibits RNA transcription of the superoxide dismutase 1 (SOD1) gene to decrease production of the SOD1 protein.

This first gene therapy for ALS is a breakthrough, but it is indicated for only a small proportion of ALS patients. Even though SOD1 gene mutations represent the second most common genetic cause of ALS after the C90rf72 gene, the proportion of patients who are candidates for tofersen is low. Efficacy is expected only in about 1% of those with familial ALS and 1% of those with sporadic ALS, or about 2% of all patients with ALS.

The evidence of benefit from a treatment with a specific target has provided the basis for concluding that “we are onto something,” Dr. Fournier said. An expert in ALS, she sees reason for excitement about the prospects in treatment with the growing focus on the underlying pathways of disease rather than the downstream consequences.

“The hope is that new gene-targeted therapies will be developed in the future to treat the broader ALS population,” said Dr. Fournier, explaining that the move toward rationally targeted treatments, whether related to gene mutations or independent molecular pathways of ALS progression, has created excitement in the field.

Numerous Disease Processes Are Potentially Targetable

As treatments are developed to address nongenetic molecular processes that contribute to the risk or progression of ALS, such as neuroinflammation or abnormal protein misfolding and aggregation, individualized treatment is likely to become key. Just as not all genetic cases share mutations in the same gene, the key molecular drivers of disease are likely to differ between patients. If so, it is hoped that biomarkers reflective of this underlying biology can be identified to appropriately target treatments.

“The excitement behind the newer targets in clinical trials is based on both basic science and early clinical data that support treatment based on specific drivers of disease,” Dr. Fournier said.

In 2023 and just prior to the FDA approval of tofersen, a set of expert consensus guidelines were published calling for genetic testing to be offered to all patients with ALS. These recommendations suggested that SOD1, C9orf72, FUS, and TARDBP should be included routinely into the panel of genes evaluated, calling for additional genes to be added as they emerge as potential therapeutic targets.

Even before these guidelines were released, genetic testing was already being offered at many centers with expertise in ALS. The rationale was to differentiate ALS with a genetic etiology from that with a nongenetic etiology, as well as to counsel family members when genetic risk was identified, but genetic testing has now assumed new urgency. In addition to the potential for offering a specific treatment for SOD1-related ALS, patients with other genetic forms of disease might be candidates for genetically focused clinical trials.

Genetic testing should be performed as soon as a diagnosis of ALS is made, according to Dr. Fournier. Although not all patients have accepted genetic testing, particularly in the past when there was no immediate clinical gain from establishing the presence of a genetic mutation, she said there is no longer any controversy about clinical relevance.
 

Genetic Testing Is Key to Genetic Therapies

“We do not want to miss the opportunity to treat patients when we have the chance,” said Dr. Fournier, referring to both the likely advantage of an early start of the approved gene therapy as well as the opportunity to participate in a clinical trial with other gene therapies in development.

Prior to the approval of tofersen, riluzole and edaravone had been the only disease-modifying agents in widespread use, but these drugs are nonspecific. There are no established biomarkers for establishing which patients are most likely to benefit.

In the case of riluzole, a pivotal trial conducted 30 years ago showed a survival benefit relative to placebo at 12 months (74% vs. 58%; P = 0.014). In a retrospective study published in 2022 that evaluated survival in a database of 4778 ALS patients of whom 3446 received riluzole, early diagnosis of ALS and prompt treatment with riluzole was associated with longer survival than delayed treatment. The benefit of edaravone has been validated with clinical measures, such as the revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R).

The retrospective study of riluzole provides the basis for predicting better benefits from disease-modifying therapies if started earlier in the course of ALS. The same premise will be explored with newer therapies that target ALS-associated genes.

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.
 

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.
 

Suggested Reading

Benatar M et al. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4.

Geronimo A et al. Ten Years of Riluzole Use in a Tertiary ALS Clinic. Muscle Nerve. 2022 Jun;65(6):659-666. doi: 10.1002/mus.27541.

Roggenbuck J et al. Evidence-Based Consensus Guidelines for ALS Genetic Testing and Counseling. Ann Clin Transl Neurol. 2023 Nov;10(11):2074-2091. doi: 10.1002/acn3.51895.

The first therapy targeted at modifying a mutant gene associated with amyotrophic lateral sclerosis (ALS), approved in early 2023, has offered reassurance that the biology of ALS, when known, is targetable. Historically, the disease has been considered a clinical diagnosis, but the progress in identifying molecular mechanisms is permitting ALS to be understood as a biological entity and suggests rationally targeted therapies will be the way forward following the inadequacy of nonselective drugs.

Despite a narrow indication, the only therapy targeted at an ALS-associated gene so far, SOD1 ALS, supports the premise that the biology of ALS can be modified, according to Christina N. Fournier, MD, an associate professor in the Department of Neurology, Emory University, Atlanta, Georgia.

About 15% of ALS Has An Identifiable Genetic Cause

A family history of ALS is present in about 10% of cases. A genetic cause can be identified in approximately 15%. Cases without an identifiable genetic etiology are considered sporadic. So far, the only approved therapy that modifies the function of a gene associated with ALS is tofersen (Qalsody, Biogen), an antisense oligonucleotide. Tofersen inhibits RNA transcription of the superoxide dismutase 1 (SOD1) gene to decrease production of the SOD1 protein.

This first gene therapy for ALS is a breakthrough, but it is indicated for only a small proportion of ALS patients. Even though SOD1 gene mutations represent the second most common genetic cause of ALS after the C90rf72 gene, the proportion of patients who are candidates for tofersen is low. Efficacy is expected only in about 1% of those with familial ALS and 1% of those with sporadic ALS, or about 2% of all patients with ALS.

The evidence of benefit from a treatment with a specific target has provided the basis for concluding that “we are onto something,” Dr. Fournier said. An expert in ALS, she sees reason for excitement about the prospects in treatment with the growing focus on the underlying pathways of disease rather than the downstream consequences.

“The hope is that new gene-targeted therapies will be developed in the future to treat the broader ALS population,” said Dr. Fournier, explaining that the move toward rationally targeted treatments, whether related to gene mutations or independent molecular pathways of ALS progression, has created excitement in the field.

Numerous Disease Processes Are Potentially Targetable

As treatments are developed to address nongenetic molecular processes that contribute to the risk or progression of ALS, such as neuroinflammation or abnormal protein misfolding and aggregation, individualized treatment is likely to become key. Just as not all genetic cases share mutations in the same gene, the key molecular drivers of disease are likely to differ between patients. If so, it is hoped that biomarkers reflective of this underlying biology can be identified to appropriately target treatments.

“The excitement behind the newer targets in clinical trials is based on both basic science and early clinical data that support treatment based on specific drivers of disease,” Dr. Fournier said.

In 2023 and just prior to the FDA approval of tofersen, a set of expert consensus guidelines were published calling for genetic testing to be offered to all patients with ALS. These recommendations suggested that SOD1, C9orf72, FUS, and TARDBP should be included routinely into the panel of genes evaluated, calling for additional genes to be added as they emerge as potential therapeutic targets.

Even before these guidelines were released, genetic testing was already being offered at many centers with expertise in ALS. The rationale was to differentiate ALS with a genetic etiology from that with a nongenetic etiology, as well as to counsel family members when genetic risk was identified, but genetic testing has now assumed new urgency. In addition to the potential for offering a specific treatment for SOD1-related ALS, patients with other genetic forms of disease might be candidates for genetically focused clinical trials.

Genetic testing should be performed as soon as a diagnosis of ALS is made, according to Dr. Fournier. Although not all patients have accepted genetic testing, particularly in the past when there was no immediate clinical gain from establishing the presence of a genetic mutation, she said there is no longer any controversy about clinical relevance.
 

Genetic Testing Is Key to Genetic Therapies

“We do not want to miss the opportunity to treat patients when we have the chance,” said Dr. Fournier, referring to both the likely advantage of an early start of the approved gene therapy as well as the opportunity to participate in a clinical trial with other gene therapies in development.

Prior to the approval of tofersen, riluzole and edaravone had been the only disease-modifying agents in widespread use, but these drugs are nonspecific. There are no established biomarkers for establishing which patients are most likely to benefit.

In the case of riluzole, a pivotal trial conducted 30 years ago showed a survival benefit relative to placebo at 12 months (74% vs. 58%; P = 0.014). In a retrospective study published in 2022 that evaluated survival in a database of 4778 ALS patients of whom 3446 received riluzole, early diagnosis of ALS and prompt treatment with riluzole was associated with longer survival than delayed treatment. The benefit of edaravone has been validated with clinical measures, such as the revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R).

The retrospective study of riluzole provides the basis for predicting better benefits from disease-modifying therapies if started earlier in the course of ALS. The same premise will be explored with newer therapies that target ALS-associated genes.

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.
 

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.
 

Suggested Reading

Benatar M et al. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4.

Geronimo A et al. Ten Years of Riluzole Use in a Tertiary ALS Clinic. Muscle Nerve. 2022 Jun;65(6):659-666. doi: 10.1002/mus.27541.

Roggenbuck J et al. Evidence-Based Consensus Guidelines for ALS Genetic Testing and Counseling. Ann Clin Transl Neurol. 2023 Nov;10(11):2074-2091. doi: 10.1002/acn3.51895.

The first therapy targeted at modifying a mutant gene associated with amyotrophic lateral sclerosis (ALS), approved in early 2023, has offered reassurance that the biology of ALS, when known, is targetable. Historically, the disease has been considered a clinical diagnosis, but the progress in identifying molecular mechanisms is permitting ALS to be understood as a biological entity and suggests rationally targeted therapies will be the way forward following the inadequacy of nonselective drugs.

Despite a narrow indication, the only therapy targeted at an ALS-associated gene so far, SOD1 ALS, supports the premise that the biology of ALS can be modified, according to Christina N. Fournier, MD, an associate professor in the Department of Neurology, Emory University, Atlanta, Georgia.

About 15% of ALS Has An Identifiable Genetic Cause

A family history of ALS is present in about 10% of cases. A genetic cause can be identified in approximately 15%. Cases without an identifiable genetic etiology are considered sporadic. So far, the only approved therapy that modifies the function of a gene associated with ALS is tofersen (Qalsody, Biogen), an antisense oligonucleotide. Tofersen inhibits RNA transcription of the superoxide dismutase 1 (SOD1) gene to decrease production of the SOD1 protein.

This first gene therapy for ALS is a breakthrough, but it is indicated for only a small proportion of ALS patients. Even though SOD1 gene mutations represent the second most common genetic cause of ALS after the C90rf72 gene, the proportion of patients who are candidates for tofersen is low. Efficacy is expected only in about 1% of those with familial ALS and 1% of those with sporadic ALS, or about 2% of all patients with ALS.

The evidence of benefit from a treatment with a specific target has provided the basis for concluding that “we are onto something,” Dr. Fournier said. An expert in ALS, she sees reason for excitement about the prospects in treatment with the growing focus on the underlying pathways of disease rather than the downstream consequences.

“The hope is that new gene-targeted therapies will be developed in the future to treat the broader ALS population,” said Dr. Fournier, explaining that the move toward rationally targeted treatments, whether related to gene mutations or independent molecular pathways of ALS progression, has created excitement in the field.

Numerous Disease Processes Are Potentially Targetable

As treatments are developed to address nongenetic molecular processes that contribute to the risk or progression of ALS, such as neuroinflammation or abnormal protein misfolding and aggregation, individualized treatment is likely to become key. Just as not all genetic cases share mutations in the same gene, the key molecular drivers of disease are likely to differ between patients. If so, it is hoped that biomarkers reflective of this underlying biology can be identified to appropriately target treatments.

“The excitement behind the newer targets in clinical trials is based on both basic science and early clinical data that support treatment based on specific drivers of disease,” Dr. Fournier said.

In 2023 and just prior to the FDA approval of tofersen, a set of expert consensus guidelines were published calling for genetic testing to be offered to all patients with ALS. These recommendations suggested that SOD1, C9orf72, FUS, and TARDBP should be included routinely into the panel of genes evaluated, calling for additional genes to be added as they emerge as potential therapeutic targets.

Even before these guidelines were released, genetic testing was already being offered at many centers with expertise in ALS. The rationale was to differentiate ALS with a genetic etiology from that with a nongenetic etiology, as well as to counsel family members when genetic risk was identified, but genetic testing has now assumed new urgency. In addition to the potential for offering a specific treatment for SOD1-related ALS, patients with other genetic forms of disease might be candidates for genetically focused clinical trials.

Genetic testing should be performed as soon as a diagnosis of ALS is made, according to Dr. Fournier. Although not all patients have accepted genetic testing, particularly in the past when there was no immediate clinical gain from establishing the presence of a genetic mutation, she said there is no longer any controversy about clinical relevance.
 

Genetic Testing Is Key to Genetic Therapies

“We do not want to miss the opportunity to treat patients when we have the chance,” said Dr. Fournier, referring to both the likely advantage of an early start of the approved gene therapy as well as the opportunity to participate in a clinical trial with other gene therapies in development.

Prior to the approval of tofersen, riluzole and edaravone had been the only disease-modifying agents in widespread use, but these drugs are nonspecific. There are no established biomarkers for establishing which patients are most likely to benefit.

In the case of riluzole, a pivotal trial conducted 30 years ago showed a survival benefit relative to placebo at 12 months (74% vs. 58%; P = 0.014). In a retrospective study published in 2022 that evaluated survival in a database of 4778 ALS patients of whom 3446 received riluzole, early diagnosis of ALS and prompt treatment with riluzole was associated with longer survival than delayed treatment. The benefit of edaravone has been validated with clinical measures, such as the revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R).

The retrospective study of riluzole provides the basis for predicting better benefits from disease-modifying therapies if started earlier in the course of ALS. The same premise will be explored with newer therapies that target ALS-associated genes.

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.
 

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.
 

Suggested Reading

Benatar M et al. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4.

Geronimo A et al. Ten Years of Riluzole Use in a Tertiary ALS Clinic. Muscle Nerve. 2022 Jun;65(6):659-666. doi: 10.1002/mus.27541.

Roggenbuck J et al. Evidence-Based Consensus Guidelines for ALS Genetic Testing and Counseling. Ann Clin Transl Neurol. 2023 Nov;10(11):2074-2091. doi: 10.1002/acn3.51895.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

COPENHAGEN — Relative to starting on an immunomodulator and then switching to a more potent anti-CD20 monoclonal antibody, the likelihood of long-term accumulation of disability in patients with multiple sclerosis (MS) is significantly lower if the more potent drug is started first, according to extension data out to 6 years.

By the most recent analysis of a phase 3 extension study, there were “fewer disability worsening events and greater likelihood of being progression free among those started on ofatumumab than those started on teriflunomide and switched,” reported Amit Bar-Or, MD, director of the Center of Neuroinflammation and Neurotherapeutics, University of Pennsylvania, Philadelphia.

Stated differently, if ofatumumab is delayed, it never fully compensates for the advantage of better early MS control in treatment-naïve patients, according to Dr. Bar-Or, who presented these data at the 2024 ECTRIMS annual meeting.
 

Anti-CD20 Disability Protection Already Seen in Pivotal Trial

In two phase 3 trials called ASCLEPIOS I and II that were published together several years ago in The New England Journal of Medicine, the anti-CD20 monoclonal antibody ofatumumab reduced the annualized relapse rate (ARR) by half (0.11 vs. 0.22). While ARR was the primary endpoint, ofatumumab was also associated with a 34% reduction (P = .002) in risk of confirmed disability worsening at 3 months (3mCDW) at a medium follow-up of 1.6 years.

After the completion of ASCLEPIOS I and II, the majority of both arms of the study were enrolled in the ALITHIOS extension study. Patients in ofatumumab arm have remained on their initially assigned drug. Patients in the teriflunomide group were switched. Characterized as the delayed ofatumumab group, they have been receiving the same 20-mg, once-monthly subcutaneous (SQ) dose of ofatumumab as those initially assigned to this drug. ALITHIOS will continue to follow both groups until 2028.

Patients have now been followed for up to 6 years. In the latest results presented at ECTRIMS, data were available for 690 patients on continuous treatment and 677 switch patients. Baseline characteristics of the two groups were similar. About half of each group were treatment naive when enrolled in the ASCLEPIOS trials.

Whether compared for 6-month confirmed disability worsening (6mCDW), 6-month progression independent of relapse activity (6mPIRA) or 6-month relapse-associated worsening (6mRAW), disease progression was consistently worse for those with delayed ofatumumab. The differences were most pronounced in those who were treatment naive when started on therapy.
 

Anti-CD20 MAB sustains Disability Protection for up to Years

For those who were treatment naive, the rates of 6mCDW at the most recent follow-up were 16.61% vs 23.74% (P = .033) for continuous and delayed ofatumumab, respectively. For the entire study, these rates were 21.09% versus 24.77%, respectively, which represented a strong trend (P = .063).

The relative rates for 6mPIRA (11.12% vs 16.75%) and 6mRAW (4.26% vs 4.82%) in treatment-naive patients also favored continuous over delayed ofatumumab, and the numerical advantage was also seen with up to 6 years of follow-up in the overall study population for 6mPIRA (15.45% vs 16.56%) and 6mRAW (5.24% vs 5.81%).

Translating these into freedom from disability, Dr. Bar-Or reported that more than 80% (83.4%) of patients on continuous ofatumumab were progression free for up to 6 years, a figure that exceeded the 76.3% free of progression in the delayed ofatumumab group.

On the basis of 6mPIRA, that absence of disability progression neared 90% (88.9%) on continuous ofatumumab relative to 83.3% for delayed ofatumumab.

An advantage for a reduction in disability accumulation for ofatumumab relative to teriflunomide was established at the end of the ASCLEPIOS I and II trial, but the latest follow-up shows that it is “sustained out to 6 years.” The advantage is achieved with no greater cost in adverse events during the early treatment period, according to Dr. Bar-Or, who noted that ofatumumab and teriflunomide were similarly well tolerated in ASCLEPIOS I and II.
 

No New Gd T1 Lesions Observed Over 12 Months

Although other anti-CD20 monoclonal antibodies have also been shown to be highly effective and often more effective than immunomodulators in the first- and second-line treatment of relapsing remitting MS (RRMS), another set of data presented at ECTRIMS 2024 looked specifically at transitioning from intravenous (IV) anti-CD20 drugs to SQ ofatumumab.

In this study, called OLIKOS, 102 RRMS patients who had received either IV ocrelizumab or IV rituximab were followed after transitioning to ofatumumab administered SQ with an autoinjector pen. The primary endpoint was the proportion of patients with no change or a reduction gadolinium-enhancing (Gd) T1 lesions over 12 months of follow-up.

“At month 12, 84 of 84 evaluable patients with evaluable MRI assessments met the primary endpoint,” reported the principal investigator Le Hua, MD, director of the Multiple Sclerosis Program, Cleveland Clinic in Ohio.

At 12 months, there were also no new or enlarging T2 lesions in 98% of patients receiving SQ ofatumumab following the transition from one of the other anti-CD20 IV drugs, but Dr. Hua characterized this as an exploratory endpoint.

The safety and tolerability data during the OLIKOS study was also reassuring with no new or unexpected safety signals for SQ ofatumumab, which has been well tolerated in the phase 3 development program. IgM and IgG levels remained stable over the course of follow-up.

High-efficacy anti-CD20 drugs were once reserved for RRMS patients with highly active disease, but long-term data, such as those generated by the ALITHIOS extension study, suggest greater efficacy with acceptable safety of these agents relative to conventional first-line RRMS therapies. Based on ALITHIOS data, Dr. Bar-Or suggested that early use of the most effective therapy appears to lead to better long-term protection from increased cumulative disability.

Dr. Bar-Or reported financial relationships with Accure, Atara, Biogen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme. Dr. Hua reported financial relationships with Alexion, EMD Serono, Genentech, Horizon, Novartis, and TG Therapeutics.

COPENHAGEN — Relative to starting on an immunomodulator and then switching to a more potent anti-CD20 monoclonal antibody, the likelihood of long-term accumulation of disability in patients with multiple sclerosis (MS) is significantly lower if the more potent drug is started first, according to extension data out to 6 years.

By the most recent analysis of a phase 3 extension study, there were “fewer disability worsening events and greater likelihood of being progression free among those started on ofatumumab than those started on teriflunomide and switched,” reported Amit Bar-Or, MD, director of the Center of Neuroinflammation and Neurotherapeutics, University of Pennsylvania, Philadelphia.

Stated differently, if ofatumumab is delayed, it never fully compensates for the advantage of better early MS control in treatment-naïve patients, according to Dr. Bar-Or, who presented these data at the 2024 ECTRIMS annual meeting.
 

Anti-CD20 Disability Protection Already Seen in Pivotal Trial

In two phase 3 trials called ASCLEPIOS I and II that were published together several years ago in The New England Journal of Medicine, the anti-CD20 monoclonal antibody ofatumumab reduced the annualized relapse rate (ARR) by half (0.11 vs. 0.22). While ARR was the primary endpoint, ofatumumab was also associated with a 34% reduction (P = .002) in risk of confirmed disability worsening at 3 months (3mCDW) at a medium follow-up of 1.6 years.

After the completion of ASCLEPIOS I and II, the majority of both arms of the study were enrolled in the ALITHIOS extension study. Patients in ofatumumab arm have remained on their initially assigned drug. Patients in the teriflunomide group were switched. Characterized as the delayed ofatumumab group, they have been receiving the same 20-mg, once-monthly subcutaneous (SQ) dose of ofatumumab as those initially assigned to this drug. ALITHIOS will continue to follow both groups until 2028.

Patients have now been followed for up to 6 years. In the latest results presented at ECTRIMS, data were available for 690 patients on continuous treatment and 677 switch patients. Baseline characteristics of the two groups were similar. About half of each group were treatment naive when enrolled in the ASCLEPIOS trials.

Whether compared for 6-month confirmed disability worsening (6mCDW), 6-month progression independent of relapse activity (6mPIRA) or 6-month relapse-associated worsening (6mRAW), disease progression was consistently worse for those with delayed ofatumumab. The differences were most pronounced in those who were treatment naive when started on therapy.
 

Anti-CD20 MAB sustains Disability Protection for up to Years

For those who were treatment naive, the rates of 6mCDW at the most recent follow-up were 16.61% vs 23.74% (P = .033) for continuous and delayed ofatumumab, respectively. For the entire study, these rates were 21.09% versus 24.77%, respectively, which represented a strong trend (P = .063).

The relative rates for 6mPIRA (11.12% vs 16.75%) and 6mRAW (4.26% vs 4.82%) in treatment-naive patients also favored continuous over delayed ofatumumab, and the numerical advantage was also seen with up to 6 years of follow-up in the overall study population for 6mPIRA (15.45% vs 16.56%) and 6mRAW (5.24% vs 5.81%).

Translating these into freedom from disability, Dr. Bar-Or reported that more than 80% (83.4%) of patients on continuous ofatumumab were progression free for up to 6 years, a figure that exceeded the 76.3% free of progression in the delayed ofatumumab group.

On the basis of 6mPIRA, that absence of disability progression neared 90% (88.9%) on continuous ofatumumab relative to 83.3% for delayed ofatumumab.

An advantage for a reduction in disability accumulation for ofatumumab relative to teriflunomide was established at the end of the ASCLEPIOS I and II trial, but the latest follow-up shows that it is “sustained out to 6 years.” The advantage is achieved with no greater cost in adverse events during the early treatment period, according to Dr. Bar-Or, who noted that ofatumumab and teriflunomide were similarly well tolerated in ASCLEPIOS I and II.
 

No New Gd T1 Lesions Observed Over 12 Months

Although other anti-CD20 monoclonal antibodies have also been shown to be highly effective and often more effective than immunomodulators in the first- and second-line treatment of relapsing remitting MS (RRMS), another set of data presented at ECTRIMS 2024 looked specifically at transitioning from intravenous (IV) anti-CD20 drugs to SQ ofatumumab.

In this study, called OLIKOS, 102 RRMS patients who had received either IV ocrelizumab or IV rituximab were followed after transitioning to ofatumumab administered SQ with an autoinjector pen. The primary endpoint was the proportion of patients with no change or a reduction gadolinium-enhancing (Gd) T1 lesions over 12 months of follow-up.

“At month 12, 84 of 84 evaluable patients with evaluable MRI assessments met the primary endpoint,” reported the principal investigator Le Hua, MD, director of the Multiple Sclerosis Program, Cleveland Clinic in Ohio.

At 12 months, there were also no new or enlarging T2 lesions in 98% of patients receiving SQ ofatumumab following the transition from one of the other anti-CD20 IV drugs, but Dr. Hua characterized this as an exploratory endpoint.

The safety and tolerability data during the OLIKOS study was also reassuring with no new or unexpected safety signals for SQ ofatumumab, which has been well tolerated in the phase 3 development program. IgM and IgG levels remained stable over the course of follow-up.

High-efficacy anti-CD20 drugs were once reserved for RRMS patients with highly active disease, but long-term data, such as those generated by the ALITHIOS extension study, suggest greater efficacy with acceptable safety of these agents relative to conventional first-line RRMS therapies. Based on ALITHIOS data, Dr. Bar-Or suggested that early use of the most effective therapy appears to lead to better long-term protection from increased cumulative disability.

Dr. Bar-Or reported financial relationships with Accure, Atara, Biogen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme. Dr. Hua reported financial relationships with Alexion, EMD Serono, Genentech, Horizon, Novartis, and TG Therapeutics.

COPENHAGEN — Relative to starting on an immunomodulator and then switching to a more potent anti-CD20 monoclonal antibody, the likelihood of long-term accumulation of disability in patients with multiple sclerosis (MS) is significantly lower if the more potent drug is started first, according to extension data out to 6 years.

By the most recent analysis of a phase 3 extension study, there were “fewer disability worsening events and greater likelihood of being progression free among those started on ofatumumab than those started on teriflunomide and switched,” reported Amit Bar-Or, MD, director of the Center of Neuroinflammation and Neurotherapeutics, University of Pennsylvania, Philadelphia.

Stated differently, if ofatumumab is delayed, it never fully compensates for the advantage of better early MS control in treatment-naïve patients, according to Dr. Bar-Or, who presented these data at the 2024 ECTRIMS annual meeting.
 

Anti-CD20 Disability Protection Already Seen in Pivotal Trial

In two phase 3 trials called ASCLEPIOS I and II that were published together several years ago in The New England Journal of Medicine, the anti-CD20 monoclonal antibody ofatumumab reduced the annualized relapse rate (ARR) by half (0.11 vs. 0.22). While ARR was the primary endpoint, ofatumumab was also associated with a 34% reduction (P = .002) in risk of confirmed disability worsening at 3 months (3mCDW) at a medium follow-up of 1.6 years.

After the completion of ASCLEPIOS I and II, the majority of both arms of the study were enrolled in the ALITHIOS extension study. Patients in ofatumumab arm have remained on their initially assigned drug. Patients in the teriflunomide group were switched. Characterized as the delayed ofatumumab group, they have been receiving the same 20-mg, once-monthly subcutaneous (SQ) dose of ofatumumab as those initially assigned to this drug. ALITHIOS will continue to follow both groups until 2028.

Patients have now been followed for up to 6 years. In the latest results presented at ECTRIMS, data were available for 690 patients on continuous treatment and 677 switch patients. Baseline characteristics of the two groups were similar. About half of each group were treatment naive when enrolled in the ASCLEPIOS trials.

Whether compared for 6-month confirmed disability worsening (6mCDW), 6-month progression independent of relapse activity (6mPIRA) or 6-month relapse-associated worsening (6mRAW), disease progression was consistently worse for those with delayed ofatumumab. The differences were most pronounced in those who were treatment naive when started on therapy.
 

Anti-CD20 MAB sustains Disability Protection for up to Years

For those who were treatment naive, the rates of 6mCDW at the most recent follow-up were 16.61% vs 23.74% (P = .033) for continuous and delayed ofatumumab, respectively. For the entire study, these rates were 21.09% versus 24.77%, respectively, which represented a strong trend (P = .063).

The relative rates for 6mPIRA (11.12% vs 16.75%) and 6mRAW (4.26% vs 4.82%) in treatment-naive patients also favored continuous over delayed ofatumumab, and the numerical advantage was also seen with up to 6 years of follow-up in the overall study population for 6mPIRA (15.45% vs 16.56%) and 6mRAW (5.24% vs 5.81%).

Translating these into freedom from disability, Dr. Bar-Or reported that more than 80% (83.4%) of patients on continuous ofatumumab were progression free for up to 6 years, a figure that exceeded the 76.3% free of progression in the delayed ofatumumab group.

On the basis of 6mPIRA, that absence of disability progression neared 90% (88.9%) on continuous ofatumumab relative to 83.3% for delayed ofatumumab.

An advantage for a reduction in disability accumulation for ofatumumab relative to teriflunomide was established at the end of the ASCLEPIOS I and II trial, but the latest follow-up shows that it is “sustained out to 6 years.” The advantage is achieved with no greater cost in adverse events during the early treatment period, according to Dr. Bar-Or, who noted that ofatumumab and teriflunomide were similarly well tolerated in ASCLEPIOS I and II.
 

No New Gd T1 Lesions Observed Over 12 Months

Although other anti-CD20 monoclonal antibodies have also been shown to be highly effective and often more effective than immunomodulators in the first- and second-line treatment of relapsing remitting MS (RRMS), another set of data presented at ECTRIMS 2024 looked specifically at transitioning from intravenous (IV) anti-CD20 drugs to SQ ofatumumab.

In this study, called OLIKOS, 102 RRMS patients who had received either IV ocrelizumab or IV rituximab were followed after transitioning to ofatumumab administered SQ with an autoinjector pen. The primary endpoint was the proportion of patients with no change or a reduction gadolinium-enhancing (Gd) T1 lesions over 12 months of follow-up.

“At month 12, 84 of 84 evaluable patients with evaluable MRI assessments met the primary endpoint,” reported the principal investigator Le Hua, MD, director of the Multiple Sclerosis Program, Cleveland Clinic in Ohio.

At 12 months, there were also no new or enlarging T2 lesions in 98% of patients receiving SQ ofatumumab following the transition from one of the other anti-CD20 IV drugs, but Dr. Hua characterized this as an exploratory endpoint.

The safety and tolerability data during the OLIKOS study was also reassuring with no new or unexpected safety signals for SQ ofatumumab, which has been well tolerated in the phase 3 development program. IgM and IgG levels remained stable over the course of follow-up.

High-efficacy anti-CD20 drugs were once reserved for RRMS patients with highly active disease, but long-term data, such as those generated by the ALITHIOS extension study, suggest greater efficacy with acceptable safety of these agents relative to conventional first-line RRMS therapies. Based on ALITHIOS data, Dr. Bar-Or suggested that early use of the most effective therapy appears to lead to better long-term protection from increased cumulative disability.

Dr. Bar-Or reported financial relationships with Accure, Atara, Biogen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme. Dr. Hua reported financial relationships with Alexion, EMD Serono, Genentech, Horizon, Novartis, and TG Therapeutics.

The Food and Drug Administration (FDA) plans to scrutinize the safety and efficacy of lab-developed tests — those designed, manufactured, and used in a single laboratory — far more thoroughly in the future.

Under a rule finalized in April, the FDA will treat facilities that develop and use lab tests as manufacturers and regulate tests as medical devices. That means that most lab tests will need an FDA review before going on sale.

The FDA will also impose new quality standards, requiring test manufacturers to report adverse events and create a registry of lab tests under the new rule, which will be phased in over 4 years.

FDA officials have been concerned for years about the reliability of commercial lab tests, which have ballooned into a multibillion-dollar industry.

Consumer groups have long urged the FDA to regulate lab tests more strictly, arguing that the lack of scrutiny allows doctors and patients to be exploited by bad actors such as Theranos, which falsely claimed that its tests could diagnose multiple diseases with a single drop of blood.

“When it comes to some of these tests that doctors are recommending for patients, many doctors are just crossing their fingers and relying on the representation of the company because nobody is checking” to verify a manufacturer’s claims, said Joshua Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
 

Nearly 12,000 Labs Making Medical Tests

Although the FDA estimates there are nearly 12,000 labs manufacturing medical tests, agency officials said they don’t know how many tests are being marketed. The FDA already requires that home test kits marketed directly to consumers, such as those used to detect COVID-19, get clearance from the agency before being sold.

“There’s plenty of time for industry to get its act together to develop the data that it might need to make a premarket application,” said Peter Lurie, MD, PhD, a former associate commissioner at the FDA. In 2015, Dr. Lurie led a report outlining some of the dangers of unregulated lab tests.

For the average physician who orders lab tests, nothing is going to immediately change because of the final rule, said Dr. Lurie, now president of the Center for Science in the Public Interest, a nonprofit consumer watchdog.

“Tomorrow, this will look just the same as it does today,” Dr. Lurie said. “For the next 3 years, the companies will be scurrying behind the scenes to comply with the early stages of implementation. But most of that will be invisible to the average practitioner.”

Dr. Lurie predicted the FDA will focus its scrutiny on tests that pose the greatest potential risk to patients, such as ones used to diagnose serious diseases or guide treatment for life-threatening conditions. “The least significant tests will likely get very limited, if any, scrutiny,” said Dr. Lurie, adding that the FDA will likely issue guidance about how it plans to define low- and high-risk tests. “My suspicion is that it will be probably a small minority of products that are subject to full premarket approval.”
 

Lab Industry Groups Push Back

But imposing new rules with the potential to affect an industry’s bottom line is no easy task.

The American Clinical Laboratory Association, which represents the lab industry, said in a statement that the FDA rule will “limit access to scores of critical tests, increase healthcare costs, and undermine innovation in new diagnostics.” Another industry group, the Association for Molecular Pathology, has warned of “significant and harmful disruption to laboratory medicine.”

The two associations have filed separate lawsuits, charging that the FDA overstepped the authority granted by Congress. In their lawsuits, groups claim that lab tests are professional services, not manufactured products. The groups noted that the Centers for Medicare & Medicaid Services (CMS) already inspects lab facilities. CMS does not assess the tests’ quality or reliability.

A recent Supreme Court decision could make those lawsuits more likely to succeed, said David Simon, JD, LLM, PhD, an assistant professor of law at the Northeastern University School of Law, Boston, Massachusetts.

In the case of Loper Bright Enterprises v. Raimondo, decided in June, justices overturned a long-standing precedent known as Chevron deference, which required courts to defer to federal agencies when interpreting ambiguous laws. That means that courts no longer have to accept the FDA’s definition of a device, Dr. Simon said.

“Because judges may have more active roles in defining agency authority, federal agencies may have correspondingly less robust roles in policymaking,” Dr. Simon wrote in an editorial coauthored with Michael J. Young, MD, MPhil, of Harvard Medical School, Boston.

The Supreme Court ruling could pressure Congress to more clearly define FDA’s ruling in regulating lab tests, Dr. Simon and Dr. Young wrote.

Members of Congress first introduced a bill to clarify the FDA’s role in regulating lab tests, called the VALID Act, in 2020. The bill stalled and, despite efforts to revive it, still hasn’t passed.

FDA officials have said they remain “open to working with Congress,” noting that any future legislation about lab-developed tests would supersede their current policy.

In an interview, Dr. Simon noted the FDA significantly narrowed the scope of the final rule in response to comments from critics who objected to an earlier version of the policy proposed in 2023. The final rule carves out several categories of tests that won’t need to apply for “premarket review.”

Notably, a “grandfather clause” will allow some lab tests already on the market to continue being sold without undergoing FDA’s premarket review process. In explaining the exemption, FDA officials said they did not want doctors and patients to lose access to tests on which they rely. But Dr. Lurie noted that because the FDA views all these tests as under its jurisdiction, the agency could opt to take a closer look “at a very old device that is causing a problem today.”

The FDA also will exempt tests approved by New York State’s Clinical Laboratory Evaluation Program, which conducts its own stringent reviews. And the FDA will continue to allow hospitals to develop tests for patients within their healthcare system without going through the FDA approval process, if no FDA-approved tests are available.

Hospital-based tests play a critical role in treating infectious diseases, said Amesh Adalja, MD, an infectious diseases specialist and senior scholar at the Johns Hopkins Center for Health Security. For example, a large research hospital treating a patient with cytomegalovirus may need to develop its own test to determine whether the infection is resistant to antiviral drugs, Dr. Adalja said.

“With novel infectious disease outbreaks, researchers are able to move quickly to make diagnostic tests months and months before commercial laboratories are able to get through regulatory processes,” Dr. Adalja said.

To help scientists respond quickly to emergencies, the FDA published special guidance for labs that develop unauthorized lab tests for disease outbreaks.

Medical groups such as the American Hospital Association and Infectious Diseases Society of America remain concerned about the burden of complying with new regulations.

“Many vital tests developed in hospitals and health systems may be subjected to unnecessary and costly paperwork,” said Stacey Hughes, executive vice president of the American Hospital Association, in a statement.

Other groups, such as the American Society of Clinical Oncology, praised the new FDA policy. In comments submitted to the FDA in 2023, the cancer group said it “emphatically supports” requiring lab tests to undergo FDA review.

“We appreciate FDA action to modernize oversight of these tests and are hopeful this rule will increase focus on the need to balance rapid diagnostic innovation with patient safety and access” Everett Vokes, MD, the group’s board chair, said in a statement released after the FDA’s final rule was published.

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

The Food and Drug Administration (FDA) plans to scrutinize the safety and efficacy of lab-developed tests — those designed, manufactured, and used in a single laboratory — far more thoroughly in the future.

Under a rule finalized in April, the FDA will treat facilities that develop and use lab tests as manufacturers and regulate tests as medical devices. That means that most lab tests will need an FDA review before going on sale.

The FDA will also impose new quality standards, requiring test manufacturers to report adverse events and create a registry of lab tests under the new rule, which will be phased in over 4 years.

FDA officials have been concerned for years about the reliability of commercial lab tests, which have ballooned into a multibillion-dollar industry.

Consumer groups have long urged the FDA to regulate lab tests more strictly, arguing that the lack of scrutiny allows doctors and patients to be exploited by bad actors such as Theranos, which falsely claimed that its tests could diagnose multiple diseases with a single drop of blood.

“When it comes to some of these tests that doctors are recommending for patients, many doctors are just crossing their fingers and relying on the representation of the company because nobody is checking” to verify a manufacturer’s claims, said Joshua Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
 

Nearly 12,000 Labs Making Medical Tests

Although the FDA estimates there are nearly 12,000 labs manufacturing medical tests, agency officials said they don’t know how many tests are being marketed. The FDA already requires that home test kits marketed directly to consumers, such as those used to detect COVID-19, get clearance from the agency before being sold.

“There’s plenty of time for industry to get its act together to develop the data that it might need to make a premarket application,” said Peter Lurie, MD, PhD, a former associate commissioner at the FDA. In 2015, Dr. Lurie led a report outlining some of the dangers of unregulated lab tests.

For the average physician who orders lab tests, nothing is going to immediately change because of the final rule, said Dr. Lurie, now president of the Center for Science in the Public Interest, a nonprofit consumer watchdog.

“Tomorrow, this will look just the same as it does today,” Dr. Lurie said. “For the next 3 years, the companies will be scurrying behind the scenes to comply with the early stages of implementation. But most of that will be invisible to the average practitioner.”

Dr. Lurie predicted the FDA will focus its scrutiny on tests that pose the greatest potential risk to patients, such as ones used to diagnose serious diseases or guide treatment for life-threatening conditions. “The least significant tests will likely get very limited, if any, scrutiny,” said Dr. Lurie, adding that the FDA will likely issue guidance about how it plans to define low- and high-risk tests. “My suspicion is that it will be probably a small minority of products that are subject to full premarket approval.”
 

Lab Industry Groups Push Back

But imposing new rules with the potential to affect an industry’s bottom line is no easy task.

The American Clinical Laboratory Association, which represents the lab industry, said in a statement that the FDA rule will “limit access to scores of critical tests, increase healthcare costs, and undermine innovation in new diagnostics.” Another industry group, the Association for Molecular Pathology, has warned of “significant and harmful disruption to laboratory medicine.”

The two associations have filed separate lawsuits, charging that the FDA overstepped the authority granted by Congress. In their lawsuits, groups claim that lab tests are professional services, not manufactured products. The groups noted that the Centers for Medicare & Medicaid Services (CMS) already inspects lab facilities. CMS does not assess the tests’ quality or reliability.

A recent Supreme Court decision could make those lawsuits more likely to succeed, said David Simon, JD, LLM, PhD, an assistant professor of law at the Northeastern University School of Law, Boston, Massachusetts.

In the case of Loper Bright Enterprises v. Raimondo, decided in June, justices overturned a long-standing precedent known as Chevron deference, which required courts to defer to federal agencies when interpreting ambiguous laws. That means that courts no longer have to accept the FDA’s definition of a device, Dr. Simon said.

“Because judges may have more active roles in defining agency authority, federal agencies may have correspondingly less robust roles in policymaking,” Dr. Simon wrote in an editorial coauthored with Michael J. Young, MD, MPhil, of Harvard Medical School, Boston.

The Supreme Court ruling could pressure Congress to more clearly define FDA’s ruling in regulating lab tests, Dr. Simon and Dr. Young wrote.

Members of Congress first introduced a bill to clarify the FDA’s role in regulating lab tests, called the VALID Act, in 2020. The bill stalled and, despite efforts to revive it, still hasn’t passed.

FDA officials have said they remain “open to working with Congress,” noting that any future legislation about lab-developed tests would supersede their current policy.

In an interview, Dr. Simon noted the FDA significantly narrowed the scope of the final rule in response to comments from critics who objected to an earlier version of the policy proposed in 2023. The final rule carves out several categories of tests that won’t need to apply for “premarket review.”

Notably, a “grandfather clause” will allow some lab tests already on the market to continue being sold without undergoing FDA’s premarket review process. In explaining the exemption, FDA officials said they did not want doctors and patients to lose access to tests on which they rely. But Dr. Lurie noted that because the FDA views all these tests as under its jurisdiction, the agency could opt to take a closer look “at a very old device that is causing a problem today.”

The FDA also will exempt tests approved by New York State’s Clinical Laboratory Evaluation Program, which conducts its own stringent reviews. And the FDA will continue to allow hospitals to develop tests for patients within their healthcare system without going through the FDA approval process, if no FDA-approved tests are available.

Hospital-based tests play a critical role in treating infectious diseases, said Amesh Adalja, MD, an infectious diseases specialist and senior scholar at the Johns Hopkins Center for Health Security. For example, a large research hospital treating a patient with cytomegalovirus may need to develop its own test to determine whether the infection is resistant to antiviral drugs, Dr. Adalja said.

“With novel infectious disease outbreaks, researchers are able to move quickly to make diagnostic tests months and months before commercial laboratories are able to get through regulatory processes,” Dr. Adalja said.

To help scientists respond quickly to emergencies, the FDA published special guidance for labs that develop unauthorized lab tests for disease outbreaks.

Medical groups such as the American Hospital Association and Infectious Diseases Society of America remain concerned about the burden of complying with new regulations.

“Many vital tests developed in hospitals and health systems may be subjected to unnecessary and costly paperwork,” said Stacey Hughes, executive vice president of the American Hospital Association, in a statement.

Other groups, such as the American Society of Clinical Oncology, praised the new FDA policy. In comments submitted to the FDA in 2023, the cancer group said it “emphatically supports” requiring lab tests to undergo FDA review.

“We appreciate FDA action to modernize oversight of these tests and are hopeful this rule will increase focus on the need to balance rapid diagnostic innovation with patient safety and access” Everett Vokes, MD, the group’s board chair, said in a statement released after the FDA’s final rule was published.

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

The Food and Drug Administration (FDA) plans to scrutinize the safety and efficacy of lab-developed tests — those designed, manufactured, and used in a single laboratory — far more thoroughly in the future.

Under a rule finalized in April, the FDA will treat facilities that develop and use lab tests as manufacturers and regulate tests as medical devices. That means that most lab tests will need an FDA review before going on sale.

The FDA will also impose new quality standards, requiring test manufacturers to report adverse events and create a registry of lab tests under the new rule, which will be phased in over 4 years.

FDA officials have been concerned for years about the reliability of commercial lab tests, which have ballooned into a multibillion-dollar industry.

Consumer groups have long urged the FDA to regulate lab tests more strictly, arguing that the lack of scrutiny allows doctors and patients to be exploited by bad actors such as Theranos, which falsely claimed that its tests could diagnose multiple diseases with a single drop of blood.

“When it comes to some of these tests that doctors are recommending for patients, many doctors are just crossing their fingers and relying on the representation of the company because nobody is checking” to verify a manufacturer’s claims, said Joshua Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
 

Nearly 12,000 Labs Making Medical Tests

Although the FDA estimates there are nearly 12,000 labs manufacturing medical tests, agency officials said they don’t know how many tests are being marketed. The FDA already requires that home test kits marketed directly to consumers, such as those used to detect COVID-19, get clearance from the agency before being sold.

“There’s plenty of time for industry to get its act together to develop the data that it might need to make a premarket application,” said Peter Lurie, MD, PhD, a former associate commissioner at the FDA. In 2015, Dr. Lurie led a report outlining some of the dangers of unregulated lab tests.

For the average physician who orders lab tests, nothing is going to immediately change because of the final rule, said Dr. Lurie, now president of the Center for Science in the Public Interest, a nonprofit consumer watchdog.

“Tomorrow, this will look just the same as it does today,” Dr. Lurie said. “For the next 3 years, the companies will be scurrying behind the scenes to comply with the early stages of implementation. But most of that will be invisible to the average practitioner.”

Dr. Lurie predicted the FDA will focus its scrutiny on tests that pose the greatest potential risk to patients, such as ones used to diagnose serious diseases or guide treatment for life-threatening conditions. “The least significant tests will likely get very limited, if any, scrutiny,” said Dr. Lurie, adding that the FDA will likely issue guidance about how it plans to define low- and high-risk tests. “My suspicion is that it will be probably a small minority of products that are subject to full premarket approval.”
 

Lab Industry Groups Push Back

But imposing new rules with the potential to affect an industry’s bottom line is no easy task.

The American Clinical Laboratory Association, which represents the lab industry, said in a statement that the FDA rule will “limit access to scores of critical tests, increase healthcare costs, and undermine innovation in new diagnostics.” Another industry group, the Association for Molecular Pathology, has warned of “significant and harmful disruption to laboratory medicine.”

The two associations have filed separate lawsuits, charging that the FDA overstepped the authority granted by Congress. In their lawsuits, groups claim that lab tests are professional services, not manufactured products. The groups noted that the Centers for Medicare & Medicaid Services (CMS) already inspects lab facilities. CMS does not assess the tests’ quality or reliability.

A recent Supreme Court decision could make those lawsuits more likely to succeed, said David Simon, JD, LLM, PhD, an assistant professor of law at the Northeastern University School of Law, Boston, Massachusetts.

In the case of Loper Bright Enterprises v. Raimondo, decided in June, justices overturned a long-standing precedent known as Chevron deference, which required courts to defer to federal agencies when interpreting ambiguous laws. That means that courts no longer have to accept the FDA’s definition of a device, Dr. Simon said.

“Because judges may have more active roles in defining agency authority, federal agencies may have correspondingly less robust roles in policymaking,” Dr. Simon wrote in an editorial coauthored with Michael J. Young, MD, MPhil, of Harvard Medical School, Boston.

The Supreme Court ruling could pressure Congress to more clearly define FDA’s ruling in regulating lab tests, Dr. Simon and Dr. Young wrote.

Members of Congress first introduced a bill to clarify the FDA’s role in regulating lab tests, called the VALID Act, in 2020. The bill stalled and, despite efforts to revive it, still hasn’t passed.

FDA officials have said they remain “open to working with Congress,” noting that any future legislation about lab-developed tests would supersede their current policy.

In an interview, Dr. Simon noted the FDA significantly narrowed the scope of the final rule in response to comments from critics who objected to an earlier version of the policy proposed in 2023. The final rule carves out several categories of tests that won’t need to apply for “premarket review.”

Notably, a “grandfather clause” will allow some lab tests already on the market to continue being sold without undergoing FDA’s premarket review process. In explaining the exemption, FDA officials said they did not want doctors and patients to lose access to tests on which they rely. But Dr. Lurie noted that because the FDA views all these tests as under its jurisdiction, the agency could opt to take a closer look “at a very old device that is causing a problem today.”

The FDA also will exempt tests approved by New York State’s Clinical Laboratory Evaluation Program, which conducts its own stringent reviews. And the FDA will continue to allow hospitals to develop tests for patients within their healthcare system without going through the FDA approval process, if no FDA-approved tests are available.

Hospital-based tests play a critical role in treating infectious diseases, said Amesh Adalja, MD, an infectious diseases specialist and senior scholar at the Johns Hopkins Center for Health Security. For example, a large research hospital treating a patient with cytomegalovirus may need to develop its own test to determine whether the infection is resistant to antiviral drugs, Dr. Adalja said.

“With novel infectious disease outbreaks, researchers are able to move quickly to make diagnostic tests months and months before commercial laboratories are able to get through regulatory processes,” Dr. Adalja said.

To help scientists respond quickly to emergencies, the FDA published special guidance for labs that develop unauthorized lab tests for disease outbreaks.

Medical groups such as the American Hospital Association and Infectious Diseases Society of America remain concerned about the burden of complying with new regulations.

“Many vital tests developed in hospitals and health systems may be subjected to unnecessary and costly paperwork,” said Stacey Hughes, executive vice president of the American Hospital Association, in a statement.

Other groups, such as the American Society of Clinical Oncology, praised the new FDA policy. In comments submitted to the FDA in 2023, the cancer group said it “emphatically supports” requiring lab tests to undergo FDA review.

“We appreciate FDA action to modernize oversight of these tests and are hopeful this rule will increase focus on the need to balance rapid diagnostic innovation with patient safety and access” Everett Vokes, MD, the group’s board chair, said in a statement released after the FDA’s final rule was published.

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

TOPLINE:

Diabetes and prediabetes are associated with accelerated brain aging with brain age gaps of 2.29 and 0.50 years, respectively. This association is more pronounced in men and those with poor cardiometabolic health but may be mitigated by a healthy lifestyle.

METHODOLOGY:

• Diabetes is a known risk factor for cognitive impairment, dementia, and global brain atrophy but conflicting results have been reported for prediabetes, and it’s unknown whether a healthy lifestyle can counteract the negative impact of prediabetes.
• Researchers examined the cross-sectional and longitudinal relationship between hyperglycemia and brain aging, as well as the potential mitigating effect of a healthy lifestyle in 31,229 dementia-free adults (mean age, 54.8 years; 53% women) from the UK Biobank, including 13,518 participants with prediabetes and 1149 with diabetes.
• The glycemic status of the participants was determined by their medical history, medication use, and A1c levels.
• The brain age gap was calculated as a difference between chronologic age and brain age estimated from MRI data from six modalities vs several hundred brain MRI phenotypes that were modeled from a subset of healthy individuals.
• The role of sex, cardiometabolic risk factors, and a healthy lifestyle and their association with brain age was also explored, with a healthy lifestyle defined as never smoking, no or light or moderate alcohol consumption, and high physical activity.

TAKEAWAY:

• Prediabetes and diabetes were associated with a higher brain age gap than normoglycemia (beta-coefficient, 0.22 and 2.01; 95% CI, 0.10-0.34 and 1.70-2.32, respectively), and diabetes was more pronounced in men vs women and those with a higher vs lower burden of cardiometabolic risk factors.
• The brain ages of those with prediabetes and diabetes were 0.50 years and 2.29 years older on average than their respective chronologic ages.
• In an exploratory longitudinal analysis of the 2414 participants with two brain MRI scans, diabetes was linked to a 0.27-year annual increase in the brain age gap, and higher A1c, but not prediabetes, was associated with a significant increase in brain age gap.
• A healthy lifestyle attenuated the association between diabetes and a higher brain age gap (P = .003), reducing it by 1.68 years, also with a significant interaction between glycemic status and lifestyle.

IN PRACTICE:

“Our findings highlight diabetes and prediabetes as ideal targets for lifestyle-based interventions to promote brain health,” the authors wrote.

SOURCE:

This study, led by Abigail Dove, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, was published online in Diabetes Care.

LIMITATIONS:

The generalizability of the findings was limited due to a healthy volunteer bias in the UK Biobank. A high proportion of missing data prevented the inclusion of diet in the healthy lifestyle construct. Reverse causality may be possible as an older brain may contribute to the development of prediabetes by making it more difficult to manage medical conditions and adhere to a healthy lifestyle. A1c levels were measured only at baseline, preventing the assessment of changes in glycemic control over time.

DISCLOSURES:

The authors reported receiving funding from the Swedish Research Council; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Board of Research; Riksbankens Jubileumsfond; Marianne and Marcus Wallenberg Foundation; Alzheimerfonden; and Demensfonden. They declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Diabetes and prediabetes are associated with accelerated brain aging with brain age gaps of 2.29 and 0.50 years, respectively. This association is more pronounced in men and those with poor cardiometabolic health but may be mitigated by a healthy lifestyle.

METHODOLOGY:

• Diabetes is a known risk factor for cognitive impairment, dementia, and global brain atrophy but conflicting results have been reported for prediabetes, and it’s unknown whether a healthy lifestyle can counteract the negative impact of prediabetes.
• Researchers examined the cross-sectional and longitudinal relationship between hyperglycemia and brain aging, as well as the potential mitigating effect of a healthy lifestyle in 31,229 dementia-free adults (mean age, 54.8 years; 53% women) from the UK Biobank, including 13,518 participants with prediabetes and 1149 with diabetes.
• The glycemic status of the participants was determined by their medical history, medication use, and A1c levels.
• The brain age gap was calculated as a difference between chronologic age and brain age estimated from MRI data from six modalities vs several hundred brain MRI phenotypes that were modeled from a subset of healthy individuals.
• The role of sex, cardiometabolic risk factors, and a healthy lifestyle and their association with brain age was also explored, with a healthy lifestyle defined as never smoking, no or light or moderate alcohol consumption, and high physical activity.

TAKEAWAY:

• Prediabetes and diabetes were associated with a higher brain age gap than normoglycemia (beta-coefficient, 0.22 and 2.01; 95% CI, 0.10-0.34 and 1.70-2.32, respectively), and diabetes was more pronounced in men vs women and those with a higher vs lower burden of cardiometabolic risk factors.
• The brain ages of those with prediabetes and diabetes were 0.50 years and 2.29 years older on average than their respective chronologic ages.
• In an exploratory longitudinal analysis of the 2414 participants with two brain MRI scans, diabetes was linked to a 0.27-year annual increase in the brain age gap, and higher A1c, but not prediabetes, was associated with a significant increase in brain age gap.
• A healthy lifestyle attenuated the association between diabetes and a higher brain age gap (P = .003), reducing it by 1.68 years, also with a significant interaction between glycemic status and lifestyle.

IN PRACTICE:

“Our findings highlight diabetes and prediabetes as ideal targets for lifestyle-based interventions to promote brain health,” the authors wrote.

SOURCE:

This study, led by Abigail Dove, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, was published online in Diabetes Care.

LIMITATIONS:

The generalizability of the findings was limited due to a healthy volunteer bias in the UK Biobank. A high proportion of missing data prevented the inclusion of diet in the healthy lifestyle construct. Reverse causality may be possible as an older brain may contribute to the development of prediabetes by making it more difficult to manage medical conditions and adhere to a healthy lifestyle. A1c levels were measured only at baseline, preventing the assessment of changes in glycemic control over time.

DISCLOSURES:

The authors reported receiving funding from the Swedish Research Council; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Board of Research; Riksbankens Jubileumsfond; Marianne and Marcus Wallenberg Foundation; Alzheimerfonden; and Demensfonden. They declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Diabetes and prediabetes are associated with accelerated brain aging with brain age gaps of 2.29 and 0.50 years, respectively. This association is more pronounced in men and those with poor cardiometabolic health but may be mitigated by a healthy lifestyle.

METHODOLOGY:

• Diabetes is a known risk factor for cognitive impairment, dementia, and global brain atrophy but conflicting results have been reported for prediabetes, and it’s unknown whether a healthy lifestyle can counteract the negative impact of prediabetes.
• Researchers examined the cross-sectional and longitudinal relationship between hyperglycemia and brain aging, as well as the potential mitigating effect of a healthy lifestyle in 31,229 dementia-free adults (mean age, 54.8 years; 53% women) from the UK Biobank, including 13,518 participants with prediabetes and 1149 with diabetes.
• The glycemic status of the participants was determined by their medical history, medication use, and A1c levels.
• The brain age gap was calculated as a difference between chronologic age and brain age estimated from MRI data from six modalities vs several hundred brain MRI phenotypes that were modeled from a subset of healthy individuals.
• The role of sex, cardiometabolic risk factors, and a healthy lifestyle and their association with brain age was also explored, with a healthy lifestyle defined as never smoking, no or light or moderate alcohol consumption, and high physical activity.

TAKEAWAY:

• Prediabetes and diabetes were associated with a higher brain age gap than normoglycemia (beta-coefficient, 0.22 and 2.01; 95% CI, 0.10-0.34 and 1.70-2.32, respectively), and diabetes was more pronounced in men vs women and those with a higher vs lower burden of cardiometabolic risk factors.
• The brain ages of those with prediabetes and diabetes were 0.50 years and 2.29 years older on average than their respective chronologic ages.
• In an exploratory longitudinal analysis of the 2414 participants with two brain MRI scans, diabetes was linked to a 0.27-year annual increase in the brain age gap, and higher A1c, but not prediabetes, was associated with a significant increase in brain age gap.
• A healthy lifestyle attenuated the association between diabetes and a higher brain age gap (P = .003), reducing it by 1.68 years, also with a significant interaction between glycemic status and lifestyle.

IN PRACTICE:

“Our findings highlight diabetes and prediabetes as ideal targets for lifestyle-based interventions to promote brain health,” the authors wrote.

SOURCE:

This study, led by Abigail Dove, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, was published online in Diabetes Care.

LIMITATIONS:

The generalizability of the findings was limited due to a healthy volunteer bias in the UK Biobank. A high proportion of missing data prevented the inclusion of diet in the healthy lifestyle construct. Reverse causality may be possible as an older brain may contribute to the development of prediabetes by making it more difficult to manage medical conditions and adhere to a healthy lifestyle. A1c levels were measured only at baseline, preventing the assessment of changes in glycemic control over time.

DISCLOSURES:

The authors reported receiving funding from the Swedish Research Council; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Board of Research; Riksbankens Jubileumsfond; Marianne and Marcus Wallenberg Foundation; Alzheimerfonden; and Demensfonden. They declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).

The phase 3 HERCULES trial showed tolebrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, delayed the time to onset of 6-month confirmed disability progression by 31%, compared with placebo.

In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.

However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.  

The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting. 

“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said. 

Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said. 

He estimated that up to 30% of patients with MS at his clinic may fall into this category. 

A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained. 

“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.

Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.

He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting. 

He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses. 

Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
 

Trial Results 

The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months. 

They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required. 

About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.

The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years. 

“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.

Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88). 

Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.

In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).
 

A ‘Head-scratcher’ Finding

Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy. 

“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Dr. Fox reported. 

He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.” 

In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group vs 1.6% in the placebo group.

A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. Fox. 

However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment. 

Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension.  
 

Weekly Liver Enzyme Testing 

Dr. Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”

The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later in 2024. 

Commenting on the trial, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.”

“The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added. 

Dr. Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
 

GEMINI Trials Also Show Slowed Disability 

Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug with teriflunomide, a standard of care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates, compared with teriflunomide. 

However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial. 

“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Dr. Fox said. 

The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.

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

COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).

The phase 3 HERCULES trial showed tolebrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, delayed the time to onset of 6-month confirmed disability progression by 31%, compared with placebo.

In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.

However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.  

The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting. 

“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said. 

Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said. 

He estimated that up to 30% of patients with MS at his clinic may fall into this category. 

A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained. 

“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.

Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.

He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting. 

He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses. 

Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
 

Trial Results 

The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months. 

They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required. 

About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.

The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years. 

“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.

Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88). 

Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.

In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).
 

A ‘Head-scratcher’ Finding

Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy. 

“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Dr. Fox reported. 

He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.” 

In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group vs 1.6% in the placebo group.

A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. Fox. 

However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment. 

Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension.  
 

Weekly Liver Enzyme Testing 

Dr. Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”

The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later in 2024. 

Commenting on the trial, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.”

“The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added. 

Dr. Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
 

GEMINI Trials Also Show Slowed Disability 

Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug with teriflunomide, a standard of care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates, compared with teriflunomide. 

However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial. 

“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Dr. Fox said. 

The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.

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

COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).

The phase 3 HERCULES trial showed tolebrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, delayed the time to onset of 6-month confirmed disability progression by 31%, compared with placebo.

In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.

However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.  

The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting. 

“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said. 

Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said. 

He estimated that up to 30% of patients with MS at his clinic may fall into this category. 

A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained. 

“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.

Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.

He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting. 

He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses. 

Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
 

Trial Results 

The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months. 

They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required. 

About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.

The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years. 

“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.

Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88). 

Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.

In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).
 

A ‘Head-scratcher’ Finding

Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy. 

“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Dr. Fox reported. 

He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.” 

In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group vs 1.6% in the placebo group.

A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. Fox. 

However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment. 

Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension.  
 

Weekly Liver Enzyme Testing 

Dr. Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”

The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later in 2024. 

Commenting on the trial, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.”

“The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added. 

Dr. Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
 

GEMINI Trials Also Show Slowed Disability 

Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug with teriflunomide, a standard of care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates, compared with teriflunomide. 

However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial. 

“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Dr. Fox said. 

The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.

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

TOPLINE:

The long-term use of muscle relaxants may benefit patients with painful spasms or cramps and neck pain, according to a systematic review of clinical studies, but they do not appear to be beneficial for low back pain, fibromyalgia, or headaches and can have adverse effects such as sedation and dry mouth.

METHODOLOGY:

• Researchers conducted a systematic review to evaluate the effectiveness of long-term use (≥ 4 weeks) of muscle relaxants for chronic pain lasting ≥ 3 months.
• They identified 30 randomized clinical trials involving 1314 patients and 14 cohort studies involving 1168 patients, grouped according to the categories of low back pain, fibromyalgia, painful cramps or spasticity, headaches, and other syndromes.
• Baclofen, tizanidine, cyclobenzaprine, eperisone, quinine, carisoprodol, orphenadrine, chlormezanone, and methocarbamol were the muscle relaxants assessed in comparison with placebo, other treatments, or untreated individuals.

TAKEAWAY:

• The long-term use of muscle relaxants reduced pain intensity in those with painful spasms or cramps and neck pain. Baclofen, orphenadrine, carisoprodol, and methocarbamol improved cramp frequency, while the use of eperisone and chlormezanone improved neck pain and enhanced the quality of sleep, respectively, in those with neck osteoarthritis.
• While some studies suggested that muscle relaxants reduced pain intensity in those with back pain and fibromyalgia, between-group differences were not observed. The benefits seen with some medications diminished after their discontinuation.
• Despite tizanidine improving pain severity in headaches, 25% participants dropped out owing to adverse effects. Although certain muscle relaxants demonstrated pain relief, others did not.
• The most common adverse effects of muscle relaxants were somnolence and dry mouth. Other adverse events included vomiting, diarrhea, nausea, weakness, and constipation.

IN PRACTICE:

“For patients already prescribed long-term SMRs [skeletal muscle relaxants], interventions are needed to assist clinicians to engage in shared decision-making with patients about deprescribing SMRs. This may be particularly true for older patients for whom risks of adverse events may be greater,” the authors wrote. “Clinicians should be vigilant for adverse effects and consider deprescribing if pain-related goals are not met.”

SOURCE:

The study, led by Benjamin J. Oldfield, MD, MHS, Yale School of Medicine, New Haven, Connecticut, was published online on September 19, 2024, in JAMA Network Open

LIMITATIONS:

This systematic review was limited to publications written in English, Spanish, and Italian language, potentially excluding studies from other regions. Variations in clinical sites, definitions of pain syndromes, medications, and durations of therapy prevented the possibility of conducting meta-analyses. Only quantitative studies were included, excluding valuable insights into patient experiences offered by qualitative studies. 

DISCLOSURES:

The study was supported by the National Institute on Drug Abuse. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The long-term use of muscle relaxants may benefit patients with painful spasms or cramps and neck pain, according to a systematic review of clinical studies, but they do not appear to be beneficial for low back pain, fibromyalgia, or headaches and can have adverse effects such as sedation and dry mouth.

METHODOLOGY:

• Researchers conducted a systematic review to evaluate the effectiveness of long-term use (≥ 4 weeks) of muscle relaxants for chronic pain lasting ≥ 3 months.
• They identified 30 randomized clinical trials involving 1314 patients and 14 cohort studies involving 1168 patients, grouped according to the categories of low back pain, fibromyalgia, painful cramps or spasticity, headaches, and other syndromes.
• Baclofen, tizanidine, cyclobenzaprine, eperisone, quinine, carisoprodol, orphenadrine, chlormezanone, and methocarbamol were the muscle relaxants assessed in comparison with placebo, other treatments, or untreated individuals.

TAKEAWAY:

• The long-term use of muscle relaxants reduced pain intensity in those with painful spasms or cramps and neck pain. Baclofen, orphenadrine, carisoprodol, and methocarbamol improved cramp frequency, while the use of eperisone and chlormezanone improved neck pain and enhanced the quality of sleep, respectively, in those with neck osteoarthritis.
• While some studies suggested that muscle relaxants reduced pain intensity in those with back pain and fibromyalgia, between-group differences were not observed. The benefits seen with some medications diminished after their discontinuation.
• Despite tizanidine improving pain severity in headaches, 25% participants dropped out owing to adverse effects. Although certain muscle relaxants demonstrated pain relief, others did not.
• The most common adverse effects of muscle relaxants were somnolence and dry mouth. Other adverse events included vomiting, diarrhea, nausea, weakness, and constipation.

IN PRACTICE:

“For patients already prescribed long-term SMRs [skeletal muscle relaxants], interventions are needed to assist clinicians to engage in shared decision-making with patients about deprescribing SMRs. This may be particularly true for older patients for whom risks of adverse events may be greater,” the authors wrote. “Clinicians should be vigilant for adverse effects and consider deprescribing if pain-related goals are not met.”

SOURCE:

The study, led by Benjamin J. Oldfield, MD, MHS, Yale School of Medicine, New Haven, Connecticut, was published online on September 19, 2024, in JAMA Network Open

LIMITATIONS:

This systematic review was limited to publications written in English, Spanish, and Italian language, potentially excluding studies from other regions. Variations in clinical sites, definitions of pain syndromes, medications, and durations of therapy prevented the possibility of conducting meta-analyses. Only quantitative studies were included, excluding valuable insights into patient experiences offered by qualitative studies. 

DISCLOSURES:

The study was supported by the National Institute on Drug Abuse. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The long-term use of muscle relaxants may benefit patients with painful spasms or cramps and neck pain, according to a systematic review of clinical studies, but they do not appear to be beneficial for low back pain, fibromyalgia, or headaches and can have adverse effects such as sedation and dry mouth.

METHODOLOGY:

• Researchers conducted a systematic review to evaluate the effectiveness of long-term use (≥ 4 weeks) of muscle relaxants for chronic pain lasting ≥ 3 months.
• They identified 30 randomized clinical trials involving 1314 patients and 14 cohort studies involving 1168 patients, grouped according to the categories of low back pain, fibromyalgia, painful cramps or spasticity, headaches, and other syndromes.
• Baclofen, tizanidine, cyclobenzaprine, eperisone, quinine, carisoprodol, orphenadrine, chlormezanone, and methocarbamol were the muscle relaxants assessed in comparison with placebo, other treatments, or untreated individuals.

TAKEAWAY:

• The long-term use of muscle relaxants reduced pain intensity in those with painful spasms or cramps and neck pain. Baclofen, orphenadrine, carisoprodol, and methocarbamol improved cramp frequency, while the use of eperisone and chlormezanone improved neck pain and enhanced the quality of sleep, respectively, in those with neck osteoarthritis.
• While some studies suggested that muscle relaxants reduced pain intensity in those with back pain and fibromyalgia, between-group differences were not observed. The benefits seen with some medications diminished after their discontinuation.
• Despite tizanidine improving pain severity in headaches, 25% participants dropped out owing to adverse effects. Although certain muscle relaxants demonstrated pain relief, others did not.
• The most common adverse effects of muscle relaxants were somnolence and dry mouth. Other adverse events included vomiting, diarrhea, nausea, weakness, and constipation.

IN PRACTICE:

“For patients already prescribed long-term SMRs [skeletal muscle relaxants], interventions are needed to assist clinicians to engage in shared decision-making with patients about deprescribing SMRs. This may be particularly true for older patients for whom risks of adverse events may be greater,” the authors wrote. “Clinicians should be vigilant for adverse effects and consider deprescribing if pain-related goals are not met.”

SOURCE:

The study, led by Benjamin J. Oldfield, MD, MHS, Yale School of Medicine, New Haven, Connecticut, was published online on September 19, 2024, in JAMA Network Open

LIMITATIONS:

This systematic review was limited to publications written in English, Spanish, and Italian language, potentially excluding studies from other regions. Variations in clinical sites, definitions of pain syndromes, medications, and durations of therapy prevented the possibility of conducting meta-analyses. Only quantitative studies were included, excluding valuable insights into patient experiences offered by qualitative studies. 

DISCLOSURES:

The study was supported by the National Institute on Drug Abuse. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Air pollution, high temperatures, and metabolic risk factors are driving global increases in stroke, contributing to 12 million cases and more than 7 million deaths from stroke each year, new data from the Global Burden of Disease (GBD) study showed.

Between 1990 and 2021, the number of people who experienced a stroke increased to 11.9 million (up by 70% since 1990), while the number of stroke survivors rose to 93.8 million (up by 86%), and stroke-related deaths rose to 7.3 million (up by 44%), making stroke the third leading cause of death worldwide after ischemic heart disease and COVID-19, investigators found.

Stroke is highly preventable, the investigators noted, with 84% of the stroke burden in 2021 attributable to 23 modifiable risk factors, including air pollution, excess body weight, high blood pressure, smoking, and physical inactivity.

This means there are “tremendous opportunities to alter the trajectory of stroke risk for the next generation,” Catherine O. Johnson, MPH, PhD, co-author and lead research scientist at the Institute for Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.

The study was published online in The Lancet Neurology.
 

Top Risk Factor for Subarachnoid Hemorrhage

Since 1990, the contribution of high temperatures to poor health and early death due to stroke has risen 72%, a trend likely to increase in the future — underscoring the impact of environmental factors on the growing stroke burden, the authors said.

“Given that ambient air pollution is reciprocally linked with ambient temperature and climate change, the importance of urgent climate actions and measures to reduce air pollution cannot be overestimated,” Dr. Johnson said.

Mitchell S.V. Elkind, MD, MS, chief clinical science officer for the American Heart Association, who wasn’t involved in the study, told this news organization that environmental factors such as air pollution, particulate matter from wildfires and other sources, and excessive heat are now recognized as major contributors to the risk for stroke. “This should not be surprising as we have long recognized the risks of stroke associated with toxins in cigarette smoke, which likely share mechanisms for vascular damage with pollutants,” Dr. Elkind said.

The data also reveal for the first time that ambient particulate matter air pollution is a top risk factor for subarachnoid hemorrhage, contributing to 14% of the death and disability caused by this serious stroke subtype, on a par with smoking.

Dr. Elkind noted that smoking is “a major risk factor for subarachnoid hemorrhage. It makes sense that particulate air pollution would therefore similarly be a risk factor for subarachnoid hemorrhage, which similarly damages blood vessels. Prior studies were likely too small or did not assess the role of air pollution in subarachnoid hemorrhage.”

The analysis also showed substantial increases between 1990 and 2021 in the global stroke burden linked to high body mass index (up by 88%), high blood sugar (up 32%), a diet high in sugar-sweetened drinks (up 23%), low physical activity (up 11%), high systolic blood pressure (up 7%), and a diet low in omega-6 polyunsaturated fatty acids (up 5%).

“And with increasing exposure to risk factors such as high blood sugar and diet high in sugar-sweetened drinks, there is a critical need for interventions focused on obesity and metabolic syndromes,” Dr. Johnson said.

“Identifying sustainable ways to work with communities to take action to prevent and control modifiable risk factors for stroke is essential to address this growing crisis,” she added.
 

Prevention Strategies Fall Short

The data also showed that stroke-related disability-adjusted life-years rose from around 121.4 million years of healthy life lost in 1990 to 160.5 million years in 2021, making stroke the fourth leading cause of health loss worldwide after COVID-19, ischemic heart disease, and neonatal disorders.

“The global growth of the number of people who develop stroke and died from or remain disabled by stroke is growing fast, strongly suggesting that currently used stroke prevention strategies are not sufficiently effective,” lead author Valery L. Feigin, MD, PhD, from Auckland University of Technology, Auckland, New Zealand, and affiliate professor at IHME, said in the release.

“New, proven effective population-wide and motivational individual prevention strategies that could be applied to all people at risk of having a stroke, regardless of the level of risk, as recommended in the recent Lancet Neurology Commission on Stroke should be implemented across the globe urgently,” said Dr. Feigin.

Dr. Elkind said the AHA supports research on the effects of air quality on risk for vascular injury and stroke and has “long advocated for policies to mitigate the adverse health impacts of air pollutants, including reduction of vehicle emissions and renewable portfolio standards, taking into account racial, ethnic, and economic disparities.”

“AHA, and the healthcare sector more broadly, must take a leadership role in recommending policies to improve environmental air quality and in working with the private sector and industry to improve air quality,” Dr. Elkind said.

In an accompanying commentary, Ming Liu, MD, and Simiao Wu, MD, PhD, West China Hospital, Sichuan University, Chengdu, China, wrote that “pragmatic solutions to the enormous and increasing stroke burden include surveillance, prevention, acute care, and rehabilitation.”

“Surveillance strategies include establishing a national-level framework for regular monitoring of stroke burden, risk factors, and healthcare services via community-based surveys and health records,” they noted.

“Artificial intelligence and mobile technologies might not only facilitate the dissemination of evidence-based health services but also increase the number of data sources and encourage participation of multidisciplinary collaborators, potentially improving the validity and accuracy of future GBD estimates,” they added.

This study was funded by the Bill & Melinda Gates Foundation. Author disclosures are listed with the original article.

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

Air pollution, high temperatures, and metabolic risk factors are driving global increases in stroke, contributing to 12 million cases and more than 7 million deaths from stroke each year, new data from the Global Burden of Disease (GBD) study showed.

Between 1990 and 2021, the number of people who experienced a stroke increased to 11.9 million (up by 70% since 1990), while the number of stroke survivors rose to 93.8 million (up by 86%), and stroke-related deaths rose to 7.3 million (up by 44%), making stroke the third leading cause of death worldwide after ischemic heart disease and COVID-19, investigators found.

Stroke is highly preventable, the investigators noted, with 84% of the stroke burden in 2021 attributable to 23 modifiable risk factors, including air pollution, excess body weight, high blood pressure, smoking, and physical inactivity.

This means there are “tremendous opportunities to alter the trajectory of stroke risk for the next generation,” Catherine O. Johnson, MPH, PhD, co-author and lead research scientist at the Institute for Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.

The study was published online in The Lancet Neurology.
 

Top Risk Factor for Subarachnoid Hemorrhage

Since 1990, the contribution of high temperatures to poor health and early death due to stroke has risen 72%, a trend likely to increase in the future — underscoring the impact of environmental factors on the growing stroke burden, the authors said.

“Given that ambient air pollution is reciprocally linked with ambient temperature and climate change, the importance of urgent climate actions and measures to reduce air pollution cannot be overestimated,” Dr. Johnson said.

Mitchell S.V. Elkind, MD, MS, chief clinical science officer for the American Heart Association, who wasn’t involved in the study, told this news organization that environmental factors such as air pollution, particulate matter from wildfires and other sources, and excessive heat are now recognized as major contributors to the risk for stroke. “This should not be surprising as we have long recognized the risks of stroke associated with toxins in cigarette smoke, which likely share mechanisms for vascular damage with pollutants,” Dr. Elkind said.

The data also reveal for the first time that ambient particulate matter air pollution is a top risk factor for subarachnoid hemorrhage, contributing to 14% of the death and disability caused by this serious stroke subtype, on a par with smoking.

Dr. Elkind noted that smoking is “a major risk factor for subarachnoid hemorrhage. It makes sense that particulate air pollution would therefore similarly be a risk factor for subarachnoid hemorrhage, which similarly damages blood vessels. Prior studies were likely too small or did not assess the role of air pollution in subarachnoid hemorrhage.”

The analysis also showed substantial increases between 1990 and 2021 in the global stroke burden linked to high body mass index (up by 88%), high blood sugar (up 32%), a diet high in sugar-sweetened drinks (up 23%), low physical activity (up 11%), high systolic blood pressure (up 7%), and a diet low in omega-6 polyunsaturated fatty acids (up 5%).

“And with increasing exposure to risk factors such as high blood sugar and diet high in sugar-sweetened drinks, there is a critical need for interventions focused on obesity and metabolic syndromes,” Dr. Johnson said.

“Identifying sustainable ways to work with communities to take action to prevent and control modifiable risk factors for stroke is essential to address this growing crisis,” she added.
 

Prevention Strategies Fall Short

The data also showed that stroke-related disability-adjusted life-years rose from around 121.4 million years of healthy life lost in 1990 to 160.5 million years in 2021, making stroke the fourth leading cause of health loss worldwide after COVID-19, ischemic heart disease, and neonatal disorders.

“The global growth of the number of people who develop stroke and died from or remain disabled by stroke is growing fast, strongly suggesting that currently used stroke prevention strategies are not sufficiently effective,” lead author Valery L. Feigin, MD, PhD, from Auckland University of Technology, Auckland, New Zealand, and affiliate professor at IHME, said in the release.

“New, proven effective population-wide and motivational individual prevention strategies that could be applied to all people at risk of having a stroke, regardless of the level of risk, as recommended in the recent Lancet Neurology Commission on Stroke should be implemented across the globe urgently,” said Dr. Feigin.

Dr. Elkind said the AHA supports research on the effects of air quality on risk for vascular injury and stroke and has “long advocated for policies to mitigate the adverse health impacts of air pollutants, including reduction of vehicle emissions and renewable portfolio standards, taking into account racial, ethnic, and economic disparities.”

“AHA, and the healthcare sector more broadly, must take a leadership role in recommending policies to improve environmental air quality and in working with the private sector and industry to improve air quality,” Dr. Elkind said.

In an accompanying commentary, Ming Liu, MD, and Simiao Wu, MD, PhD, West China Hospital, Sichuan University, Chengdu, China, wrote that “pragmatic solutions to the enormous and increasing stroke burden include surveillance, prevention, acute care, and rehabilitation.”

“Surveillance strategies include establishing a national-level framework for regular monitoring of stroke burden, risk factors, and healthcare services via community-based surveys and health records,” they noted.

“Artificial intelligence and mobile technologies might not only facilitate the dissemination of evidence-based health services but also increase the number of data sources and encourage participation of multidisciplinary collaborators, potentially improving the validity and accuracy of future GBD estimates,” they added.

This study was funded by the Bill & Melinda Gates Foundation. Author disclosures are listed with the original article.

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

Air pollution, high temperatures, and metabolic risk factors are driving global increases in stroke, contributing to 12 million cases and more than 7 million deaths from stroke each year, new data from the Global Burden of Disease (GBD) study showed.

Between 1990 and 2021, the number of people who experienced a stroke increased to 11.9 million (up by 70% since 1990), while the number of stroke survivors rose to 93.8 million (up by 86%), and stroke-related deaths rose to 7.3 million (up by 44%), making stroke the third leading cause of death worldwide after ischemic heart disease and COVID-19, investigators found.

Stroke is highly preventable, the investigators noted, with 84% of the stroke burden in 2021 attributable to 23 modifiable risk factors, including air pollution, excess body weight, high blood pressure, smoking, and physical inactivity.

This means there are “tremendous opportunities to alter the trajectory of stroke risk for the next generation,” Catherine O. Johnson, MPH, PhD, co-author and lead research scientist at the Institute for Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.

The study was published online in The Lancet Neurology.
 

Top Risk Factor for Subarachnoid Hemorrhage

Since 1990, the contribution of high temperatures to poor health and early death due to stroke has risen 72%, a trend likely to increase in the future — underscoring the impact of environmental factors on the growing stroke burden, the authors said.

“Given that ambient air pollution is reciprocally linked with ambient temperature and climate change, the importance of urgent climate actions and measures to reduce air pollution cannot be overestimated,” Dr. Johnson said.

Mitchell S.V. Elkind, MD, MS, chief clinical science officer for the American Heart Association, who wasn’t involved in the study, told this news organization that environmental factors such as air pollution, particulate matter from wildfires and other sources, and excessive heat are now recognized as major contributors to the risk for stroke. “This should not be surprising as we have long recognized the risks of stroke associated with toxins in cigarette smoke, which likely share mechanisms for vascular damage with pollutants,” Dr. Elkind said.

The data also reveal for the first time that ambient particulate matter air pollution is a top risk factor for subarachnoid hemorrhage, contributing to 14% of the death and disability caused by this serious stroke subtype, on a par with smoking.

Dr. Elkind noted that smoking is “a major risk factor for subarachnoid hemorrhage. It makes sense that particulate air pollution would therefore similarly be a risk factor for subarachnoid hemorrhage, which similarly damages blood vessels. Prior studies were likely too small or did not assess the role of air pollution in subarachnoid hemorrhage.”

The analysis also showed substantial increases between 1990 and 2021 in the global stroke burden linked to high body mass index (up by 88%), high blood sugar (up 32%), a diet high in sugar-sweetened drinks (up 23%), low physical activity (up 11%), high systolic blood pressure (up 7%), and a diet low in omega-6 polyunsaturated fatty acids (up 5%).

“And with increasing exposure to risk factors such as high blood sugar and diet high in sugar-sweetened drinks, there is a critical need for interventions focused on obesity and metabolic syndromes,” Dr. Johnson said.

“Identifying sustainable ways to work with communities to take action to prevent and control modifiable risk factors for stroke is essential to address this growing crisis,” she added.
 

Prevention Strategies Fall Short

The data also showed that stroke-related disability-adjusted life-years rose from around 121.4 million years of healthy life lost in 1990 to 160.5 million years in 2021, making stroke the fourth leading cause of health loss worldwide after COVID-19, ischemic heart disease, and neonatal disorders.

“The global growth of the number of people who develop stroke and died from or remain disabled by stroke is growing fast, strongly suggesting that currently used stroke prevention strategies are not sufficiently effective,” lead author Valery L. Feigin, MD, PhD, from Auckland University of Technology, Auckland, New Zealand, and affiliate professor at IHME, said in the release.

“New, proven effective population-wide and motivational individual prevention strategies that could be applied to all people at risk of having a stroke, regardless of the level of risk, as recommended in the recent Lancet Neurology Commission on Stroke should be implemented across the globe urgently,” said Dr. Feigin.

Dr. Elkind said the AHA supports research on the effects of air quality on risk for vascular injury and stroke and has “long advocated for policies to mitigate the adverse health impacts of air pollutants, including reduction of vehicle emissions and renewable portfolio standards, taking into account racial, ethnic, and economic disparities.”

“AHA, and the healthcare sector more broadly, must take a leadership role in recommending policies to improve environmental air quality and in working with the private sector and industry to improve air quality,” Dr. Elkind said.

In an accompanying commentary, Ming Liu, MD, and Simiao Wu, MD, PhD, West China Hospital, Sichuan University, Chengdu, China, wrote that “pragmatic solutions to the enormous and increasing stroke burden include surveillance, prevention, acute care, and rehabilitation.”

“Surveillance strategies include establishing a national-level framework for regular monitoring of stroke burden, risk factors, and healthcare services via community-based surveys and health records,” they noted.

“Artificial intelligence and mobile technologies might not only facilitate the dissemination of evidence-based health services but also increase the number of data sources and encourage participation of multidisciplinary collaborators, potentially improving the validity and accuracy of future GBD estimates,” they added.

This study was funded by the Bill & Melinda Gates Foundation. Author disclosures are listed with the original article.

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