TBD Meeting (2962-24)

DENVER — A retrospective analysis of pediatric patients with Lennox-Gastaut syndrome (LGS) suggests that the antiseizure medication cenobamate (SK Life Sciences) in combination with existing lines of therapy may be associated with fewer hospital in-patient days and emergency room visits. The conclusions were reached by comparing outcomes to patient historical data, though they were not analyzed statistically.

A Proof-of-Concept Study

In an interview, Karen Keough, MD, who presented the study during a poster session at the 2024 annual meeting of the American Academy of Neurology, conceded the key limitation was that the researchers were not able to perform statistical analysis due to the nature of the data. “It’s just showing trends. It’s proof of concept that cenobamate can be effective in one of the most refractory forms of epilepsy, which always includes focal seizures. That’s what led to the initial FDA indication, but we also know that this medication has a lot of promise and is probably going to be effective in other forms of epilepsy and probably in other seizure types,” said Dr. Keough, who is a neurologist at Pediatrix Child Neurology Consultants of Austin, Texas.

Although she has seen significant improvements in many patients, Dr. Keough reported that most patients become refractory again. “Unfortunately, honeymoons are probably real in cenobamate. Continuing to follow those patients as I do, since they’re my own patients, I have quite a few who had more than a year of seizure freedom, [but] their seizures are back, though not as bad as they were before cenobamate. I just can’t get them back to that 100% control category. I do have a few that are still in the 100% control category, but not very many,” she said.

She also presented a retrospective chart review of 36 LGS patients between the ages of 1 and 27 years at the American Epilepsy Society in December 2023, which showed that addition of cenobamate was associated with a reduction in seizure frequency in 85% of patients. “It was a profound number of patients who had long periods of seizure freedom,” she said.
 

A Promising Treatment Option

Dr. Keough is considering moving cenobamate up in the treatment sequence of new LGS patients. “I don’t use cenobamate first line in anyone because we have good first-line agents for simple epilepsy in Lennox-Gastaut, but I’m bringing out cenobamate pretty early in the course, because I do think it has superior efficacy compared with most other drugs that we have available. Most of my patients are very established and they’ve seen lots of other drugs. For many patients, there are only a couple of drugs left on the list that [they] have never tried, but we’re going to put cenobamate at the top of that. For my newer diagnoses, I’m going to bring it out much earlier,” she said, though other drugs such as clobazam (Onfi) would still rank ahead of cenobamate.

The study was drawn from records of the HealthVerity Marketplace Database, which includes more than 150 commercial, Medicare, and Medicaid payers. It included 76 patients aged 17 or under who took at least one antiseizure medication between May 2020 and December 2022, and who had filled at least two prescriptions of cenobamate and had 180 or more days of medical and pharmacy enrollment. The mean age was 13.4 years (5.3% 0-5 years, 15.8% 6-11 years, 78.9% 12-17 years), and 40.8% were female. Seizure types included absence (17.1%), focal (75.0%), and generalized tonic-clonic (86.8%). All patients had a history of intractable seizures, 80.3% had a history of status epilepticus, and 28.9% had a history of infantile seizures. A little more than one fourth (27.6%) of patients had commercial insurance. In the previous 90 days, 21.1% had had an emergency room visit or in-patient hospital stay.

Common antiseizure medications taken with cenobamate included cannabidiol (n = 14), clobazam (n = 8), and levetiracetam (n = 18).

During the cenobamate treatment period, patients had a lower incidence of epilepsy-related inpatient days per year (3.36 vs 3.94), epilepsy-related ER visits per year (0.66 vs 1.19), and likelihood of requiring a new line of epilepsy therapy (35.5% vs 100%).
 

‘Promising’ Results, but More Research Is Needed

The fact that cenobamate was used in combination with other therapies, plus the lack of a control group, makes it difficult to determine if cenobamate was actually responsible for the improvements, according to Nassim Zecavati, MD, who was asked for comment on the study. “I think the results are promising, but there’s obviously a need for a randomized, controlled trial to understand whether it was this medication or the combination of cenobamate with [other medications]. How do we know that this isn’t a compound effect, that it’s multifactorial, and a combination of multiple medications versus the cenobamate?” she said.

Still, she noted that LGS patients are highly vulnerable to hospital admissions and status epilepticus, making the parameters examined in the study valid and important. “I think that this drug likely has a role in the treatment of patients with LGS, particularly pediatric patients. I think we just need more data,” said Dr. Zecavati, who is director of Epilepsy at the Children’s Hospital of Richmond in Virginia and associate professor of Neurology at Virginia Commonwealth University.

Dr. Keough is a speaker for SK Life Sciences. Dr. Zecavati has no relevant financial disclosures.

DENVER — A retrospective analysis of pediatric patients with Lennox-Gastaut syndrome (LGS) suggests that the antiseizure medication cenobamate (SK Life Sciences) in combination with existing lines of therapy may be associated with fewer hospital in-patient days and emergency room visits. The conclusions were reached by comparing outcomes to patient historical data, though they were not analyzed statistically.

A Proof-of-Concept Study

In an interview, Karen Keough, MD, who presented the study during a poster session at the 2024 annual meeting of the American Academy of Neurology, conceded the key limitation was that the researchers were not able to perform statistical analysis due to the nature of the data. “It’s just showing trends. It’s proof of concept that cenobamate can be effective in one of the most refractory forms of epilepsy, which always includes focal seizures. That’s what led to the initial FDA indication, but we also know that this medication has a lot of promise and is probably going to be effective in other forms of epilepsy and probably in other seizure types,” said Dr. Keough, who is a neurologist at Pediatrix Child Neurology Consultants of Austin, Texas.

Although she has seen significant improvements in many patients, Dr. Keough reported that most patients become refractory again. “Unfortunately, honeymoons are probably real in cenobamate. Continuing to follow those patients as I do, since they’re my own patients, I have quite a few who had more than a year of seizure freedom, [but] their seizures are back, though not as bad as they were before cenobamate. I just can’t get them back to that 100% control category. I do have a few that are still in the 100% control category, but not very many,” she said.

She also presented a retrospective chart review of 36 LGS patients between the ages of 1 and 27 years at the American Epilepsy Society in December 2023, which showed that addition of cenobamate was associated with a reduction in seizure frequency in 85% of patients. “It was a profound number of patients who had long periods of seizure freedom,” she said.
 

A Promising Treatment Option

Dr. Keough is considering moving cenobamate up in the treatment sequence of new LGS patients. “I don’t use cenobamate first line in anyone because we have good first-line agents for simple epilepsy in Lennox-Gastaut, but I’m bringing out cenobamate pretty early in the course, because I do think it has superior efficacy compared with most other drugs that we have available. Most of my patients are very established and they’ve seen lots of other drugs. For many patients, there are only a couple of drugs left on the list that [they] have never tried, but we’re going to put cenobamate at the top of that. For my newer diagnoses, I’m going to bring it out much earlier,” she said, though other drugs such as clobazam (Onfi) would still rank ahead of cenobamate.

The study was drawn from records of the HealthVerity Marketplace Database, which includes more than 150 commercial, Medicare, and Medicaid payers. It included 76 patients aged 17 or under who took at least one antiseizure medication between May 2020 and December 2022, and who had filled at least two prescriptions of cenobamate and had 180 or more days of medical and pharmacy enrollment. The mean age was 13.4 years (5.3% 0-5 years, 15.8% 6-11 years, 78.9% 12-17 years), and 40.8% were female. Seizure types included absence (17.1%), focal (75.0%), and generalized tonic-clonic (86.8%). All patients had a history of intractable seizures, 80.3% had a history of status epilepticus, and 28.9% had a history of infantile seizures. A little more than one fourth (27.6%) of patients had commercial insurance. In the previous 90 days, 21.1% had had an emergency room visit or in-patient hospital stay.

Common antiseizure medications taken with cenobamate included cannabidiol (n = 14), clobazam (n = 8), and levetiracetam (n = 18).

During the cenobamate treatment period, patients had a lower incidence of epilepsy-related inpatient days per year (3.36 vs 3.94), epilepsy-related ER visits per year (0.66 vs 1.19), and likelihood of requiring a new line of epilepsy therapy (35.5% vs 100%).
 

‘Promising’ Results, but More Research Is Needed

The fact that cenobamate was used in combination with other therapies, plus the lack of a control group, makes it difficult to determine if cenobamate was actually responsible for the improvements, according to Nassim Zecavati, MD, who was asked for comment on the study. “I think the results are promising, but there’s obviously a need for a randomized, controlled trial to understand whether it was this medication or the combination of cenobamate with [other medications]. How do we know that this isn’t a compound effect, that it’s multifactorial, and a combination of multiple medications versus the cenobamate?” she said.

Still, she noted that LGS patients are highly vulnerable to hospital admissions and status epilepticus, making the parameters examined in the study valid and important. “I think that this drug likely has a role in the treatment of patients with LGS, particularly pediatric patients. I think we just need more data,” said Dr. Zecavati, who is director of Epilepsy at the Children’s Hospital of Richmond in Virginia and associate professor of Neurology at Virginia Commonwealth University.

Dr. Keough is a speaker for SK Life Sciences. Dr. Zecavati has no relevant financial disclosures.

DENVER — A retrospective analysis of pediatric patients with Lennox-Gastaut syndrome (LGS) suggests that the antiseizure medication cenobamate (SK Life Sciences) in combination with existing lines of therapy may be associated with fewer hospital in-patient days and emergency room visits. The conclusions were reached by comparing outcomes to patient historical data, though they were not analyzed statistically.

A Proof-of-Concept Study

In an interview, Karen Keough, MD, who presented the study during a poster session at the 2024 annual meeting of the American Academy of Neurology, conceded the key limitation was that the researchers were not able to perform statistical analysis due to the nature of the data. “It’s just showing trends. It’s proof of concept that cenobamate can be effective in one of the most refractory forms of epilepsy, which always includes focal seizures. That’s what led to the initial FDA indication, but we also know that this medication has a lot of promise and is probably going to be effective in other forms of epilepsy and probably in other seizure types,” said Dr. Keough, who is a neurologist at Pediatrix Child Neurology Consultants of Austin, Texas.

Although she has seen significant improvements in many patients, Dr. Keough reported that most patients become refractory again. “Unfortunately, honeymoons are probably real in cenobamate. Continuing to follow those patients as I do, since they’re my own patients, I have quite a few who had more than a year of seizure freedom, [but] their seizures are back, though not as bad as they were before cenobamate. I just can’t get them back to that 100% control category. I do have a few that are still in the 100% control category, but not very many,” she said.

She also presented a retrospective chart review of 36 LGS patients between the ages of 1 and 27 years at the American Epilepsy Society in December 2023, which showed that addition of cenobamate was associated with a reduction in seizure frequency in 85% of patients. “It was a profound number of patients who had long periods of seizure freedom,” she said.
 

A Promising Treatment Option

Dr. Keough is considering moving cenobamate up in the treatment sequence of new LGS patients. “I don’t use cenobamate first line in anyone because we have good first-line agents for simple epilepsy in Lennox-Gastaut, but I’m bringing out cenobamate pretty early in the course, because I do think it has superior efficacy compared with most other drugs that we have available. Most of my patients are very established and they’ve seen lots of other drugs. For many patients, there are only a couple of drugs left on the list that [they] have never tried, but we’re going to put cenobamate at the top of that. For my newer diagnoses, I’m going to bring it out much earlier,” she said, though other drugs such as clobazam (Onfi) would still rank ahead of cenobamate.

The study was drawn from records of the HealthVerity Marketplace Database, which includes more than 150 commercial, Medicare, and Medicaid payers. It included 76 patients aged 17 or under who took at least one antiseizure medication between May 2020 and December 2022, and who had filled at least two prescriptions of cenobamate and had 180 or more days of medical and pharmacy enrollment. The mean age was 13.4 years (5.3% 0-5 years, 15.8% 6-11 years, 78.9% 12-17 years), and 40.8% were female. Seizure types included absence (17.1%), focal (75.0%), and generalized tonic-clonic (86.8%). All patients had a history of intractable seizures, 80.3% had a history of status epilepticus, and 28.9% had a history of infantile seizures. A little more than one fourth (27.6%) of patients had commercial insurance. In the previous 90 days, 21.1% had had an emergency room visit or in-patient hospital stay.

Common antiseizure medications taken with cenobamate included cannabidiol (n = 14), clobazam (n = 8), and levetiracetam (n = 18).

During the cenobamate treatment period, patients had a lower incidence of epilepsy-related inpatient days per year (3.36 vs 3.94), epilepsy-related ER visits per year (0.66 vs 1.19), and likelihood of requiring a new line of epilepsy therapy (35.5% vs 100%).
 

‘Promising’ Results, but More Research Is Needed

The fact that cenobamate was used in combination with other therapies, plus the lack of a control group, makes it difficult to determine if cenobamate was actually responsible for the improvements, according to Nassim Zecavati, MD, who was asked for comment on the study. “I think the results are promising, but there’s obviously a need for a randomized, controlled trial to understand whether it was this medication or the combination of cenobamate with [other medications]. How do we know that this isn’t a compound effect, that it’s multifactorial, and a combination of multiple medications versus the cenobamate?” she said.

Still, she noted that LGS patients are highly vulnerable to hospital admissions and status epilepticus, making the parameters examined in the study valid and important. “I think that this drug likely has a role in the treatment of patients with LGS, particularly pediatric patients. I think we just need more data,” said Dr. Zecavati, who is director of Epilepsy at the Children’s Hospital of Richmond in Virginia and associate professor of Neurology at Virginia Commonwealth University.

Dr. Keough is a speaker for SK Life Sciences. Dr. Zecavati has no relevant financial disclosures.

New guidelines to manage peripheral neuropathy related to Sjögren disease have been developed by a multidisciplinary team of physicians from across medicine.

The guidelines will provide an evidence-based resource for the assessment, diagnosis, and treatment of various peripheral neuropathies related to the disorder.

Up until now, the field has been “haphazard and chaotic,” lead author George Sarka, MD, DrPH, MPH, director of the CME Committee for MemorialCare, Saddleback Medical Center, Laguna Hills, California, and member of the Sjögren Foundation PNS Guidelines Topic Review Group (TRG), told this news organization.

Dr. Sarka discussed the initiative at the American Academy of Neurology 2024 annual meeting.


 

Severe, Complex Illness

Sjögren disease is the second most common autoimmune rheumatic disorder after rheumatoid arthritis, affecting an estimated 4 million Americans. Women make up most of the patient population at a ratio of 9:1.

The condition typically affects the mucous membranes and moisture-secreting glands of the eyes and mouth, resulting in decreased tears and saliva. But peripheral nervous system (PNS) manifestations often precede these symptoms and can occur in up to 60% of Sjögren disease cases.

“Traditionally, Sjögren’s was looked at as a dry eye and dry mouth disease, but we realize now that it’s so much broader than that,” said Dr. Sarka. “It’s a severe, systemic, and complex illness that can affect any body organ or system, and the nervous system is frequently affected.”

PNS manifestations cause more than mere discomfort; they can lead to diagnostic and management challenges, costly treatments, and diminished quality of life.

Getting a proper diagnosis goes a long way toward improving the quality of life for these patients, Steven Mandel, MD, clinical professor of neurology at the Zucker School of Medicine at Hofstra-Northwell, adjunct clinical professor of medicine at NY Medical College, New York City, and member of the TRG, told this news organization.

The problem is, doctors don’t always think an autoimmune disorder is causing the symptoms, said Dr. Sarka. “There’s an old adage in neurology that if you don’t think about it, you’re going to miss it; you have to ask, and that’s what we’re trying to get people to do.”

The condition often accompanies other immune system disorders such as rheumatoid arthritis and lupus. But as patients are referred back and forth between ophthalmologists, rheumatologists, and neurologists, the condition is often missed. “It could be 4 or 5 years before a definitive diagnosis of Sjögren’s is made,” said Dr. Sarka.

He believes the education system is partly to blame. “Medical schools have been very deficient in teaching people about recognizing Sjögren disease.”

That leaves many physicians at a loss about “what to do with these patients when they walk in the door,” said Dr. Mandel. “They don’t know how to manage them; they don’t know how to diagnose them; and they don’t know how to treat them.”

Developing guidelines with multispecialty collaboration was “absolutely critical” in addressing this knowledge gap, Dr. Mandel added. That process involved “a very rigorous and transparent methodology so that it would be accepted by all the professionals involved in Sjögren’s,” he said.

The process took 3 years and involved amassing and grading the evidence, getting consensus from committee members, developing recommendations, and getting feedback and external review.
 

Scant Evidence

An early literature search revealed very little evidence on PNS manifestations in patients with Sjögren disease, so the guideline committee “leaned very heavily on expert opinion” to develop recommendations, Kathy Hammitt, MA, vice president of Medical and Scientific Affairs, Sjögren’s Foundation, told this news organization.

The literature search also showed different terms are used to describe PNS, “which is where the chaos comes in,” said Dr. Sarka.

Experts from different specialties worked together to define and align nomenclature used by various specialists. They developed definitions for seven PNS categories including mononeuropathy, large fiber neuropathy, small fiber neuropathy, demyelinating polyradiculoneuropathy, ganglionopathy, vasculitis neuropathy, and autoimmune nervous system neuropathy.

The guidelines pertaining to PNS manifestations encompass a spectrum of neurologic abnormalities, including cranial neuropathies (trigeminal neuropathy or acute facial neuropathy), polyneuropathies (large fiber neuropathy, small fiber neuropathy, demyelinating polyradiculoneuropathy, vasculitis neuropathy, or ganglionopathy), and autonomic nervous system (ANS) neuropathies (postural tachycardia, orthostatic hypotension, or autonomic dysfunction).
 

Key Steps

The guidelines address two key steps for each PNS manifestation — the workup and evaluation of patients with suspected ANS manifestation including standard evaluations, diagnostic tests, and treatment. The experts developed 31 best practices for diagnosis and workup and 20 treatment recommendations.

Initial assessment of potential ANS involvement includes asking patients about orthostatic postural lightheadedness and difficulties with digestion, urination, sweating, and sexual function.

Treatment of autoimmune diseases typically focuses on relieving symptoms and can include steroids, the anticonvulsant gabapentin, the monoclonal antibody rituximab, and intravenous immunoglobulin. “The type of neuropathy will mandate or suggest certain therapies over others,” said Dr. Sarka, adding that a patient can have more than one neuropathy.

Therapeutics for Sjögren disease is another example of an area that has been “very haphazard,” he added.

The guidelines are aimed not just at specialists but also at general practitioners who treat many of these patients. But Dr. Hammitt emphasized that neurologists can be “instrumental” in identifying Sjögren disease in patients with PNS symptoms.

“Our hope is that specialists — in this case, neurologists — will recognize the potential for this condition in their PNS patients and ensure referral to a rheumatologist or knowledgeable family practitioner to manage overall care.”

The committee will soon submit its manuscript to the AAN for publication.

“Once published, we will have a robust dissemination strategy to ensure that providers, patients, and policymakers are aware of, and use, this very valuable resource,” said Dr. Hammitt.

No conflicts of interest were reported.

A version of this article appeared on Medscape.com.

New guidelines to manage peripheral neuropathy related to Sjögren disease have been developed by a multidisciplinary team of physicians from across medicine.

The guidelines will provide an evidence-based resource for the assessment, diagnosis, and treatment of various peripheral neuropathies related to the disorder.

Up until now, the field has been “haphazard and chaotic,” lead author George Sarka, MD, DrPH, MPH, director of the CME Committee for MemorialCare, Saddleback Medical Center, Laguna Hills, California, and member of the Sjögren Foundation PNS Guidelines Topic Review Group (TRG), told this news organization.

Dr. Sarka discussed the initiative at the American Academy of Neurology 2024 annual meeting.


 

Severe, Complex Illness

Sjögren disease is the second most common autoimmune rheumatic disorder after rheumatoid arthritis, affecting an estimated 4 million Americans. Women make up most of the patient population at a ratio of 9:1.

The condition typically affects the mucous membranes and moisture-secreting glands of the eyes and mouth, resulting in decreased tears and saliva. But peripheral nervous system (PNS) manifestations often precede these symptoms and can occur in up to 60% of Sjögren disease cases.

“Traditionally, Sjögren’s was looked at as a dry eye and dry mouth disease, but we realize now that it’s so much broader than that,” said Dr. Sarka. “It’s a severe, systemic, and complex illness that can affect any body organ or system, and the nervous system is frequently affected.”

PNS manifestations cause more than mere discomfort; they can lead to diagnostic and management challenges, costly treatments, and diminished quality of life.

Getting a proper diagnosis goes a long way toward improving the quality of life for these patients, Steven Mandel, MD, clinical professor of neurology at the Zucker School of Medicine at Hofstra-Northwell, adjunct clinical professor of medicine at NY Medical College, New York City, and member of the TRG, told this news organization.

The problem is, doctors don’t always think an autoimmune disorder is causing the symptoms, said Dr. Sarka. “There’s an old adage in neurology that if you don’t think about it, you’re going to miss it; you have to ask, and that’s what we’re trying to get people to do.”

The condition often accompanies other immune system disorders such as rheumatoid arthritis and lupus. But as patients are referred back and forth between ophthalmologists, rheumatologists, and neurologists, the condition is often missed. “It could be 4 or 5 years before a definitive diagnosis of Sjögren’s is made,” said Dr. Sarka.

He believes the education system is partly to blame. “Medical schools have been very deficient in teaching people about recognizing Sjögren disease.”

That leaves many physicians at a loss about “what to do with these patients when they walk in the door,” said Dr. Mandel. “They don’t know how to manage them; they don’t know how to diagnose them; and they don’t know how to treat them.”

Developing guidelines with multispecialty collaboration was “absolutely critical” in addressing this knowledge gap, Dr. Mandel added. That process involved “a very rigorous and transparent methodology so that it would be accepted by all the professionals involved in Sjögren’s,” he said.

The process took 3 years and involved amassing and grading the evidence, getting consensus from committee members, developing recommendations, and getting feedback and external review.
 

Scant Evidence

An early literature search revealed very little evidence on PNS manifestations in patients with Sjögren disease, so the guideline committee “leaned very heavily on expert opinion” to develop recommendations, Kathy Hammitt, MA, vice president of Medical and Scientific Affairs, Sjögren’s Foundation, told this news organization.

The literature search also showed different terms are used to describe PNS, “which is where the chaos comes in,” said Dr. Sarka.

Experts from different specialties worked together to define and align nomenclature used by various specialists. They developed definitions for seven PNS categories including mononeuropathy, large fiber neuropathy, small fiber neuropathy, demyelinating polyradiculoneuropathy, ganglionopathy, vasculitis neuropathy, and autoimmune nervous system neuropathy.

The guidelines pertaining to PNS manifestations encompass a spectrum of neurologic abnormalities, including cranial neuropathies (trigeminal neuropathy or acute facial neuropathy), polyneuropathies (large fiber neuropathy, small fiber neuropathy, demyelinating polyradiculoneuropathy, vasculitis neuropathy, or ganglionopathy), and autonomic nervous system (ANS) neuropathies (postural tachycardia, orthostatic hypotension, or autonomic dysfunction).
 

Key Steps

The guidelines address two key steps for each PNS manifestation — the workup and evaluation of patients with suspected ANS manifestation including standard evaluations, diagnostic tests, and treatment. The experts developed 31 best practices for diagnosis and workup and 20 treatment recommendations.

Initial assessment of potential ANS involvement includes asking patients about orthostatic postural lightheadedness and difficulties with digestion, urination, sweating, and sexual function.

Treatment of autoimmune diseases typically focuses on relieving symptoms and can include steroids, the anticonvulsant gabapentin, the monoclonal antibody rituximab, and intravenous immunoglobulin. “The type of neuropathy will mandate or suggest certain therapies over others,” said Dr. Sarka, adding that a patient can have more than one neuropathy.

Therapeutics for Sjögren disease is another example of an area that has been “very haphazard,” he added.

The guidelines are aimed not just at specialists but also at general practitioners who treat many of these patients. But Dr. Hammitt emphasized that neurologists can be “instrumental” in identifying Sjögren disease in patients with PNS symptoms.

“Our hope is that specialists — in this case, neurologists — will recognize the potential for this condition in their PNS patients and ensure referral to a rheumatologist or knowledgeable family practitioner to manage overall care.”

The committee will soon submit its manuscript to the AAN for publication.

“Once published, we will have a robust dissemination strategy to ensure that providers, patients, and policymakers are aware of, and use, this very valuable resource,” said Dr. Hammitt.

No conflicts of interest were reported.

A version of this article appeared on Medscape.com.

New guidelines to manage peripheral neuropathy related to Sjögren disease have been developed by a multidisciplinary team of physicians from across medicine.

The guidelines will provide an evidence-based resource for the assessment, diagnosis, and treatment of various peripheral neuropathies related to the disorder.

Up until now, the field has been “haphazard and chaotic,” lead author George Sarka, MD, DrPH, MPH, director of the CME Committee for MemorialCare, Saddleback Medical Center, Laguna Hills, California, and member of the Sjögren Foundation PNS Guidelines Topic Review Group (TRG), told this news organization.

Dr. Sarka discussed the initiative at the American Academy of Neurology 2024 annual meeting.


 

Severe, Complex Illness

Sjögren disease is the second most common autoimmune rheumatic disorder after rheumatoid arthritis, affecting an estimated 4 million Americans. Women make up most of the patient population at a ratio of 9:1.

The condition typically affects the mucous membranes and moisture-secreting glands of the eyes and mouth, resulting in decreased tears and saliva. But peripheral nervous system (PNS) manifestations often precede these symptoms and can occur in up to 60% of Sjögren disease cases.

“Traditionally, Sjögren’s was looked at as a dry eye and dry mouth disease, but we realize now that it’s so much broader than that,” said Dr. Sarka. “It’s a severe, systemic, and complex illness that can affect any body organ or system, and the nervous system is frequently affected.”

PNS manifestations cause more than mere discomfort; they can lead to diagnostic and management challenges, costly treatments, and diminished quality of life.

Getting a proper diagnosis goes a long way toward improving the quality of life for these patients, Steven Mandel, MD, clinical professor of neurology at the Zucker School of Medicine at Hofstra-Northwell, adjunct clinical professor of medicine at NY Medical College, New York City, and member of the TRG, told this news organization.

The problem is, doctors don’t always think an autoimmune disorder is causing the symptoms, said Dr. Sarka. “There’s an old adage in neurology that if you don’t think about it, you’re going to miss it; you have to ask, and that’s what we’re trying to get people to do.”

The condition often accompanies other immune system disorders such as rheumatoid arthritis and lupus. But as patients are referred back and forth between ophthalmologists, rheumatologists, and neurologists, the condition is often missed. “It could be 4 or 5 years before a definitive diagnosis of Sjögren’s is made,” said Dr. Sarka.

He believes the education system is partly to blame. “Medical schools have been very deficient in teaching people about recognizing Sjögren disease.”

That leaves many physicians at a loss about “what to do with these patients when they walk in the door,” said Dr. Mandel. “They don’t know how to manage them; they don’t know how to diagnose them; and they don’t know how to treat them.”

Developing guidelines with multispecialty collaboration was “absolutely critical” in addressing this knowledge gap, Dr. Mandel added. That process involved “a very rigorous and transparent methodology so that it would be accepted by all the professionals involved in Sjögren’s,” he said.

The process took 3 years and involved amassing and grading the evidence, getting consensus from committee members, developing recommendations, and getting feedback and external review.
 

Scant Evidence

An early literature search revealed very little evidence on PNS manifestations in patients with Sjögren disease, so the guideline committee “leaned very heavily on expert opinion” to develop recommendations, Kathy Hammitt, MA, vice president of Medical and Scientific Affairs, Sjögren’s Foundation, told this news organization.

The literature search also showed different terms are used to describe PNS, “which is where the chaos comes in,” said Dr. Sarka.

Experts from different specialties worked together to define and align nomenclature used by various specialists. They developed definitions for seven PNS categories including mononeuropathy, large fiber neuropathy, small fiber neuropathy, demyelinating polyradiculoneuropathy, ganglionopathy, vasculitis neuropathy, and autoimmune nervous system neuropathy.

The guidelines pertaining to PNS manifestations encompass a spectrum of neurologic abnormalities, including cranial neuropathies (trigeminal neuropathy or acute facial neuropathy), polyneuropathies (large fiber neuropathy, small fiber neuropathy, demyelinating polyradiculoneuropathy, vasculitis neuropathy, or ganglionopathy), and autonomic nervous system (ANS) neuropathies (postural tachycardia, orthostatic hypotension, or autonomic dysfunction).
 

Key Steps

The guidelines address two key steps for each PNS manifestation — the workup and evaluation of patients with suspected ANS manifestation including standard evaluations, diagnostic tests, and treatment. The experts developed 31 best practices for diagnosis and workup and 20 treatment recommendations.

Initial assessment of potential ANS involvement includes asking patients about orthostatic postural lightheadedness and difficulties with digestion, urination, sweating, and sexual function.

Treatment of autoimmune diseases typically focuses on relieving symptoms and can include steroids, the anticonvulsant gabapentin, the monoclonal antibody rituximab, and intravenous immunoglobulin. “The type of neuropathy will mandate or suggest certain therapies over others,” said Dr. Sarka, adding that a patient can have more than one neuropathy.

Therapeutics for Sjögren disease is another example of an area that has been “very haphazard,” he added.

The guidelines are aimed not just at specialists but also at general practitioners who treat many of these patients. But Dr. Hammitt emphasized that neurologists can be “instrumental” in identifying Sjögren disease in patients with PNS symptoms.

“Our hope is that specialists — in this case, neurologists — will recognize the potential for this condition in their PNS patients and ensure referral to a rheumatologist or knowledgeable family practitioner to manage overall care.”

The committee will soon submit its manuscript to the AAN for publication.

“Once published, we will have a robust dissemination strategy to ensure that providers, patients, and policymakers are aware of, and use, this very valuable resource,” said Dr. Hammitt.

No conflicts of interest were reported.

A version of this article appeared on Medscape.com.

DENVER — Two new drugs are headed toward pivotal trials after making their endpoints in phase 2 treatment-resistant epilepsy studies, while a first-in-man study of an implantable product suggests a new direction for this disease , according to new data presented at the 2024 annual meeting of the American Academy of Neurology.

Of the two drugs evaluated in phase 2 trials, one is a highly targeted TARP-8–dependent AMPA receptor antagonist known as ES-481. The other is XEN1101, a novel potassium channel opener that was well tolerated as well as effective.

TARP inhibitors, which act on transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor regulatory proteins, are already available for the control of epilepsy, but ES-481 might be different, according to Terrence J. O’Brien, MD, department of neuroscience, Monash University, Melbourne, Australia.
 

First-in-Class TARP Inhibitor Is Tested

As a “first-in-class, potent and selective antagonist of the TARP-γ8 AMPA receptor,” ES-481 is “predicted to effectively suppress focal seizures arising from the hippocampus and limbic system,” he said. Dr. O’Brien claims that this specificity of action appears to circumvent central nervous system side effects in studies so far.

In the phase 2a multicenter, randomized trial, 22 patients with drug-resistant epilepsy of any type (focal, generalized, or mixed) were randomized to ES-481 or placebo. In the ES-481 arm, the dose was escalated each week, climbing from 25 mg once-daily, to 25 mg twice-daily, 50 mg twice-daily, and then to 75 mg twice daily. At the end of 4 weeks and after a 7-day washout, the randomized groups were crossed over to the opposite therapy for another 4 weeks.

When data were confined to the first treatment period to avoid a carry-over effect, there was a consistent advantage for active treatment over placebo. At the highest 75-mg twice-daily dose of ES-481, the reduction in seizure frequency was 80% vs 49% on placebo ( P < .05).

The rate of complete remission at the end of the study was not greater for ES-481, but higher proportions of patients on active therapy achieved reductions from baseline in seizure activity when defined as greater than 30% (72.77% vs 36.4%) or greater than 50% (36.4% vs 18.2%). P values for these differences were not provided.

Differences in EEG were not observed, but Dr. O’Brien reported that 18 of the subjects had no EEG activity at baseline, diminishing the opportunity to show a difference.
 

Open-Label Study Supports Controlled Data

Sixteen patients have entered an open-label extension with sustained suppression of seizure activity relative to baseline observed so far, Dr. O’Brien reported.

ES-481 was well tolerated. There were no significant changes in lab values, and all four of the adverse events leading to discontinuation occurred on placebo. There were higher rates of dizziness, insomnia, gait disturbance, and dysarthria associated with ES-481 than placebo, but the rate of serious adverse events was lower (4.8% vs 14.3%).

These response rates are noteworthy because patients had severe disease with diminishing therapeutic options, according to Dr. O’Brien. For entry, patients were required to be taking one to four antiseizure medications while still experiencing seizure activity. The patients averaged one interictal epileptiform discharge and/or seizure per hour on EEG.

Large-scale, double-blind, controlled studies are planned and warranted on the basis of these data, according to Dr. O’Brien, who emphasized that benefit was achieved with a low relative risk of significant adverse events.
 

New Potassium Channel Opener Shows Promise

Data with the selective potassium channel opener XEN1101 from the previously published phase 2b X-TOLE trial were reported in two parts. The first set of data involved an analysis of response by baseline activity. The other set of data were generated by an ongoing open-label extension (OLE) of X-TOLE.

In X-TOLE, which randomized 325 patients with treatment-resistant focal-onset seizures (FOS) to one of three doses of XEN-1011 or placebo, the median reduction in FOS at the highest dose of 25 mg once-daily XEN-1011 was 52.8% vs placebo (P < .001).

In the new analysis, the goal was to look at efficacy of the 25-mg dose across differences in baseline severity, reported Roger J. Porter, MD, adjunct professor of neurology, University of Pennsylvania, Philadelphia.

Generally, a greater response was observed for those with less severe disease. For example, the response rate defined as greater than 50% reduction in seizure frequency on XEN1101 was higher for those with a baseline seizure activity of 8.5 seizures/month or fewer relative to more (65.5% vs 50.6%) and six or fewer antiseizure medications relative to more (64.2% vs 40.0%).

Pointing out that the study enrolled a challenging group of patients, Dr. Porter said that the data do not rule out efficacy “across the spectrum of epilepsy severity,” but he did suggest that these data will provide context for the coming phase 3 trials.

In the OLE data presented by Jacqueline French, MD, professor of neurology at the Langone School of Medicine of New York University, the efficacy and safety of XEN1101 taken with food has been consistent with what was observed in the double-blind trial. With up to 2 years of follow-up in the planned 5-year OLE, which is evaluating 20 mg once-daily taken with food, 60% are still on therapy,

For those followed for 24 months, 23.6% are completely seizure free, according to Dr. French. For those followed at least 12 months, 31.5% have achieved a median percent reduction in monthly seizure activity of 90% or more; 41.8% a reduction of 75% or more; and 69.7% a reduction of 50% or more.

The side-effect profile has also been consistent with that seen in the phase 2b trial. Dizziness and other mild to moderate side effects that often accompany antiseizure medications have been observed, along with modest weight gain, but there have been no new safety signals over long-term use.

If a planned phase 3 study enrolling patients with localized and general epilepsy confirms these phase 2 data, Dr. French indicated that it has the potential to advance a potassium channel opener that is both efficacious and well tolerated.
 

First-in-Man Study Performed With Stem Cell Product

The investigational product for treatment-resistant epilepsy has data on just five patients. Yet, the two patients followed the longest, both of which had highly treatment-resistant epilepsy, have had reductions in seizure activity exceeding 95%, according to Cory Nicholas, PhD, the chief executive officer of Neurona Therapeutics.

NRTX-100 is a GABAergic interneuron product derived from human pluripotent stem cells. The NRTX cells are surgically transplanted into the head and body of the hippocampus in patients with unilateral temporal lobe epilepsy with hippocampal sclerosis. The procedure is performed with MRI guidance, and patients are placed on immunosuppression that starts 1 week before surgery and is tapered 1 year later.

In this first-in-man study, the primary outcome of interest was safety. There have been no adverse events associated with this stem cell product in follow-up so far, according to Dr. Nicholas, who presented data on the first 5 of 10 procedures that have been completed so far.

Consistent with the prior work in animal models, it takes several months for the reduction in seizures to be achieved and, in animal models, to see improved functionality. It is notable that the reductions in seizure activity observed over time in those patients followed the longest have been accompanied by evidence of neurocognitive improvement, Dr. Nicholas reported.

“The efficacy has seemed durable so far, and we expect incremental improvement in clinical response over time,” said Dr. Nicholas, who reported that the Food and Drug Administration has already approved a second clinical study.
 

Are New Antiseizure Therapies Needed?

The value of this and the other emerging therapies is that “no treatment for epilepsy works well in every patient. We continue to need a wide array of treatments to find the one right for the patient in front of us,” said Nassim Zecavati, MD, director of Epilepsy, Children’s Hospital, Virginia Commonwealth University, Richmond.

Asked to comment on the promise of these three therapies, Dr. Zecavati suggested each is intriguing for different reasons. AMPA receptor antagonists have proven to be a promising drug class so far, suggesting that “another could be helpful.” Potassium channel openers appear to have “a great mechanism of action,” but Dr. Zecavati said drugs in this class with a more favorable safety profile are needed.

As for NRTX-1001, she was intrigued with its novelty. She speculated that it might have particular promise for intractable drug-resistant epilepsy in patients who are not candidates for standard surgical strategies but might tolerate a less invasive procedure.

“My question might be who is going to perform this procedure,” Dr. Zecavati said. Noting that experience and skill might be needed to achieve an optimal result with cell transplantation into the brain, she said she will be waiting for more studies that might answer this question and to determine where, if effective, it would fit among current options.

Dr. O’Brien reported financial relationships with Eisai, Kinoxis, Livanova, Supernus, and UCB Pharma. Dr. Porter reported financial relationships with Axonis, Engrail, Longboard, Neurocrine, and Xenon, which provided funding for the study he discussed. Dr. French has financial relationships with more than 20 pharmaceutical companies, including Xenon, which provided funding for the study she discussed. Dr. Nicholas is chief executive officer of Neurona Therapeutics. Dr. Zecavati reported no potential conflicts of interest.

DENVER — Two new drugs are headed toward pivotal trials after making their endpoints in phase 2 treatment-resistant epilepsy studies, while a first-in-man study of an implantable product suggests a new direction for this disease , according to new data presented at the 2024 annual meeting of the American Academy of Neurology.

Of the two drugs evaluated in phase 2 trials, one is a highly targeted TARP-8–dependent AMPA receptor antagonist known as ES-481. The other is XEN1101, a novel potassium channel opener that was well tolerated as well as effective.

TARP inhibitors, which act on transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor regulatory proteins, are already available for the control of epilepsy, but ES-481 might be different, according to Terrence J. O’Brien, MD, department of neuroscience, Monash University, Melbourne, Australia.
 

First-in-Class TARP Inhibitor Is Tested

As a “first-in-class, potent and selective antagonist of the TARP-γ8 AMPA receptor,” ES-481 is “predicted to effectively suppress focal seizures arising from the hippocampus and limbic system,” he said. Dr. O’Brien claims that this specificity of action appears to circumvent central nervous system side effects in studies so far.

In the phase 2a multicenter, randomized trial, 22 patients with drug-resistant epilepsy of any type (focal, generalized, or mixed) were randomized to ES-481 or placebo. In the ES-481 arm, the dose was escalated each week, climbing from 25 mg once-daily, to 25 mg twice-daily, 50 mg twice-daily, and then to 75 mg twice daily. At the end of 4 weeks and after a 7-day washout, the randomized groups were crossed over to the opposite therapy for another 4 weeks.

When data were confined to the first treatment period to avoid a carry-over effect, there was a consistent advantage for active treatment over placebo. At the highest 75-mg twice-daily dose of ES-481, the reduction in seizure frequency was 80% vs 49% on placebo ( P < .05).

The rate of complete remission at the end of the study was not greater for ES-481, but higher proportions of patients on active therapy achieved reductions from baseline in seizure activity when defined as greater than 30% (72.77% vs 36.4%) or greater than 50% (36.4% vs 18.2%). P values for these differences were not provided.

Differences in EEG were not observed, but Dr. O’Brien reported that 18 of the subjects had no EEG activity at baseline, diminishing the opportunity to show a difference.
 

Open-Label Study Supports Controlled Data

Sixteen patients have entered an open-label extension with sustained suppression of seizure activity relative to baseline observed so far, Dr. O’Brien reported.

ES-481 was well tolerated. There were no significant changes in lab values, and all four of the adverse events leading to discontinuation occurred on placebo. There were higher rates of dizziness, insomnia, gait disturbance, and dysarthria associated with ES-481 than placebo, but the rate of serious adverse events was lower (4.8% vs 14.3%).

These response rates are noteworthy because patients had severe disease with diminishing therapeutic options, according to Dr. O’Brien. For entry, patients were required to be taking one to four antiseizure medications while still experiencing seizure activity. The patients averaged one interictal epileptiform discharge and/or seizure per hour on EEG.

Large-scale, double-blind, controlled studies are planned and warranted on the basis of these data, according to Dr. O’Brien, who emphasized that benefit was achieved with a low relative risk of significant adverse events.
 

New Potassium Channel Opener Shows Promise

Data with the selective potassium channel opener XEN1101 from the previously published phase 2b X-TOLE trial were reported in two parts. The first set of data involved an analysis of response by baseline activity. The other set of data were generated by an ongoing open-label extension (OLE) of X-TOLE.

In X-TOLE, which randomized 325 patients with treatment-resistant focal-onset seizures (FOS) to one of three doses of XEN-1011 or placebo, the median reduction in FOS at the highest dose of 25 mg once-daily XEN-1011 was 52.8% vs placebo (P < .001).

In the new analysis, the goal was to look at efficacy of the 25-mg dose across differences in baseline severity, reported Roger J. Porter, MD, adjunct professor of neurology, University of Pennsylvania, Philadelphia.

Generally, a greater response was observed for those with less severe disease. For example, the response rate defined as greater than 50% reduction in seizure frequency on XEN1101 was higher for those with a baseline seizure activity of 8.5 seizures/month or fewer relative to more (65.5% vs 50.6%) and six or fewer antiseizure medications relative to more (64.2% vs 40.0%).

Pointing out that the study enrolled a challenging group of patients, Dr. Porter said that the data do not rule out efficacy “across the spectrum of epilepsy severity,” but he did suggest that these data will provide context for the coming phase 3 trials.

In the OLE data presented by Jacqueline French, MD, professor of neurology at the Langone School of Medicine of New York University, the efficacy and safety of XEN1101 taken with food has been consistent with what was observed in the double-blind trial. With up to 2 years of follow-up in the planned 5-year OLE, which is evaluating 20 mg once-daily taken with food, 60% are still on therapy,

For those followed for 24 months, 23.6% are completely seizure free, according to Dr. French. For those followed at least 12 months, 31.5% have achieved a median percent reduction in monthly seizure activity of 90% or more; 41.8% a reduction of 75% or more; and 69.7% a reduction of 50% or more.

The side-effect profile has also been consistent with that seen in the phase 2b trial. Dizziness and other mild to moderate side effects that often accompany antiseizure medications have been observed, along with modest weight gain, but there have been no new safety signals over long-term use.

If a planned phase 3 study enrolling patients with localized and general epilepsy confirms these phase 2 data, Dr. French indicated that it has the potential to advance a potassium channel opener that is both efficacious and well tolerated.
 

First-in-Man Study Performed With Stem Cell Product

The investigational product for treatment-resistant epilepsy has data on just five patients. Yet, the two patients followed the longest, both of which had highly treatment-resistant epilepsy, have had reductions in seizure activity exceeding 95%, according to Cory Nicholas, PhD, the chief executive officer of Neurona Therapeutics.

NRTX-100 is a GABAergic interneuron product derived from human pluripotent stem cells. The NRTX cells are surgically transplanted into the head and body of the hippocampus in patients with unilateral temporal lobe epilepsy with hippocampal sclerosis. The procedure is performed with MRI guidance, and patients are placed on immunosuppression that starts 1 week before surgery and is tapered 1 year later.

In this first-in-man study, the primary outcome of interest was safety. There have been no adverse events associated with this stem cell product in follow-up so far, according to Dr. Nicholas, who presented data on the first 5 of 10 procedures that have been completed so far.

Consistent with the prior work in animal models, it takes several months for the reduction in seizures to be achieved and, in animal models, to see improved functionality. It is notable that the reductions in seizure activity observed over time in those patients followed the longest have been accompanied by evidence of neurocognitive improvement, Dr. Nicholas reported.

“The efficacy has seemed durable so far, and we expect incremental improvement in clinical response over time,” said Dr. Nicholas, who reported that the Food and Drug Administration has already approved a second clinical study.
 

Are New Antiseizure Therapies Needed?

The value of this and the other emerging therapies is that “no treatment for epilepsy works well in every patient. We continue to need a wide array of treatments to find the one right for the patient in front of us,” said Nassim Zecavati, MD, director of Epilepsy, Children’s Hospital, Virginia Commonwealth University, Richmond.

Asked to comment on the promise of these three therapies, Dr. Zecavati suggested each is intriguing for different reasons. AMPA receptor antagonists have proven to be a promising drug class so far, suggesting that “another could be helpful.” Potassium channel openers appear to have “a great mechanism of action,” but Dr. Zecavati said drugs in this class with a more favorable safety profile are needed.

As for NRTX-1001, she was intrigued with its novelty. She speculated that it might have particular promise for intractable drug-resistant epilepsy in patients who are not candidates for standard surgical strategies but might tolerate a less invasive procedure.

“My question might be who is going to perform this procedure,” Dr. Zecavati said. Noting that experience and skill might be needed to achieve an optimal result with cell transplantation into the brain, she said she will be waiting for more studies that might answer this question and to determine where, if effective, it would fit among current options.

Dr. O’Brien reported financial relationships with Eisai, Kinoxis, Livanova, Supernus, and UCB Pharma. Dr. Porter reported financial relationships with Axonis, Engrail, Longboard, Neurocrine, and Xenon, which provided funding for the study he discussed. Dr. French has financial relationships with more than 20 pharmaceutical companies, including Xenon, which provided funding for the study she discussed. Dr. Nicholas is chief executive officer of Neurona Therapeutics. Dr. Zecavati reported no potential conflicts of interest.

DENVER — Two new drugs are headed toward pivotal trials after making their endpoints in phase 2 treatment-resistant epilepsy studies, while a first-in-man study of an implantable product suggests a new direction for this disease , according to new data presented at the 2024 annual meeting of the American Academy of Neurology.

Of the two drugs evaluated in phase 2 trials, one is a highly targeted TARP-8–dependent AMPA receptor antagonist known as ES-481. The other is XEN1101, a novel potassium channel opener that was well tolerated as well as effective.

TARP inhibitors, which act on transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor regulatory proteins, are already available for the control of epilepsy, but ES-481 might be different, according to Terrence J. O’Brien, MD, department of neuroscience, Monash University, Melbourne, Australia.
 

First-in-Class TARP Inhibitor Is Tested

As a “first-in-class, potent and selective antagonist of the TARP-γ8 AMPA receptor,” ES-481 is “predicted to effectively suppress focal seizures arising from the hippocampus and limbic system,” he said. Dr. O’Brien claims that this specificity of action appears to circumvent central nervous system side effects in studies so far.

In the phase 2a multicenter, randomized trial, 22 patients with drug-resistant epilepsy of any type (focal, generalized, or mixed) were randomized to ES-481 or placebo. In the ES-481 arm, the dose was escalated each week, climbing from 25 mg once-daily, to 25 mg twice-daily, 50 mg twice-daily, and then to 75 mg twice daily. At the end of 4 weeks and after a 7-day washout, the randomized groups were crossed over to the opposite therapy for another 4 weeks.

When data were confined to the first treatment period to avoid a carry-over effect, there was a consistent advantage for active treatment over placebo. At the highest 75-mg twice-daily dose of ES-481, the reduction in seizure frequency was 80% vs 49% on placebo ( P < .05).

The rate of complete remission at the end of the study was not greater for ES-481, but higher proportions of patients on active therapy achieved reductions from baseline in seizure activity when defined as greater than 30% (72.77% vs 36.4%) or greater than 50% (36.4% vs 18.2%). P values for these differences were not provided.

Differences in EEG were not observed, but Dr. O’Brien reported that 18 of the subjects had no EEG activity at baseline, diminishing the opportunity to show a difference.
 

Open-Label Study Supports Controlled Data

Sixteen patients have entered an open-label extension with sustained suppression of seizure activity relative to baseline observed so far, Dr. O’Brien reported.

ES-481 was well tolerated. There were no significant changes in lab values, and all four of the adverse events leading to discontinuation occurred on placebo. There were higher rates of dizziness, insomnia, gait disturbance, and dysarthria associated with ES-481 than placebo, but the rate of serious adverse events was lower (4.8% vs 14.3%).

These response rates are noteworthy because patients had severe disease with diminishing therapeutic options, according to Dr. O’Brien. For entry, patients were required to be taking one to four antiseizure medications while still experiencing seizure activity. The patients averaged one interictal epileptiform discharge and/or seizure per hour on EEG.

Large-scale, double-blind, controlled studies are planned and warranted on the basis of these data, according to Dr. O’Brien, who emphasized that benefit was achieved with a low relative risk of significant adverse events.
 

New Potassium Channel Opener Shows Promise

Data with the selective potassium channel opener XEN1101 from the previously published phase 2b X-TOLE trial were reported in two parts. The first set of data involved an analysis of response by baseline activity. The other set of data were generated by an ongoing open-label extension (OLE) of X-TOLE.

In X-TOLE, which randomized 325 patients with treatment-resistant focal-onset seizures (FOS) to one of three doses of XEN-1011 or placebo, the median reduction in FOS at the highest dose of 25 mg once-daily XEN-1011 was 52.8% vs placebo (P < .001).

In the new analysis, the goal was to look at efficacy of the 25-mg dose across differences in baseline severity, reported Roger J. Porter, MD, adjunct professor of neurology, University of Pennsylvania, Philadelphia.

Generally, a greater response was observed for those with less severe disease. For example, the response rate defined as greater than 50% reduction in seizure frequency on XEN1101 was higher for those with a baseline seizure activity of 8.5 seizures/month or fewer relative to more (65.5% vs 50.6%) and six or fewer antiseizure medications relative to more (64.2% vs 40.0%).

Pointing out that the study enrolled a challenging group of patients, Dr. Porter said that the data do not rule out efficacy “across the spectrum of epilepsy severity,” but he did suggest that these data will provide context for the coming phase 3 trials.

In the OLE data presented by Jacqueline French, MD, professor of neurology at the Langone School of Medicine of New York University, the efficacy and safety of XEN1101 taken with food has been consistent with what was observed in the double-blind trial. With up to 2 years of follow-up in the planned 5-year OLE, which is evaluating 20 mg once-daily taken with food, 60% are still on therapy,

For those followed for 24 months, 23.6% are completely seizure free, according to Dr. French. For those followed at least 12 months, 31.5% have achieved a median percent reduction in monthly seizure activity of 90% or more; 41.8% a reduction of 75% or more; and 69.7% a reduction of 50% or more.

The side-effect profile has also been consistent with that seen in the phase 2b trial. Dizziness and other mild to moderate side effects that often accompany antiseizure medications have been observed, along with modest weight gain, but there have been no new safety signals over long-term use.

If a planned phase 3 study enrolling patients with localized and general epilepsy confirms these phase 2 data, Dr. French indicated that it has the potential to advance a potassium channel opener that is both efficacious and well tolerated.
 

First-in-Man Study Performed With Stem Cell Product

The investigational product for treatment-resistant epilepsy has data on just five patients. Yet, the two patients followed the longest, both of which had highly treatment-resistant epilepsy, have had reductions in seizure activity exceeding 95%, according to Cory Nicholas, PhD, the chief executive officer of Neurona Therapeutics.

NRTX-100 is a GABAergic interneuron product derived from human pluripotent stem cells. The NRTX cells are surgically transplanted into the head and body of the hippocampus in patients with unilateral temporal lobe epilepsy with hippocampal sclerosis. The procedure is performed with MRI guidance, and patients are placed on immunosuppression that starts 1 week before surgery and is tapered 1 year later.

In this first-in-man study, the primary outcome of interest was safety. There have been no adverse events associated with this stem cell product in follow-up so far, according to Dr. Nicholas, who presented data on the first 5 of 10 procedures that have been completed so far.

Consistent with the prior work in animal models, it takes several months for the reduction in seizures to be achieved and, in animal models, to see improved functionality. It is notable that the reductions in seizure activity observed over time in those patients followed the longest have been accompanied by evidence of neurocognitive improvement, Dr. Nicholas reported.

“The efficacy has seemed durable so far, and we expect incremental improvement in clinical response over time,” said Dr. Nicholas, who reported that the Food and Drug Administration has already approved a second clinical study.
 

Are New Antiseizure Therapies Needed?

The value of this and the other emerging therapies is that “no treatment for epilepsy works well in every patient. We continue to need a wide array of treatments to find the one right for the patient in front of us,” said Nassim Zecavati, MD, director of Epilepsy, Children’s Hospital, Virginia Commonwealth University, Richmond.

Asked to comment on the promise of these three therapies, Dr. Zecavati suggested each is intriguing for different reasons. AMPA receptor antagonists have proven to be a promising drug class so far, suggesting that “another could be helpful.” Potassium channel openers appear to have “a great mechanism of action,” but Dr. Zecavati said drugs in this class with a more favorable safety profile are needed.

As for NRTX-1001, she was intrigued with its novelty. She speculated that it might have particular promise for intractable drug-resistant epilepsy in patients who are not candidates for standard surgical strategies but might tolerate a less invasive procedure.

“My question might be who is going to perform this procedure,” Dr. Zecavati said. Noting that experience and skill might be needed to achieve an optimal result with cell transplantation into the brain, she said she will be waiting for more studies that might answer this question and to determine where, if effective, it would fit among current options.

Dr. O’Brien reported financial relationships with Eisai, Kinoxis, Livanova, Supernus, and UCB Pharma. Dr. Porter reported financial relationships with Axonis, Engrail, Longboard, Neurocrine, and Xenon, which provided funding for the study he discussed. Dr. French has financial relationships with more than 20 pharmaceutical companies, including Xenon, which provided funding for the study she discussed. Dr. Nicholas is chief executive officer of Neurona Therapeutics. Dr. Zecavati reported no potential conflicts of interest.

DENVER — Among patients with major depressive disorder, transcranial magnetic stimulation (TMS) had similar efficacy to electroconvulsive therapy (ECT), according to results from a retrospective study of patients treated in the past 20 years.

“We always learn in our textbooks that after about two or three medication trials is when you can start exploring more serious treatment protocols, such as ECT or TMS, but a lot of these patients weren’t going forward with it, and I was curious about it. I figured that TMS, which is a less expensive, less scary procedure that patients would more likely be open to, that is also approved for treatment resistant depression, would be a good alternative to ECT,” said Anuttham Kandhadai, a third-year medical student at University of Texas Medical Branch at Galveston, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
 

Study Findings Lead to More Questions

The researchers found lower rates of depressive episodes, suicidal attempts, and suicidal ideation among patients treated with TMS, but an important limitation was that the researchers did not know the severity of the depression in the two patient groups, according to Branch Coslett, MD, who attended the session and has performed research with TMS to treat aphasia in stroke patients. “I think it’s a very interesting study, and certainly something worth pursuing, but given that ECT is only used as a last resort, whereas TMS is often used as a second-line therapy, I think you’re really talking about very different populations that have had these treatments,” said Dr. Coslett.

Mr. Kandhadai recognized the limitations of the study and looks forward to expanding the research. “I’d love to explore cost effectiveness of the treatments. I’d love to explore patient familiarity and patient comfort with different treatments. And I’d also love to explore a more controlled study that can determine how severe someone’s depression is, and then be able to control for that and explore the outcomes based on the treatment protocol,” he said.

The ideal comparative study would be prospective, “but that will never be done. One Flew Over the Cuckoo’s Nest and similar sources of information have really poisoned the well,” said Dr. Coslett. However, he noted that advances have been made in ECT, and that targeting the right hemisphere produces fewer side effects: “The outcomes from unilateral right hemisphere stimulation are said to be every bit as good or maybe better, and you don’t get the confusion, you don’t get the memory loss, you don’t get all that sort of stuff that you’d expect when somebody has a prolonged, generalized tonic-clonic seizure.”

Still, people are naturally reluctant to undergo ECT. “I’ve seen it. It’s pretty barbaric. It’s better now and at my institution, people do get it, but they really, really have to be intractable,” he said.
 

Comparing Treatment Options

Mr. Kandhadai and his co-authors used the TriNetX database to identify patients with treatment-resistant major depressive disorder who received TMS or ECT in the past 20 years. There were 2,916 patients in both cohorts, who were matched by age, sex, ethnicity, mood and behavioral disorders, endocrine disorders, intellectual disabilities, cerebrovascular disease, and other nervous system disorders. The mean age at treatment was 48.2 years, 38.5% were male, and 3.1% were Black or African American.

Short-term outcomes favored TMS, including the frequency of disorientation (0.41% vs 2.81%), retrograde amnesia (0.34% vs 0.65%), and headache (4.36% vs 7.20%). Long-term outcomes from 1 month to 5 years post treatment were also better in the TMS group, including depressive episodes (44.99% vs 53.77%), suicide attempts (3.98% vs 6.86%), and suicidal ideation (12.38% vs 23.49%). Kaplan-Meier curve analysis between 1 month and 5 years showed a benefit to TMS in probability of not experiencing a depressive episode, and not experiencing suicidal ideation.

“ECT has been the gold standard of treatment resistant depression for a long time, and it deserves to be. I think it’s something you should offer your patients. Not everyone might be comfortable with it, and if they’re not, I think it’s important to not stop the conversation there, but to offer something like TMS because TMS is something that might be more accessible to patients. It might be more affordable, and it might be less scary,” said Mr. Kandhadai

Mr. Kandhadai and Dr. Coslett have no relevant financial disclosures.

DENVER — Among patients with major depressive disorder, transcranial magnetic stimulation (TMS) had similar efficacy to electroconvulsive therapy (ECT), according to results from a retrospective study of patients treated in the past 20 years.

“We always learn in our textbooks that after about two or three medication trials is when you can start exploring more serious treatment protocols, such as ECT or TMS, but a lot of these patients weren’t going forward with it, and I was curious about it. I figured that TMS, which is a less expensive, less scary procedure that patients would more likely be open to, that is also approved for treatment resistant depression, would be a good alternative to ECT,” said Anuttham Kandhadai, a third-year medical student at University of Texas Medical Branch at Galveston, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
 

Study Findings Lead to More Questions

The researchers found lower rates of depressive episodes, suicidal attempts, and suicidal ideation among patients treated with TMS, but an important limitation was that the researchers did not know the severity of the depression in the two patient groups, according to Branch Coslett, MD, who attended the session and has performed research with TMS to treat aphasia in stroke patients. “I think it’s a very interesting study, and certainly something worth pursuing, but given that ECT is only used as a last resort, whereas TMS is often used as a second-line therapy, I think you’re really talking about very different populations that have had these treatments,” said Dr. Coslett.

Mr. Kandhadai recognized the limitations of the study and looks forward to expanding the research. “I’d love to explore cost effectiveness of the treatments. I’d love to explore patient familiarity and patient comfort with different treatments. And I’d also love to explore a more controlled study that can determine how severe someone’s depression is, and then be able to control for that and explore the outcomes based on the treatment protocol,” he said.

The ideal comparative study would be prospective, “but that will never be done. One Flew Over the Cuckoo’s Nest and similar sources of information have really poisoned the well,” said Dr. Coslett. However, he noted that advances have been made in ECT, and that targeting the right hemisphere produces fewer side effects: “The outcomes from unilateral right hemisphere stimulation are said to be every bit as good or maybe better, and you don’t get the confusion, you don’t get the memory loss, you don’t get all that sort of stuff that you’d expect when somebody has a prolonged, generalized tonic-clonic seizure.”

Still, people are naturally reluctant to undergo ECT. “I’ve seen it. It’s pretty barbaric. It’s better now and at my institution, people do get it, but they really, really have to be intractable,” he said.
 

Comparing Treatment Options

Mr. Kandhadai and his co-authors used the TriNetX database to identify patients with treatment-resistant major depressive disorder who received TMS or ECT in the past 20 years. There were 2,916 patients in both cohorts, who were matched by age, sex, ethnicity, mood and behavioral disorders, endocrine disorders, intellectual disabilities, cerebrovascular disease, and other nervous system disorders. The mean age at treatment was 48.2 years, 38.5% were male, and 3.1% were Black or African American.

Short-term outcomes favored TMS, including the frequency of disorientation (0.41% vs 2.81%), retrograde amnesia (0.34% vs 0.65%), and headache (4.36% vs 7.20%). Long-term outcomes from 1 month to 5 years post treatment were also better in the TMS group, including depressive episodes (44.99% vs 53.77%), suicide attempts (3.98% vs 6.86%), and suicidal ideation (12.38% vs 23.49%). Kaplan-Meier curve analysis between 1 month and 5 years showed a benefit to TMS in probability of not experiencing a depressive episode, and not experiencing suicidal ideation.

“ECT has been the gold standard of treatment resistant depression for a long time, and it deserves to be. I think it’s something you should offer your patients. Not everyone might be comfortable with it, and if they’re not, I think it’s important to not stop the conversation there, but to offer something like TMS because TMS is something that might be more accessible to patients. It might be more affordable, and it might be less scary,” said Mr. Kandhadai

Mr. Kandhadai and Dr. Coslett have no relevant financial disclosures.

DENVER — Among patients with major depressive disorder, transcranial magnetic stimulation (TMS) had similar efficacy to electroconvulsive therapy (ECT), according to results from a retrospective study of patients treated in the past 20 years.

“We always learn in our textbooks that after about two or three medication trials is when you can start exploring more serious treatment protocols, such as ECT or TMS, but a lot of these patients weren’t going forward with it, and I was curious about it. I figured that TMS, which is a less expensive, less scary procedure that patients would more likely be open to, that is also approved for treatment resistant depression, would be a good alternative to ECT,” said Anuttham Kandhadai, a third-year medical student at University of Texas Medical Branch at Galveston, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
 

Study Findings Lead to More Questions

The researchers found lower rates of depressive episodes, suicidal attempts, and suicidal ideation among patients treated with TMS, but an important limitation was that the researchers did not know the severity of the depression in the two patient groups, according to Branch Coslett, MD, who attended the session and has performed research with TMS to treat aphasia in stroke patients. “I think it’s a very interesting study, and certainly something worth pursuing, but given that ECT is only used as a last resort, whereas TMS is often used as a second-line therapy, I think you’re really talking about very different populations that have had these treatments,” said Dr. Coslett.

Mr. Kandhadai recognized the limitations of the study and looks forward to expanding the research. “I’d love to explore cost effectiveness of the treatments. I’d love to explore patient familiarity and patient comfort with different treatments. And I’d also love to explore a more controlled study that can determine how severe someone’s depression is, and then be able to control for that and explore the outcomes based on the treatment protocol,” he said.

The ideal comparative study would be prospective, “but that will never be done. One Flew Over the Cuckoo’s Nest and similar sources of information have really poisoned the well,” said Dr. Coslett. However, he noted that advances have been made in ECT, and that targeting the right hemisphere produces fewer side effects: “The outcomes from unilateral right hemisphere stimulation are said to be every bit as good or maybe better, and you don’t get the confusion, you don’t get the memory loss, you don’t get all that sort of stuff that you’d expect when somebody has a prolonged, generalized tonic-clonic seizure.”

Still, people are naturally reluctant to undergo ECT. “I’ve seen it. It’s pretty barbaric. It’s better now and at my institution, people do get it, but they really, really have to be intractable,” he said.
 

Comparing Treatment Options

Mr. Kandhadai and his co-authors used the TriNetX database to identify patients with treatment-resistant major depressive disorder who received TMS or ECT in the past 20 years. There were 2,916 patients in both cohorts, who were matched by age, sex, ethnicity, mood and behavioral disorders, endocrine disorders, intellectual disabilities, cerebrovascular disease, and other nervous system disorders. The mean age at treatment was 48.2 years, 38.5% were male, and 3.1% were Black or African American.

Short-term outcomes favored TMS, including the frequency of disorientation (0.41% vs 2.81%), retrograde amnesia (0.34% vs 0.65%), and headache (4.36% vs 7.20%). Long-term outcomes from 1 month to 5 years post treatment were also better in the TMS group, including depressive episodes (44.99% vs 53.77%), suicide attempts (3.98% vs 6.86%), and suicidal ideation (12.38% vs 23.49%). Kaplan-Meier curve analysis between 1 month and 5 years showed a benefit to TMS in probability of not experiencing a depressive episode, and not experiencing suicidal ideation.

“ECT has been the gold standard of treatment resistant depression for a long time, and it deserves to be. I think it’s something you should offer your patients. Not everyone might be comfortable with it, and if they’re not, I think it’s important to not stop the conversation there, but to offer something like TMS because TMS is something that might be more accessible to patients. It might be more affordable, and it might be less scary,” said Mr. Kandhadai

Mr. Kandhadai and Dr. Coslett have no relevant financial disclosures.

DENVER – Real-world, US claims-based data show major gaps in the care and management of three major neurologic disorders: Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (MS).

Investigators led by Nikki Win, PhD, medical manager/team lead, OMNI Scientific Strategy and Collaborations, US Medical Affairs, Genentech/Roche, found that patients with Parkinson’s disease were referred to a specialist most often, followed by those with MS and those with AD. 

The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
 

National Neurologist Shortage

The national neurologist shortage, coupled with the growing incidence of Alzheimer’s disease, Parkinson’s disease, MS, and other conditions has led the AAN and other organizations to call for expanding the role of primary care physicians in the diagnosis and management of neurologic disorders, the leading global cause of disability.

“These neurological conditions are increasing in prevalence and there’s a limited number of neurologists, so we wanted to understand what this looks like in the US,” Dr. Win said.

“There is a need to understand the patient journey from primary care to neurology care, from presentation of a suspected neurological disorder to diagnosis, referral to a specialist, and the time elapsed before the specialist visit for Alzheimer’s disease, MS, and Parkinson’s disease in the US,” Dr. Win added. 

Timely and accurate diagnoses of neurologic disorders can optimize treatment outcomes. Because many of these diseases are first detected during a visit with a primary care physician, it is important to understand the timeline from the initial visit to a specialist referral, the investigators noted. 
 

Analyzing Trends in Specialist Referrals

Using claims data from the Optum Normative Health Information database, researchers identified 48,525 adults with Alzheimer’s disease, 26,431 with Parkinson’s disease, and 8169 with MS who received a diagnosis from a primary care physician between 2016 and 2021.

They examined the proportion, timing, and demographic factors associated with referrals from primary care clinicians or other healthcare providers to specialists including neurologists, neurosurgeons, psychiatrists, and geriatric medicine specialists.

Results showed that patients with Parkinson’s disease were referred to a specialist most often (53%), followed by those with MS (42%) and those with Alzheimer’s disease (27%).

Individuals with Alzheimer’s disease waited the longest for a specialist referral, with a median of 10 months between the time of referral and the first specialist visit compared with 5.7 months for patients with Parkinson’s disease and 2.6 months for MS patients.

“Some patients with common conditions like Alzheimer’s disease, MS, and Parkinson’s disease don’t see a neurologist, and when they do, it can take as long as 10 months,” said Dr. Win.

Using zip code heatmaps, researchers found that the proportion of referrals for all neurologic disorders was higher in the Midwest and Northeast, whereas patients in the South and West were less likely to receive a referral. 

Referrals for Alzheimer’s disease were low nationwide, except for some areas of Michigan and New England. California had the lowest referral rate for MS, followed by regions in the South and Northeast. Patients with Parkinson’s disease living in the Midwest and Northeast were more likely than those in the West to receive a specialist referral. 

Previous studies have reported regional shortages of neurologists, said Dr. Win. “Our data seem to correlate that in terms of the areas with lower referral patterns, but as to whether that is causative or correlative, we don’t know.” 

Odds of referral were also influenced by demographic characteristics such as sex, age, race, and ethnicity, investigators found. 

For example, there were fewer referrals with increasing age across all three neurologic disorders, and men were more likely than women to be referred for Alzheimer’s disease and Parkinson’s disease. Compared with White patients, Parkinson’s disease referrals were less likely among African American, Asian, and Hispanic patients and Alzheimer’s disease referrals were less common among Asian and Hispanic patients.

Insurance status also affected referrals. People with MS and Parkinson’s disease who had commercial insurance were referred more often than were those with Medicare Advantage, said Dr. Win.

She also noted, “Additional research is needed to understand how being referred or not being referred to a neurologist actually impacts patient treatment, care and outcomes.”
 

Neurology Challenges

Commenting on the research, Thomas Vidic, MD, a community neurologist in Elkhart, Indiana, and clinical professor of neurology at Indiana University School of Medicine at South Bend, said that he was surprised by the variation in wait times for patients.

This, he said, could reflect a study limitation or a higher comfort level among primary care doctors in treating dementia.

With respect to MS, Dr. Vidic said that he believes primary care physicians may not be uncertain about prescribing the approved medications for the disease because there are so many of them.

In addition, patients with Alzheimer’s disease are older and perhaps less accepting of being referred to a specialist that may be hours away.

The bottom line for Dr. Vidic, though, is the lack of specialists. “It comes back to the fact we’re not doing a good job of having community neurologists available to take care of these problems,” he said.

The issue of community neurologist shortages was underlined by the study’s findings about geographic gaps in specialist referrals across the country, he said.

Neurologists make up about 2% of the medical workforce and this has remained static for some time, Dr. Vidic noted. Meanwhile, people are living longer and developing more neurologic diseases.

Dr. Vidic also pointed to the lack of neurology training programs. “There has not been a significant change in the number of programs in the last 10-15 years,” he said.

Study funding was not disclosed. Dr. Win reports receiving personal compensation for serving as an employee of Genentech and has stock in Genentech. Dr. Vidic reports no relevant financial disclosures.

A version of this article appeared on Medscape.com.

DENVER – Real-world, US claims-based data show major gaps in the care and management of three major neurologic disorders: Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (MS).

Investigators led by Nikki Win, PhD, medical manager/team lead, OMNI Scientific Strategy and Collaborations, US Medical Affairs, Genentech/Roche, found that patients with Parkinson’s disease were referred to a specialist most often, followed by those with MS and those with AD. 

The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
 

National Neurologist Shortage

The national neurologist shortage, coupled with the growing incidence of Alzheimer’s disease, Parkinson’s disease, MS, and other conditions has led the AAN and other organizations to call for expanding the role of primary care physicians in the diagnosis and management of neurologic disorders, the leading global cause of disability.

“These neurological conditions are increasing in prevalence and there’s a limited number of neurologists, so we wanted to understand what this looks like in the US,” Dr. Win said.

“There is a need to understand the patient journey from primary care to neurology care, from presentation of a suspected neurological disorder to diagnosis, referral to a specialist, and the time elapsed before the specialist visit for Alzheimer’s disease, MS, and Parkinson’s disease in the US,” Dr. Win added. 

Timely and accurate diagnoses of neurologic disorders can optimize treatment outcomes. Because many of these diseases are first detected during a visit with a primary care physician, it is important to understand the timeline from the initial visit to a specialist referral, the investigators noted. 
 

Analyzing Trends in Specialist Referrals

Using claims data from the Optum Normative Health Information database, researchers identified 48,525 adults with Alzheimer’s disease, 26,431 with Parkinson’s disease, and 8169 with MS who received a diagnosis from a primary care physician between 2016 and 2021.

They examined the proportion, timing, and demographic factors associated with referrals from primary care clinicians or other healthcare providers to specialists including neurologists, neurosurgeons, psychiatrists, and geriatric medicine specialists.

Results showed that patients with Parkinson’s disease were referred to a specialist most often (53%), followed by those with MS (42%) and those with Alzheimer’s disease (27%).

Individuals with Alzheimer’s disease waited the longest for a specialist referral, with a median of 10 months between the time of referral and the first specialist visit compared with 5.7 months for patients with Parkinson’s disease and 2.6 months for MS patients.

“Some patients with common conditions like Alzheimer’s disease, MS, and Parkinson’s disease don’t see a neurologist, and when they do, it can take as long as 10 months,” said Dr. Win.

Using zip code heatmaps, researchers found that the proportion of referrals for all neurologic disorders was higher in the Midwest and Northeast, whereas patients in the South and West were less likely to receive a referral. 

Referrals for Alzheimer’s disease were low nationwide, except for some areas of Michigan and New England. California had the lowest referral rate for MS, followed by regions in the South and Northeast. Patients with Parkinson’s disease living in the Midwest and Northeast were more likely than those in the West to receive a specialist referral. 

Previous studies have reported regional shortages of neurologists, said Dr. Win. “Our data seem to correlate that in terms of the areas with lower referral patterns, but as to whether that is causative or correlative, we don’t know.” 

Odds of referral were also influenced by demographic characteristics such as sex, age, race, and ethnicity, investigators found. 

For example, there were fewer referrals with increasing age across all three neurologic disorders, and men were more likely than women to be referred for Alzheimer’s disease and Parkinson’s disease. Compared with White patients, Parkinson’s disease referrals were less likely among African American, Asian, and Hispanic patients and Alzheimer’s disease referrals were less common among Asian and Hispanic patients.

Insurance status also affected referrals. People with MS and Parkinson’s disease who had commercial insurance were referred more often than were those with Medicare Advantage, said Dr. Win.

She also noted, “Additional research is needed to understand how being referred or not being referred to a neurologist actually impacts patient treatment, care and outcomes.”
 

Neurology Challenges

Commenting on the research, Thomas Vidic, MD, a community neurologist in Elkhart, Indiana, and clinical professor of neurology at Indiana University School of Medicine at South Bend, said that he was surprised by the variation in wait times for patients.

This, he said, could reflect a study limitation or a higher comfort level among primary care doctors in treating dementia.

With respect to MS, Dr. Vidic said that he believes primary care physicians may not be uncertain about prescribing the approved medications for the disease because there are so many of them.

In addition, patients with Alzheimer’s disease are older and perhaps less accepting of being referred to a specialist that may be hours away.

The bottom line for Dr. Vidic, though, is the lack of specialists. “It comes back to the fact we’re not doing a good job of having community neurologists available to take care of these problems,” he said.

The issue of community neurologist shortages was underlined by the study’s findings about geographic gaps in specialist referrals across the country, he said.

Neurologists make up about 2% of the medical workforce and this has remained static for some time, Dr. Vidic noted. Meanwhile, people are living longer and developing more neurologic diseases.

Dr. Vidic also pointed to the lack of neurology training programs. “There has not been a significant change in the number of programs in the last 10-15 years,” he said.

Study funding was not disclosed. Dr. Win reports receiving personal compensation for serving as an employee of Genentech and has stock in Genentech. Dr. Vidic reports no relevant financial disclosures.

A version of this article appeared on Medscape.com.

DENVER – Real-world, US claims-based data show major gaps in the care and management of three major neurologic disorders: Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (MS).

Investigators led by Nikki Win, PhD, medical manager/team lead, OMNI Scientific Strategy and Collaborations, US Medical Affairs, Genentech/Roche, found that patients with Parkinson’s disease were referred to a specialist most often, followed by those with MS and those with AD. 

The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
 

National Neurologist Shortage

The national neurologist shortage, coupled with the growing incidence of Alzheimer’s disease, Parkinson’s disease, MS, and other conditions has led the AAN and other organizations to call for expanding the role of primary care physicians in the diagnosis and management of neurologic disorders, the leading global cause of disability.

“These neurological conditions are increasing in prevalence and there’s a limited number of neurologists, so we wanted to understand what this looks like in the US,” Dr. Win said.

“There is a need to understand the patient journey from primary care to neurology care, from presentation of a suspected neurological disorder to diagnosis, referral to a specialist, and the time elapsed before the specialist visit for Alzheimer’s disease, MS, and Parkinson’s disease in the US,” Dr. Win added. 

Timely and accurate diagnoses of neurologic disorders can optimize treatment outcomes. Because many of these diseases are first detected during a visit with a primary care physician, it is important to understand the timeline from the initial visit to a specialist referral, the investigators noted. 
 

Analyzing Trends in Specialist Referrals

Using claims data from the Optum Normative Health Information database, researchers identified 48,525 adults with Alzheimer’s disease, 26,431 with Parkinson’s disease, and 8169 with MS who received a diagnosis from a primary care physician between 2016 and 2021.

They examined the proportion, timing, and demographic factors associated with referrals from primary care clinicians or other healthcare providers to specialists including neurologists, neurosurgeons, psychiatrists, and geriatric medicine specialists.

Results showed that patients with Parkinson’s disease were referred to a specialist most often (53%), followed by those with MS (42%) and those with Alzheimer’s disease (27%).

Individuals with Alzheimer’s disease waited the longest for a specialist referral, with a median of 10 months between the time of referral and the first specialist visit compared with 5.7 months for patients with Parkinson’s disease and 2.6 months for MS patients.

“Some patients with common conditions like Alzheimer’s disease, MS, and Parkinson’s disease don’t see a neurologist, and when they do, it can take as long as 10 months,” said Dr. Win.

Using zip code heatmaps, researchers found that the proportion of referrals for all neurologic disorders was higher in the Midwest and Northeast, whereas patients in the South and West were less likely to receive a referral. 

Referrals for Alzheimer’s disease were low nationwide, except for some areas of Michigan and New England. California had the lowest referral rate for MS, followed by regions in the South and Northeast. Patients with Parkinson’s disease living in the Midwest and Northeast were more likely than those in the West to receive a specialist referral. 

Previous studies have reported regional shortages of neurologists, said Dr. Win. “Our data seem to correlate that in terms of the areas with lower referral patterns, but as to whether that is causative or correlative, we don’t know.” 

Odds of referral were also influenced by demographic characteristics such as sex, age, race, and ethnicity, investigators found. 

For example, there were fewer referrals with increasing age across all three neurologic disorders, and men were more likely than women to be referred for Alzheimer’s disease and Parkinson’s disease. Compared with White patients, Parkinson’s disease referrals were less likely among African American, Asian, and Hispanic patients and Alzheimer’s disease referrals were less common among Asian and Hispanic patients.

Insurance status also affected referrals. People with MS and Parkinson’s disease who had commercial insurance were referred more often than were those with Medicare Advantage, said Dr. Win.

She also noted, “Additional research is needed to understand how being referred or not being referred to a neurologist actually impacts patient treatment, care and outcomes.”
 

Neurology Challenges

Commenting on the research, Thomas Vidic, MD, a community neurologist in Elkhart, Indiana, and clinical professor of neurology at Indiana University School of Medicine at South Bend, said that he was surprised by the variation in wait times for patients.

This, he said, could reflect a study limitation or a higher comfort level among primary care doctors in treating dementia.

With respect to MS, Dr. Vidic said that he believes primary care physicians may not be uncertain about prescribing the approved medications for the disease because there are so many of them.

In addition, patients with Alzheimer’s disease are older and perhaps less accepting of being referred to a specialist that may be hours away.

The bottom line for Dr. Vidic, though, is the lack of specialists. “It comes back to the fact we’re not doing a good job of having community neurologists available to take care of these problems,” he said.

The issue of community neurologist shortages was underlined by the study’s findings about geographic gaps in specialist referrals across the country, he said.

Neurologists make up about 2% of the medical workforce and this has remained static for some time, Dr. Vidic noted. Meanwhile, people are living longer and developing more neurologic diseases.

Dr. Vidic also pointed to the lack of neurology training programs. “There has not been a significant change in the number of programs in the last 10-15 years,” he said.

Study funding was not disclosed. Dr. Win reports receiving personal compensation for serving as an employee of Genentech and has stock in Genentech. Dr. Vidic reports no relevant financial disclosures.

A version of this article appeared on Medscape.com.

DENVER — A first-in-class monoclonal antibody (riliprubart, Sanofi) that inhibits complement activation showed good activity versus IVIG in chronic inflammatory demyelinating polyneuropathy (CIDP), with good results in treatment-refractory and treatment-naive patients, according to results from a phase 2 clinical trial.

‘Impressive’ Results

The results were impressive, especially given that riliprubart outperformed IVIG, according to Frank Tennigkeit, PhD, senior director of pediatric development rare diseases at UCB Biosciences, who attended the session at the 2024 annual meeting of the American Academy of Neurology, where the study was presented. “There are few trials on CIDP, and the standard data are IVIG data.

“This is really amazing, especially in refractory patients. I turned to my neighbor [during the presentation] and said, ‘I’ve never seen CIDP data that good in my life. It works in all kinds of different patient populations, and also on the refractory ones. That’s what you want. That’s where the need is. And you saw a consistent effect and a strong effect on top of standard of care,” said Dr. Tennigkeit.

“It’s impressive. The only problem with CIDP is that it’s very difficult to compare treatments, because everyone has a different outcome. This was an open-label study, so there’s always a confounding bias. The proof of the pudding is going to be in a phase 3 blinded, randomized trial, but what I really admire about them, and I thought was very gutsy, is that they’re going head-to-head versus IVIG. I haven’t seen anyone who’s done that yet [in CIDP],” said Shalom Patole, MD, an internist and telehealth consultant in India, who also attended the session.
 

An Open-Label Phase 2 Study

The study had a somewhat unique design, according to Richard Lewis, MD, who presented the results. It was an open-label design that examined three subpopulations: 25 who had objective response to treatments (standard of care [SOC]–treated, mean age, 58.2 years; 80% male), 18 refractory patients who had been off treatment for up to 12 weeks (SOC-refractory, mean age, 63.9 years; 61% male), and 12 patients who had not been treated at all for at least 6 months or were treatment-naive (SOC-naive, mean age, 59.1 years; 67% male).

At 24 weeks, “if you looked at the treated group, 88% of those patients improved to remain stable, and only 12% relapsed. Most significantly, these patients who had responded to their IVIG, who were supposedly doing pretty well, 44% of those actually got better, so they improved from what would have been a pretty good baseline. The refractory patients, despite flunking the other treatments, 50% actually passed or improved with the treatment, so a significant response rate in a group that was not responding so well,” said Dr. Lewis, who is a neurologist at Cedars Sinai Medical Center.

The researchers also found that treatment with riliprubart led to inhibition of complement activity and a trend in reduction in neurofilament light chain levels by week 24 in all three groups.

Treatment-emergent adverse events occurred in 60% of the SOC-treated group, 72% of the SOC-refractory group, and 75% of the SOC-naive group, though grade 3 or higher events were rare (4%, 17%, and 8%, respectively). There was one death in the SOC-treated group and one in the SOC-refractory group. Both patients were elderly and had comorbid conditions.
 

Challenging the Current Standard of Care

The data have led to two additional phase 3 trials, one in refractory patients (Mobilize), and another for patients treated with IVIG who have residual disability (Vitalize). Sanofi is also planning a phase 3, placebo-controlled trial with one arm that will compare the antibody to IVIG, “which is a pretty ambitious trial design,” admitted Dr. Lewis.

Such a strategy is risky, but it could represent a big payoff for Sanofi if the phase 3 studies replicate the phase 2 studies. “No one would be using IVIG anymore if you beat IVIG by 50%. That will be the standard. If you do the trial [versus IVIG], you have a higher risk, but if you win it, you will win big,” said Dr. Tennigkeit.

The study was funded by Sanofi. Dr. Lewis has financial relationships with CSL Behring, Grifols, Pfizer, Sanofi, Argenx, Pharnext, Roche, Johnson & Johnson, Takeda, Boehringer Ingelheim, Nuvig, Dianthus, Janssen, Medscape, Alexion, Alnylam, and Novartis. Dr. Tennigkeit is an employee of UCB Biosciences. Dr. Patole has no relevant financial disclosures.

DENVER — A first-in-class monoclonal antibody (riliprubart, Sanofi) that inhibits complement activation showed good activity versus IVIG in chronic inflammatory demyelinating polyneuropathy (CIDP), with good results in treatment-refractory and treatment-naive patients, according to results from a phase 2 clinical trial.

‘Impressive’ Results

The results were impressive, especially given that riliprubart outperformed IVIG, according to Frank Tennigkeit, PhD, senior director of pediatric development rare diseases at UCB Biosciences, who attended the session at the 2024 annual meeting of the American Academy of Neurology, where the study was presented. “There are few trials on CIDP, and the standard data are IVIG data.

“This is really amazing, especially in refractory patients. I turned to my neighbor [during the presentation] and said, ‘I’ve never seen CIDP data that good in my life. It works in all kinds of different patient populations, and also on the refractory ones. That’s what you want. That’s where the need is. And you saw a consistent effect and a strong effect on top of standard of care,” said Dr. Tennigkeit.

“It’s impressive. The only problem with CIDP is that it’s very difficult to compare treatments, because everyone has a different outcome. This was an open-label study, so there’s always a confounding bias. The proof of the pudding is going to be in a phase 3 blinded, randomized trial, but what I really admire about them, and I thought was very gutsy, is that they’re going head-to-head versus IVIG. I haven’t seen anyone who’s done that yet [in CIDP],” said Shalom Patole, MD, an internist and telehealth consultant in India, who also attended the session.
 

An Open-Label Phase 2 Study

The study had a somewhat unique design, according to Richard Lewis, MD, who presented the results. It was an open-label design that examined three subpopulations: 25 who had objective response to treatments (standard of care [SOC]–treated, mean age, 58.2 years; 80% male), 18 refractory patients who had been off treatment for up to 12 weeks (SOC-refractory, mean age, 63.9 years; 61% male), and 12 patients who had not been treated at all for at least 6 months or were treatment-naive (SOC-naive, mean age, 59.1 years; 67% male).

At 24 weeks, “if you looked at the treated group, 88% of those patients improved to remain stable, and only 12% relapsed. Most significantly, these patients who had responded to their IVIG, who were supposedly doing pretty well, 44% of those actually got better, so they improved from what would have been a pretty good baseline. The refractory patients, despite flunking the other treatments, 50% actually passed or improved with the treatment, so a significant response rate in a group that was not responding so well,” said Dr. Lewis, who is a neurologist at Cedars Sinai Medical Center.

The researchers also found that treatment with riliprubart led to inhibition of complement activity and a trend in reduction in neurofilament light chain levels by week 24 in all three groups.

Treatment-emergent adverse events occurred in 60% of the SOC-treated group, 72% of the SOC-refractory group, and 75% of the SOC-naive group, though grade 3 or higher events were rare (4%, 17%, and 8%, respectively). There was one death in the SOC-treated group and one in the SOC-refractory group. Both patients were elderly and had comorbid conditions.
 

Challenging the Current Standard of Care

The data have led to two additional phase 3 trials, one in refractory patients (Mobilize), and another for patients treated with IVIG who have residual disability (Vitalize). Sanofi is also planning a phase 3, placebo-controlled trial with one arm that will compare the antibody to IVIG, “which is a pretty ambitious trial design,” admitted Dr. Lewis.

Such a strategy is risky, but it could represent a big payoff for Sanofi if the phase 3 studies replicate the phase 2 studies. “No one would be using IVIG anymore if you beat IVIG by 50%. That will be the standard. If you do the trial [versus IVIG], you have a higher risk, but if you win it, you will win big,” said Dr. Tennigkeit.

The study was funded by Sanofi. Dr. Lewis has financial relationships with CSL Behring, Grifols, Pfizer, Sanofi, Argenx, Pharnext, Roche, Johnson & Johnson, Takeda, Boehringer Ingelheim, Nuvig, Dianthus, Janssen, Medscape, Alexion, Alnylam, and Novartis. Dr. Tennigkeit is an employee of UCB Biosciences. Dr. Patole has no relevant financial disclosures.

DENVER — A first-in-class monoclonal antibody (riliprubart, Sanofi) that inhibits complement activation showed good activity versus IVIG in chronic inflammatory demyelinating polyneuropathy (CIDP), with good results in treatment-refractory and treatment-naive patients, according to results from a phase 2 clinical trial.

‘Impressive’ Results

The results were impressive, especially given that riliprubart outperformed IVIG, according to Frank Tennigkeit, PhD, senior director of pediatric development rare diseases at UCB Biosciences, who attended the session at the 2024 annual meeting of the American Academy of Neurology, where the study was presented. “There are few trials on CIDP, and the standard data are IVIG data.

“This is really amazing, especially in refractory patients. I turned to my neighbor [during the presentation] and said, ‘I’ve never seen CIDP data that good in my life. It works in all kinds of different patient populations, and also on the refractory ones. That’s what you want. That’s where the need is. And you saw a consistent effect and a strong effect on top of standard of care,” said Dr. Tennigkeit.

“It’s impressive. The only problem with CIDP is that it’s very difficult to compare treatments, because everyone has a different outcome. This was an open-label study, so there’s always a confounding bias. The proof of the pudding is going to be in a phase 3 blinded, randomized trial, but what I really admire about them, and I thought was very gutsy, is that they’re going head-to-head versus IVIG. I haven’t seen anyone who’s done that yet [in CIDP],” said Shalom Patole, MD, an internist and telehealth consultant in India, who also attended the session.
 

An Open-Label Phase 2 Study

The study had a somewhat unique design, according to Richard Lewis, MD, who presented the results. It was an open-label design that examined three subpopulations: 25 who had objective response to treatments (standard of care [SOC]–treated, mean age, 58.2 years; 80% male), 18 refractory patients who had been off treatment for up to 12 weeks (SOC-refractory, mean age, 63.9 years; 61% male), and 12 patients who had not been treated at all for at least 6 months or were treatment-naive (SOC-naive, mean age, 59.1 years; 67% male).

At 24 weeks, “if you looked at the treated group, 88% of those patients improved to remain stable, and only 12% relapsed. Most significantly, these patients who had responded to their IVIG, who were supposedly doing pretty well, 44% of those actually got better, so they improved from what would have been a pretty good baseline. The refractory patients, despite flunking the other treatments, 50% actually passed or improved with the treatment, so a significant response rate in a group that was not responding so well,” said Dr. Lewis, who is a neurologist at Cedars Sinai Medical Center.

The researchers also found that treatment with riliprubart led to inhibition of complement activity and a trend in reduction in neurofilament light chain levels by week 24 in all three groups.

Treatment-emergent adverse events occurred in 60% of the SOC-treated group, 72% of the SOC-refractory group, and 75% of the SOC-naive group, though grade 3 or higher events were rare (4%, 17%, and 8%, respectively). There was one death in the SOC-treated group and one in the SOC-refractory group. Both patients were elderly and had comorbid conditions.
 

Challenging the Current Standard of Care

The data have led to two additional phase 3 trials, one in refractory patients (Mobilize), and another for patients treated with IVIG who have residual disability (Vitalize). Sanofi is also planning a phase 3, placebo-controlled trial with one arm that will compare the antibody to IVIG, “which is a pretty ambitious trial design,” admitted Dr. Lewis.

Such a strategy is risky, but it could represent a big payoff for Sanofi if the phase 3 studies replicate the phase 2 studies. “No one would be using IVIG anymore if you beat IVIG by 50%. That will be the standard. If you do the trial [versus IVIG], you have a higher risk, but if you win it, you will win big,” said Dr. Tennigkeit.

The study was funded by Sanofi. Dr. Lewis has financial relationships with CSL Behring, Grifols, Pfizer, Sanofi, Argenx, Pharnext, Roche, Johnson & Johnson, Takeda, Boehringer Ingelheim, Nuvig, Dianthus, Janssen, Medscape, Alexion, Alnylam, and Novartis. Dr. Tennigkeit is an employee of UCB Biosciences. Dr. Patole has no relevant financial disclosures.

DENVER — A medical education initiative for internal medicine residents and medical students that offers instruction on assessing common neurologic conditions boosted trainees’ confidence in caring for neurology patients and could help address the US neurologist shortage, a new report suggested.

Bedside Rounding Alliance for Internal Medicine and Neurology Residents (BRAINs) moves training from the lecture hall to the bedside, offering instruction on obtaining a focused neurologic history and performing a focused neurologic physical exam for common neurologic symptoms.

Almost 100% of trainees surveyed gave the program a favorable rating, citing patient exposure and bedside training from neurology educators as keys to its success.

As internal medicine providers are often “the first to lay eyes” on patients with a neurology complaint, it’s important they “have a basic level of comfort” in addressing patients’ common questions and concerns, study author Prashanth Rajarajan, MD, PhD, a resident in the Department of Neurology at Brigham and Women’s Hospital, Boston, told this news organization.

The findings were presented at the 2024 annual meeting of the American Academy of Neurology.
 

Addressing ‘Neurophobia’

Neurology is often viewed by medical trainees as the most difficult subspecialty, Dr. Rajarajan said. Many have what he calls “neurophobia,” which he defines as “a discomfort with assessing and treating neurologic complaints.”

A survey at his institution showed 62% of internal medicine residents lacked the confidence to diagnose and treat neurologic diseases, he reported.

BRAINs is a structured neurology trainee-led, inpatient bedside teaching session for internal medicine residents, medical students, and others that aims to increase trainees’ confidence in assessing patients with common neurologic symptoms.

The program includes a biweekly 45-minute session. Most of the session is spent at the bedside and involves demonstrations and practice of a focused neurologic history and physical exam.

Participants receive feedback from educators, typically neurology residents or fellows in epilepsy, stroke, or some other neurology subspecialty. It also includes a short discussion on pertinent diagnostics, management, and other topics.

Surveys evaluating the program and teaching skill development were completed by 59 residents and 15 neurology educators who participated in BRAINs between 2022 and 2024.

Over 90% of trainees (54) agreed BRAINs sessions met the program’s objective (5 were neutral); 49 agreed it increased confidence in taking a neuro history (9 were neutral and 1 disagreed); 56 felt it boosted their confidence in doing a neuro exam (3 were neutral); and 56 said BRAINs is more effective than traditional lecture-based didactics (3 were neutral).

All the residents rated the material covered as appropriate for their level of training; 88% considered the 45-minute session length appropriate; and 98% had a favorable impression of the program as a whole.

When asked to identify the most helpful aspect of the program, 82% cited more patient exposure and 81% more bedside teaching.

All educators reported that the sessions were an effective way to practice near-peer teaching skills. Most (87%) felt the experience was more effective at accomplishing learning objectives than preparing and giving traditional didactic lectures, and 80% agreed it also gave them an opportunity to get to know their medical colleagues.
 

Use It or Lose It

Dr. Rajarajan noted that the program doesn’t require significant planning or extra staff, is not resource-intensive, and can be adapted to different services such as emergency departments and other learner populations.

But time will tell if the newfound confidence of those taking the program actually lasts.

“You have to keep using it,” he said. “You use it or lose it when comes to these skills.”

Commenting on the initiative, Denney Zimmerman, DO, Neurocritical Care Faculty, Blount Memorial Hospital, Maryville, Tennessee, and cochair of the AAN session featuring the study, called the program a good example of one way to counteract “neurophobia” and address the widespread neurologist shortage in the United States.

A 2019 AAN report showed that by 2025, almost every state in the United States will have a mismatch between the number of practicing neurologists and the demand from patients with neurologic conditions. The report offered several ways to address the shortage, including more neurology-focused training for internal medicine doctors during their residency.

“They’re usually on the front line, both in the hospital and in the clinics, and can help expedite patients who need to be seen by neurology sooner rather than later,” Dr. Zimmerman said.

Dr. Zimmerman noted that the study assessed how well participants perceived the program but not whether it improved their skills.

He pointed out that different groups may assess different diseases during their training session. “I think it’s important to ensure you’re hitting all the major topics.”

The study received funding from MGB Centers of Expertise Education Grant. Drs. Rajarajan and Zimmerman reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

DENVER — A medical education initiative for internal medicine residents and medical students that offers instruction on assessing common neurologic conditions boosted trainees’ confidence in caring for neurology patients and could help address the US neurologist shortage, a new report suggested.

Bedside Rounding Alliance for Internal Medicine and Neurology Residents (BRAINs) moves training from the lecture hall to the bedside, offering instruction on obtaining a focused neurologic history and performing a focused neurologic physical exam for common neurologic symptoms.

Almost 100% of trainees surveyed gave the program a favorable rating, citing patient exposure and bedside training from neurology educators as keys to its success.

As internal medicine providers are often “the first to lay eyes” on patients with a neurology complaint, it’s important they “have a basic level of comfort” in addressing patients’ common questions and concerns, study author Prashanth Rajarajan, MD, PhD, a resident in the Department of Neurology at Brigham and Women’s Hospital, Boston, told this news organization.

The findings were presented at the 2024 annual meeting of the American Academy of Neurology.
 

Addressing ‘Neurophobia’

Neurology is often viewed by medical trainees as the most difficult subspecialty, Dr. Rajarajan said. Many have what he calls “neurophobia,” which he defines as “a discomfort with assessing and treating neurologic complaints.”

A survey at his institution showed 62% of internal medicine residents lacked the confidence to diagnose and treat neurologic diseases, he reported.

BRAINs is a structured neurology trainee-led, inpatient bedside teaching session for internal medicine residents, medical students, and others that aims to increase trainees’ confidence in assessing patients with common neurologic symptoms.

The program includes a biweekly 45-minute session. Most of the session is spent at the bedside and involves demonstrations and practice of a focused neurologic history and physical exam.

Participants receive feedback from educators, typically neurology residents or fellows in epilepsy, stroke, or some other neurology subspecialty. It also includes a short discussion on pertinent diagnostics, management, and other topics.

Surveys evaluating the program and teaching skill development were completed by 59 residents and 15 neurology educators who participated in BRAINs between 2022 and 2024.

Over 90% of trainees (54) agreed BRAINs sessions met the program’s objective (5 were neutral); 49 agreed it increased confidence in taking a neuro history (9 were neutral and 1 disagreed); 56 felt it boosted their confidence in doing a neuro exam (3 were neutral); and 56 said BRAINs is more effective than traditional lecture-based didactics (3 were neutral).

All the residents rated the material covered as appropriate for their level of training; 88% considered the 45-minute session length appropriate; and 98% had a favorable impression of the program as a whole.

When asked to identify the most helpful aspect of the program, 82% cited more patient exposure and 81% more bedside teaching.

All educators reported that the sessions were an effective way to practice near-peer teaching skills. Most (87%) felt the experience was more effective at accomplishing learning objectives than preparing and giving traditional didactic lectures, and 80% agreed it also gave them an opportunity to get to know their medical colleagues.
 

Use It or Lose It

Dr. Rajarajan noted that the program doesn’t require significant planning or extra staff, is not resource-intensive, and can be adapted to different services such as emergency departments and other learner populations.

But time will tell if the newfound confidence of those taking the program actually lasts.

“You have to keep using it,” he said. “You use it or lose it when comes to these skills.”

Commenting on the initiative, Denney Zimmerman, DO, Neurocritical Care Faculty, Blount Memorial Hospital, Maryville, Tennessee, and cochair of the AAN session featuring the study, called the program a good example of one way to counteract “neurophobia” and address the widespread neurologist shortage in the United States.

A 2019 AAN report showed that by 2025, almost every state in the United States will have a mismatch between the number of practicing neurologists and the demand from patients with neurologic conditions. The report offered several ways to address the shortage, including more neurology-focused training for internal medicine doctors during their residency.

“They’re usually on the front line, both in the hospital and in the clinics, and can help expedite patients who need to be seen by neurology sooner rather than later,” Dr. Zimmerman said.

Dr. Zimmerman noted that the study assessed how well participants perceived the program but not whether it improved their skills.

He pointed out that different groups may assess different diseases during their training session. “I think it’s important to ensure you’re hitting all the major topics.”

The study received funding from MGB Centers of Expertise Education Grant. Drs. Rajarajan and Zimmerman reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

DENVER — A medical education initiative for internal medicine residents and medical students that offers instruction on assessing common neurologic conditions boosted trainees’ confidence in caring for neurology patients and could help address the US neurologist shortage, a new report suggested.

Bedside Rounding Alliance for Internal Medicine and Neurology Residents (BRAINs) moves training from the lecture hall to the bedside, offering instruction on obtaining a focused neurologic history and performing a focused neurologic physical exam for common neurologic symptoms.

Almost 100% of trainees surveyed gave the program a favorable rating, citing patient exposure and bedside training from neurology educators as keys to its success.

As internal medicine providers are often “the first to lay eyes” on patients with a neurology complaint, it’s important they “have a basic level of comfort” in addressing patients’ common questions and concerns, study author Prashanth Rajarajan, MD, PhD, a resident in the Department of Neurology at Brigham and Women’s Hospital, Boston, told this news organization.

The findings were presented at the 2024 annual meeting of the American Academy of Neurology.
 

Addressing ‘Neurophobia’

Neurology is often viewed by medical trainees as the most difficult subspecialty, Dr. Rajarajan said. Many have what he calls “neurophobia,” which he defines as “a discomfort with assessing and treating neurologic complaints.”

A survey at his institution showed 62% of internal medicine residents lacked the confidence to diagnose and treat neurologic diseases, he reported.

BRAINs is a structured neurology trainee-led, inpatient bedside teaching session for internal medicine residents, medical students, and others that aims to increase trainees’ confidence in assessing patients with common neurologic symptoms.

The program includes a biweekly 45-minute session. Most of the session is spent at the bedside and involves demonstrations and practice of a focused neurologic history and physical exam.

Participants receive feedback from educators, typically neurology residents or fellows in epilepsy, stroke, or some other neurology subspecialty. It also includes a short discussion on pertinent diagnostics, management, and other topics.

Surveys evaluating the program and teaching skill development were completed by 59 residents and 15 neurology educators who participated in BRAINs between 2022 and 2024.

Over 90% of trainees (54) agreed BRAINs sessions met the program’s objective (5 were neutral); 49 agreed it increased confidence in taking a neuro history (9 were neutral and 1 disagreed); 56 felt it boosted their confidence in doing a neuro exam (3 were neutral); and 56 said BRAINs is more effective than traditional lecture-based didactics (3 were neutral).

All the residents rated the material covered as appropriate for their level of training; 88% considered the 45-minute session length appropriate; and 98% had a favorable impression of the program as a whole.

When asked to identify the most helpful aspect of the program, 82% cited more patient exposure and 81% more bedside teaching.

All educators reported that the sessions were an effective way to practice near-peer teaching skills. Most (87%) felt the experience was more effective at accomplishing learning objectives than preparing and giving traditional didactic lectures, and 80% agreed it also gave them an opportunity to get to know their medical colleagues.
 

Use It or Lose It

Dr. Rajarajan noted that the program doesn’t require significant planning or extra staff, is not resource-intensive, and can be adapted to different services such as emergency departments and other learner populations.

But time will tell if the newfound confidence of those taking the program actually lasts.

“You have to keep using it,” he said. “You use it or lose it when comes to these skills.”

Commenting on the initiative, Denney Zimmerman, DO, Neurocritical Care Faculty, Blount Memorial Hospital, Maryville, Tennessee, and cochair of the AAN session featuring the study, called the program a good example of one way to counteract “neurophobia” and address the widespread neurologist shortage in the United States.

A 2019 AAN report showed that by 2025, almost every state in the United States will have a mismatch between the number of practicing neurologists and the demand from patients with neurologic conditions. The report offered several ways to address the shortage, including more neurology-focused training for internal medicine doctors during their residency.

“They’re usually on the front line, both in the hospital and in the clinics, and can help expedite patients who need to be seen by neurology sooner rather than later,” Dr. Zimmerman said.

Dr. Zimmerman noted that the study assessed how well participants perceived the program but not whether it improved their skills.

He pointed out that different groups may assess different diseases during their training session. “I think it’s important to ensure you’re hitting all the major topics.”

The study received funding from MGB Centers of Expertise Education Grant. Drs. Rajarajan and Zimmerman reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Alerting neurologists via telemedicine that a patient with suspected acute stroke is en route to the hospital significantly enhances the speed at which thrombolysis is administered and increases the number of patients who receive timelier, potentially lifesaving treatment, new research showed.

“This preliminary evidence supports adopting teleneurology prenotification as a best practice within health systems that have telestroke capabilities,” said study investigator Mark McDonald, MD, a neurologist at TeleSpecialists, Fort Myers, Florida.

The findings were presented at the 2024 annual meeting of the American Academy of Neurology.
 

Best Practices

The impact of emergency medical services prenotification, which refers to paramedics alerting receiving hospital emergency departments (EDs) of a suspected stroke on the way for appropriate preparations to be made, is well-defined, said Dr. McDonald.

“What we’re proposing as a best practice is not only should the ED or ED provider be aware, but there needs to be a system in place for standardizing communication to the neurology team so they’re aware, too.”

Prenotification allows a neurologist to “get on the screen to begin coordinating with the ED team to adequately prepare for the possibility of thrombolytic treatment,” he added.

Currently, teleneurology prenotification, he said, is variable and its benefits unclear.

Dr. McDonald said “his organization, TeleSpecialists, maintains a large detailed medical records database for emergency-related, teleneurology, and other cases. For stroke, it recommends 15 best practices” for facilities including prenotification of teleneurology.

Other best practices include evaluating and administering thrombolysis in the CT imaging suite, a preassembled stroke kit that includes antihypertensives and thrombolytic agents, ensuring a weigh bed is available to determine the exact dose of thrombolysis treatment, and implementing “mock” stroke alerts, said Dr. McDonald.

From the database, researchers extracted acute telestroke consultations seen in the ED in 103 facilities in 15 states. Facilities that did not adhere to the 14 best practices other than teleneurologist prenotification were excluded from the analysis.

Of 9290 patients included in the study, 731 were treated with thrombolysis at prenotification facilities (median age, 69 years; median National Institutes of Health Stroke Score [NIHSS], 8) and 31 were treated at facilities without prenotification (median age, 63 years; median NIHSS score, 4). The thrombolytic treatment rate was 8.5% at prenotification facilities versus 4.8% at facilities without prenotification — a difference that was statistically significant.

Prenotification facilities had a significantly shorter median door-to-needle (DTN) time than those without such a process at 35 versus 43 minutes. In addition, there was a statistically significant difference in the percentage of patients with times less than 60 minutes at approximately 88% at prenotification facilities versus about 68% at the facilities without prenotification.
 

Case-Level Analysis

However, just because a facility adheres to teleneurology prenotification as a whole, doesn’t mean it occurs in every case. Researchers explored the impact of teleneurology prenotification at the case level rather than the facility level.

“That gave us a bit more insight into the real impact because it’s not just being at a facility with the best practice; it’s actually working case by case to see whether it happened or not and that’s where we get the most compelling findings,” said Dr. McDonald.

Of 761 treatment cases, there was prenotification to the neurology team in 401 cases. In 360 cases, prenotification did not occur.

The median DTN time was 29 minutes in the group with actual prenotification vs 41.5 minutes in the group without actual prenotification, a difference that was statistically significant, Dr. McDonald said.

As for treatment within 30 minutes of arrival, 50.4% of patients in the teleneurology prenotification group versus 18.9% in the no prenotification group — a statistically significant difference.

DTN time of less than 30 minutes is increasingly used as a target. “Being treated within this time frame improves outcomes and reduces length of hospital stay,” said Dr. McDonald.

The prenotification group also had a statistically significant higher percentage of treatment within 60 minutes of hospital arrival (93.5% vs 80%).

These new findings should help convince health and telestroke systems that teleneurology prenotification is worth implementing. “We want to achieve consensus on this as a best practice,” said Dr. McDonald.

Prenotification, he added, “coordinates the process and eliminates unnecessary and time-consuming steps.”

Dr. McDonald plans to prospectively study prenotification by collecting data on a facility before and after implementing a prenotification process.
 

Compelling Evidence

Commenting on the research, David L. Tirschwell, MD, Harborview Medical Center, Department of Neurology, Seattle, who cochaired the AAN session featuring the research, said the study provides compelling evidence that teleneurologist prenotification improves DTN time.

“Prenotifications are often standard of care in many healthcare settings and should likely be considered a best practice. When possible, extending such prenotification to a teleconsultant would make sense, and these preliminary data support that approach.”

However, more details are needed “to consider whether the intervention is possibly generalizable to other telestroke practices across the United States,” said Dr. Tirschwell.

Dr. McDonald reported receiving personal compensation for serving as a consultant for Syntrillo Inc. and has stock in Syntrillo Inc. Dr. Tirschwell reported no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

Alerting neurologists via telemedicine that a patient with suspected acute stroke is en route to the hospital significantly enhances the speed at which thrombolysis is administered and increases the number of patients who receive timelier, potentially lifesaving treatment, new research showed.

“This preliminary evidence supports adopting teleneurology prenotification as a best practice within health systems that have telestroke capabilities,” said study investigator Mark McDonald, MD, a neurologist at TeleSpecialists, Fort Myers, Florida.

The findings were presented at the 2024 annual meeting of the American Academy of Neurology.
 

Best Practices

The impact of emergency medical services prenotification, which refers to paramedics alerting receiving hospital emergency departments (EDs) of a suspected stroke on the way for appropriate preparations to be made, is well-defined, said Dr. McDonald.

“What we’re proposing as a best practice is not only should the ED or ED provider be aware, but there needs to be a system in place for standardizing communication to the neurology team so they’re aware, too.”

Prenotification allows a neurologist to “get on the screen to begin coordinating with the ED team to adequately prepare for the possibility of thrombolytic treatment,” he added.

Currently, teleneurology prenotification, he said, is variable and its benefits unclear.

Dr. McDonald said “his organization, TeleSpecialists, maintains a large detailed medical records database for emergency-related, teleneurology, and other cases. For stroke, it recommends 15 best practices” for facilities including prenotification of teleneurology.

Other best practices include evaluating and administering thrombolysis in the CT imaging suite, a preassembled stroke kit that includes antihypertensives and thrombolytic agents, ensuring a weigh bed is available to determine the exact dose of thrombolysis treatment, and implementing “mock” stroke alerts, said Dr. McDonald.

From the database, researchers extracted acute telestroke consultations seen in the ED in 103 facilities in 15 states. Facilities that did not adhere to the 14 best practices other than teleneurologist prenotification were excluded from the analysis.

Of 9290 patients included in the study, 731 were treated with thrombolysis at prenotification facilities (median age, 69 years; median National Institutes of Health Stroke Score [NIHSS], 8) and 31 were treated at facilities without prenotification (median age, 63 years; median NIHSS score, 4). The thrombolytic treatment rate was 8.5% at prenotification facilities versus 4.8% at facilities without prenotification — a difference that was statistically significant.

Prenotification facilities had a significantly shorter median door-to-needle (DTN) time than those without such a process at 35 versus 43 minutes. In addition, there was a statistically significant difference in the percentage of patients with times less than 60 minutes at approximately 88% at prenotification facilities versus about 68% at the facilities without prenotification.
 

Case-Level Analysis

However, just because a facility adheres to teleneurology prenotification as a whole, doesn’t mean it occurs in every case. Researchers explored the impact of teleneurology prenotification at the case level rather than the facility level.

“That gave us a bit more insight into the real impact because it’s not just being at a facility with the best practice; it’s actually working case by case to see whether it happened or not and that’s where we get the most compelling findings,” said Dr. McDonald.

Of 761 treatment cases, there was prenotification to the neurology team in 401 cases. In 360 cases, prenotification did not occur.

The median DTN time was 29 minutes in the group with actual prenotification vs 41.5 minutes in the group without actual prenotification, a difference that was statistically significant, Dr. McDonald said.

As for treatment within 30 minutes of arrival, 50.4% of patients in the teleneurology prenotification group versus 18.9% in the no prenotification group — a statistically significant difference.

DTN time of less than 30 minutes is increasingly used as a target. “Being treated within this time frame improves outcomes and reduces length of hospital stay,” said Dr. McDonald.

The prenotification group also had a statistically significant higher percentage of treatment within 60 minutes of hospital arrival (93.5% vs 80%).

These new findings should help convince health and telestroke systems that teleneurology prenotification is worth implementing. “We want to achieve consensus on this as a best practice,” said Dr. McDonald.

Prenotification, he added, “coordinates the process and eliminates unnecessary and time-consuming steps.”

Dr. McDonald plans to prospectively study prenotification by collecting data on a facility before and after implementing a prenotification process.
 

Compelling Evidence

Commenting on the research, David L. Tirschwell, MD, Harborview Medical Center, Department of Neurology, Seattle, who cochaired the AAN session featuring the research, said the study provides compelling evidence that teleneurologist prenotification improves DTN time.

“Prenotifications are often standard of care in many healthcare settings and should likely be considered a best practice. When possible, extending such prenotification to a teleconsultant would make sense, and these preliminary data support that approach.”

However, more details are needed “to consider whether the intervention is possibly generalizable to other telestroke practices across the United States,” said Dr. Tirschwell.

Dr. McDonald reported receiving personal compensation for serving as a consultant for Syntrillo Inc. and has stock in Syntrillo Inc. Dr. Tirschwell reported no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

Alerting neurologists via telemedicine that a patient with suspected acute stroke is en route to the hospital significantly enhances the speed at which thrombolysis is administered and increases the number of patients who receive timelier, potentially lifesaving treatment, new research showed.

“This preliminary evidence supports adopting teleneurology prenotification as a best practice within health systems that have telestroke capabilities,” said study investigator Mark McDonald, MD, a neurologist at TeleSpecialists, Fort Myers, Florida.

The findings were presented at the 2024 annual meeting of the American Academy of Neurology.
 

Best Practices

The impact of emergency medical services prenotification, which refers to paramedics alerting receiving hospital emergency departments (EDs) of a suspected stroke on the way for appropriate preparations to be made, is well-defined, said Dr. McDonald.

“What we’re proposing as a best practice is not only should the ED or ED provider be aware, but there needs to be a system in place for standardizing communication to the neurology team so they’re aware, too.”

Prenotification allows a neurologist to “get on the screen to begin coordinating with the ED team to adequately prepare for the possibility of thrombolytic treatment,” he added.

Currently, teleneurology prenotification, he said, is variable and its benefits unclear.

Dr. McDonald said “his organization, TeleSpecialists, maintains a large detailed medical records database for emergency-related, teleneurology, and other cases. For stroke, it recommends 15 best practices” for facilities including prenotification of teleneurology.

Other best practices include evaluating and administering thrombolysis in the CT imaging suite, a preassembled stroke kit that includes antihypertensives and thrombolytic agents, ensuring a weigh bed is available to determine the exact dose of thrombolysis treatment, and implementing “mock” stroke alerts, said Dr. McDonald.

From the database, researchers extracted acute telestroke consultations seen in the ED in 103 facilities in 15 states. Facilities that did not adhere to the 14 best practices other than teleneurologist prenotification were excluded from the analysis.

Of 9290 patients included in the study, 731 were treated with thrombolysis at prenotification facilities (median age, 69 years; median National Institutes of Health Stroke Score [NIHSS], 8) and 31 were treated at facilities without prenotification (median age, 63 years; median NIHSS score, 4). The thrombolytic treatment rate was 8.5% at prenotification facilities versus 4.8% at facilities without prenotification — a difference that was statistically significant.

Prenotification facilities had a significantly shorter median door-to-needle (DTN) time than those without such a process at 35 versus 43 minutes. In addition, there was a statistically significant difference in the percentage of patients with times less than 60 minutes at approximately 88% at prenotification facilities versus about 68% at the facilities without prenotification.
 

Case-Level Analysis

However, just because a facility adheres to teleneurology prenotification as a whole, doesn’t mean it occurs in every case. Researchers explored the impact of teleneurology prenotification at the case level rather than the facility level.

“That gave us a bit more insight into the real impact because it’s not just being at a facility with the best practice; it’s actually working case by case to see whether it happened or not and that’s where we get the most compelling findings,” said Dr. McDonald.

Of 761 treatment cases, there was prenotification to the neurology team in 401 cases. In 360 cases, prenotification did not occur.

The median DTN time was 29 minutes in the group with actual prenotification vs 41.5 minutes in the group without actual prenotification, a difference that was statistically significant, Dr. McDonald said.

As for treatment within 30 minutes of arrival, 50.4% of patients in the teleneurology prenotification group versus 18.9% in the no prenotification group — a statistically significant difference.

DTN time of less than 30 minutes is increasingly used as a target. “Being treated within this time frame improves outcomes and reduces length of hospital stay,” said Dr. McDonald.

The prenotification group also had a statistically significant higher percentage of treatment within 60 minutes of hospital arrival (93.5% vs 80%).

These new findings should help convince health and telestroke systems that teleneurology prenotification is worth implementing. “We want to achieve consensus on this as a best practice,” said Dr. McDonald.

Prenotification, he added, “coordinates the process and eliminates unnecessary and time-consuming steps.”

Dr. McDonald plans to prospectively study prenotification by collecting data on a facility before and after implementing a prenotification process.
 

Compelling Evidence

Commenting on the research, David L. Tirschwell, MD, Harborview Medical Center, Department of Neurology, Seattle, who cochaired the AAN session featuring the research, said the study provides compelling evidence that teleneurologist prenotification improves DTN time.

“Prenotifications are often standard of care in many healthcare settings and should likely be considered a best practice. When possible, extending such prenotification to a teleconsultant would make sense, and these preliminary data support that approach.”

However, more details are needed “to consider whether the intervention is possibly generalizable to other telestroke practices across the United States,” said Dr. Tirschwell.

Dr. McDonald reported receiving personal compensation for serving as a consultant for Syntrillo Inc. and has stock in Syntrillo Inc. Dr. Tirschwell reported no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

DENVER — Treatment with AXS-05, a combination of dextromethorphan and bupropion, demonstrated rapid, sustained, and clinically meaningful improvement in agitation related to Alzheimer’s disease and was generally well tolerated in the phase 3 ACCORD trial. 

More than half of participants in the open-label extension period of the randomized clinical trial responded to the medication, which was associated with a 3.6-fold lower risk for relapse compared with placebo. 

“The positive efficacy and favorable safety results with AXS-05 support its potential to fulfill a high unmet need for the treatment of Alzheimer’s disease agitation,” said Anton P. Porsteinsson, MD, director of the Alzheimer’s Disease Care, Research and Education Program, University of Rochester, New York. 

The findings were presented at the 2024 annual meeting of the American Academy of Neurology. 
 

Common and Disruptive

Agitation is reported in up to 70% of patients with Alzheimer’s disease and is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition. Alzheimer’s disease-related agitation has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality.

A previous phase 2/3 study of AXS-05 showed that the investigative agent led to rapid and significantly improvement in Alzheimer’s disease agitation, as measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score, compared with placebo. 

ACCORD was a phase 3, randomized, double-blind, placebo-controlled withdrawal trial evaluating the efficacy and safety of AXS-05 in patients with Alzheimer’s disease agitation. 

In the open-label period, 178 adults with probable Alzheimer’s disease and clinically significant agitation received AXS-05 (titrated to 45 mg dextromethorphan/105 mg bupropion twice daily) for up to 9 weeks.

A total of 108 (61%) patients had a sustained response, with 30% or more improvement from baseline in the CMAI total score and improvement on the Patient Global Impression of Change that were both maintained for 4 or more consecutive weeks. These patients entered the double-blind phase and were randomly allocated to receive twice-daily AXS-05 or placebo for up to 26 weeks.

In the double-blind period, AXS-05 “substantially and statistically” increased the time to relapse of agitation symptoms compared with placebo (hazard ratio [HR], 0.275; P = .014).

“The risk of relapse was 3.6-fold lower with AXS-05 compared with placebo,” Dr. Porsteinsson reported. 

AXS-05 was also associated with a significantly lower relapse rate compared with placebo (7.5% vs 25.9%; P = .018).

Rates of discontinuation in the double-blind period owing to adverse events (AEs) were low (0% for AXS-05 and 1.9% for placebo). Three serious AEs were reported: one in the AXS-05 group (fecaloma), which was not related to study medication, and two in the placebo group (cardiac arrest, femur fracture).

Falls were reported in four participants in the AXS-05 group, none of which were related to study medication or associated with serious AEs, and in two participants in the placebo group, one of which was associated with femur fracture.

One death was reported in the placebo group. There was no evidence of cognitive decline with AXS-05, and treatment was not associated with sedation. 
 

Promising Agent 

Commenting on this research, Glen R. Finney, MD, director of the Geisinger Memory and Cognition Clinic in Wilkes-Barre, Pennsylvania, said the data “look promising as a safe way to help address acute agitation and reduce agitation reoccurrence.

“Agitation is a common, distressing, and sometimes safety issue for people fighting Alzheimer’s disease, and there’s very little evidence for efficacy and significant side effect issues for current medical management of agitation in Alzheimer’s disease,” said Dr. Finney, who was not part of the study.

He noted that first-line strategies for addressing agitation involve behavioral and environmental interventions. 

“See if there’s a reason for the agitation and address that. Look for triggers for agitation and avoid those. Find places, things, and interactions that help people with Alzheimer’s disease avoid agitation: familiar locations, music, simple engaging activities. Reassurance, redirection, and distraction can help de-escalate agitation. Provide a safe environment that reduces safety risks,” Dr. Finney explained. 

The next step, when medically appropriate, is trying acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine, and then adding memantine, a weak N-methyl-D-aspartate receptor antagonist. 

“These medications can help reduce the risk of agitation,” Dr. Finney said. 

“Beyond that, the evidence becomes weaker for any specific treatments, and that is where treatments with emerging evidence of efficacy and safety like dextromethorphan-bupropion become important,” Dr. Finney added. 

Last May, the US Food and Drug Administration (FDA) approved the antipsychotic brexpiprazole (Rexulti) for Alzheimer’s disease-related agitation, making it the first FDA-approved drug for this indication. 

The drug includes a boxed warning for medications in this class that older patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk for death.

“There’s certainly a need to have multiple options for treating agitation in individuals with Alzheimer’s disease,” said Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association. 

Dr. Edelmayer, who was not part of the study, noted that in the ACCORD study, AXS-05 “significantly delayed the relapse or prevented the relapse with Alzheimer’s disease agitation compared with the placebo group and it was generally well tolerated, but it will be important to make sure that there’s more thorough review of the data overall to be sure that it’s both safe and effective.”

The study was funded by Axsome Therapeutics, the manufacturer of AXS-05. Dr. Porsteinsson has disclosed no relevant conflicts of interest. Dr. Finney and Dr. Edelmayer have no relevant disclosures.

A version of this article appeared on Medscape.com.

DENVER — Treatment with AXS-05, a combination of dextromethorphan and bupropion, demonstrated rapid, sustained, and clinically meaningful improvement in agitation related to Alzheimer’s disease and was generally well tolerated in the phase 3 ACCORD trial. 

More than half of participants in the open-label extension period of the randomized clinical trial responded to the medication, which was associated with a 3.6-fold lower risk for relapse compared with placebo. 

“The positive efficacy and favorable safety results with AXS-05 support its potential to fulfill a high unmet need for the treatment of Alzheimer’s disease agitation,” said Anton P. Porsteinsson, MD, director of the Alzheimer’s Disease Care, Research and Education Program, University of Rochester, New York. 

The findings were presented at the 2024 annual meeting of the American Academy of Neurology. 
 

Common and Disruptive

Agitation is reported in up to 70% of patients with Alzheimer’s disease and is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition. Alzheimer’s disease-related agitation has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality.

A previous phase 2/3 study of AXS-05 showed that the investigative agent led to rapid and significantly improvement in Alzheimer’s disease agitation, as measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score, compared with placebo. 

ACCORD was a phase 3, randomized, double-blind, placebo-controlled withdrawal trial evaluating the efficacy and safety of AXS-05 in patients with Alzheimer’s disease agitation. 

In the open-label period, 178 adults with probable Alzheimer’s disease and clinically significant agitation received AXS-05 (titrated to 45 mg dextromethorphan/105 mg bupropion twice daily) for up to 9 weeks.

A total of 108 (61%) patients had a sustained response, with 30% or more improvement from baseline in the CMAI total score and improvement on the Patient Global Impression of Change that were both maintained for 4 or more consecutive weeks. These patients entered the double-blind phase and were randomly allocated to receive twice-daily AXS-05 or placebo for up to 26 weeks.

In the double-blind period, AXS-05 “substantially and statistically” increased the time to relapse of agitation symptoms compared with placebo (hazard ratio [HR], 0.275; P = .014).

“The risk of relapse was 3.6-fold lower with AXS-05 compared with placebo,” Dr. Porsteinsson reported. 

AXS-05 was also associated with a significantly lower relapse rate compared with placebo (7.5% vs 25.9%; P = .018).

Rates of discontinuation in the double-blind period owing to adverse events (AEs) were low (0% for AXS-05 and 1.9% for placebo). Three serious AEs were reported: one in the AXS-05 group (fecaloma), which was not related to study medication, and two in the placebo group (cardiac arrest, femur fracture).

Falls were reported in four participants in the AXS-05 group, none of which were related to study medication or associated with serious AEs, and in two participants in the placebo group, one of which was associated with femur fracture.

One death was reported in the placebo group. There was no evidence of cognitive decline with AXS-05, and treatment was not associated with sedation. 
 

Promising Agent 

Commenting on this research, Glen R. Finney, MD, director of the Geisinger Memory and Cognition Clinic in Wilkes-Barre, Pennsylvania, said the data “look promising as a safe way to help address acute agitation and reduce agitation reoccurrence.

“Agitation is a common, distressing, and sometimes safety issue for people fighting Alzheimer’s disease, and there’s very little evidence for efficacy and significant side effect issues for current medical management of agitation in Alzheimer’s disease,” said Dr. Finney, who was not part of the study.

He noted that first-line strategies for addressing agitation involve behavioral and environmental interventions. 

“See if there’s a reason for the agitation and address that. Look for triggers for agitation and avoid those. Find places, things, and interactions that help people with Alzheimer’s disease avoid agitation: familiar locations, music, simple engaging activities. Reassurance, redirection, and distraction can help de-escalate agitation. Provide a safe environment that reduces safety risks,” Dr. Finney explained. 

The next step, when medically appropriate, is trying acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine, and then adding memantine, a weak N-methyl-D-aspartate receptor antagonist. 

“These medications can help reduce the risk of agitation,” Dr. Finney said. 

“Beyond that, the evidence becomes weaker for any specific treatments, and that is where treatments with emerging evidence of efficacy and safety like dextromethorphan-bupropion become important,” Dr. Finney added. 

Last May, the US Food and Drug Administration (FDA) approved the antipsychotic brexpiprazole (Rexulti) for Alzheimer’s disease-related agitation, making it the first FDA-approved drug for this indication. 

The drug includes a boxed warning for medications in this class that older patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk for death.

“There’s certainly a need to have multiple options for treating agitation in individuals with Alzheimer’s disease,” said Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association. 

Dr. Edelmayer, who was not part of the study, noted that in the ACCORD study, AXS-05 “significantly delayed the relapse or prevented the relapse with Alzheimer’s disease agitation compared with the placebo group and it was generally well tolerated, but it will be important to make sure that there’s more thorough review of the data overall to be sure that it’s both safe and effective.”

The study was funded by Axsome Therapeutics, the manufacturer of AXS-05. Dr. Porsteinsson has disclosed no relevant conflicts of interest. Dr. Finney and Dr. Edelmayer have no relevant disclosures.

A version of this article appeared on Medscape.com.

DENVER — Treatment with AXS-05, a combination of dextromethorphan and bupropion, demonstrated rapid, sustained, and clinically meaningful improvement in agitation related to Alzheimer’s disease and was generally well tolerated in the phase 3 ACCORD trial. 

More than half of participants in the open-label extension period of the randomized clinical trial responded to the medication, which was associated with a 3.6-fold lower risk for relapse compared with placebo. 

“The positive efficacy and favorable safety results with AXS-05 support its potential to fulfill a high unmet need for the treatment of Alzheimer’s disease agitation,” said Anton P. Porsteinsson, MD, director of the Alzheimer’s Disease Care, Research and Education Program, University of Rochester, New York. 

The findings were presented at the 2024 annual meeting of the American Academy of Neurology. 
 

Common and Disruptive

Agitation is reported in up to 70% of patients with Alzheimer’s disease and is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition. Alzheimer’s disease-related agitation has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality.

A previous phase 2/3 study of AXS-05 showed that the investigative agent led to rapid and significantly improvement in Alzheimer’s disease agitation, as measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score, compared with placebo. 

ACCORD was a phase 3, randomized, double-blind, placebo-controlled withdrawal trial evaluating the efficacy and safety of AXS-05 in patients with Alzheimer’s disease agitation. 

In the open-label period, 178 adults with probable Alzheimer’s disease and clinically significant agitation received AXS-05 (titrated to 45 mg dextromethorphan/105 mg bupropion twice daily) for up to 9 weeks.

A total of 108 (61%) patients had a sustained response, with 30% or more improvement from baseline in the CMAI total score and improvement on the Patient Global Impression of Change that were both maintained for 4 or more consecutive weeks. These patients entered the double-blind phase and were randomly allocated to receive twice-daily AXS-05 or placebo for up to 26 weeks.

In the double-blind period, AXS-05 “substantially and statistically” increased the time to relapse of agitation symptoms compared with placebo (hazard ratio [HR], 0.275; P = .014).

“The risk of relapse was 3.6-fold lower with AXS-05 compared with placebo,” Dr. Porsteinsson reported. 

AXS-05 was also associated with a significantly lower relapse rate compared with placebo (7.5% vs 25.9%; P = .018).

Rates of discontinuation in the double-blind period owing to adverse events (AEs) were low (0% for AXS-05 and 1.9% for placebo). Three serious AEs were reported: one in the AXS-05 group (fecaloma), which was not related to study medication, and two in the placebo group (cardiac arrest, femur fracture).

Falls were reported in four participants in the AXS-05 group, none of which were related to study medication or associated with serious AEs, and in two participants in the placebo group, one of which was associated with femur fracture.

One death was reported in the placebo group. There was no evidence of cognitive decline with AXS-05, and treatment was not associated with sedation. 
 

Promising Agent 

Commenting on this research, Glen R. Finney, MD, director of the Geisinger Memory and Cognition Clinic in Wilkes-Barre, Pennsylvania, said the data “look promising as a safe way to help address acute agitation and reduce agitation reoccurrence.

“Agitation is a common, distressing, and sometimes safety issue for people fighting Alzheimer’s disease, and there’s very little evidence for efficacy and significant side effect issues for current medical management of agitation in Alzheimer’s disease,” said Dr. Finney, who was not part of the study.

He noted that first-line strategies for addressing agitation involve behavioral and environmental interventions. 

“See if there’s a reason for the agitation and address that. Look for triggers for agitation and avoid those. Find places, things, and interactions that help people with Alzheimer’s disease avoid agitation: familiar locations, music, simple engaging activities. Reassurance, redirection, and distraction can help de-escalate agitation. Provide a safe environment that reduces safety risks,” Dr. Finney explained. 

The next step, when medically appropriate, is trying acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine, and then adding memantine, a weak N-methyl-D-aspartate receptor antagonist. 

“These medications can help reduce the risk of agitation,” Dr. Finney said. 

“Beyond that, the evidence becomes weaker for any specific treatments, and that is where treatments with emerging evidence of efficacy and safety like dextromethorphan-bupropion become important,” Dr. Finney added. 

Last May, the US Food and Drug Administration (FDA) approved the antipsychotic brexpiprazole (Rexulti) for Alzheimer’s disease-related agitation, making it the first FDA-approved drug for this indication. 

The drug includes a boxed warning for medications in this class that older patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk for death.

“There’s certainly a need to have multiple options for treating agitation in individuals with Alzheimer’s disease,” said Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association. 

Dr. Edelmayer, who was not part of the study, noted that in the ACCORD study, AXS-05 “significantly delayed the relapse or prevented the relapse with Alzheimer’s disease agitation compared with the placebo group and it was generally well tolerated, but it will be important to make sure that there’s more thorough review of the data overall to be sure that it’s both safe and effective.”

The study was funded by Axsome Therapeutics, the manufacturer of AXS-05. Dr. Porsteinsson has disclosed no relevant conflicts of interest. Dr. Finney and Dr. Edelmayer have no relevant disclosures.

A version of this article appeared on Medscape.com.

DENVER — Unlike a first trial of PB&TURSO, which led to regulatory approval of this combination therapy in 2022, a second larger and longer multicenter placebo-controlled study was unable to show any significant benefit on primary or secondary endpoints.

As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.

Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.

vandenBerg_Frederick_UTRECHT_web.JPG

PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
 

ALSFRS-R Served as Primary Endpoint in Both Trials

In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).

The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.

In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.

For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.

Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.

As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
 

Differences Between Two Trials Were Evaluated

The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.

When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.

An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.

Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
 

‘Unfortunate’ Results

Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.

Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.

In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.

“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.

However, he believes that the study will still have value for better understanding ALS.

“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”

Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.

DENVER — Unlike a first trial of PB&TURSO, which led to regulatory approval of this combination therapy in 2022, a second larger and longer multicenter placebo-controlled study was unable to show any significant benefit on primary or secondary endpoints.

As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.

Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.

vandenBerg_Frederick_UTRECHT_web.JPG

PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
 

ALSFRS-R Served as Primary Endpoint in Both Trials

In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).

The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.

In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.

For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.

Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.

As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
 

Differences Between Two Trials Were Evaluated

The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.

When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.

An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.

Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
 

‘Unfortunate’ Results

Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.

Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.

In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.

“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.

However, he believes that the study will still have value for better understanding ALS.

“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”

Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.

DENVER — Unlike a first trial of PB&TURSO, which led to regulatory approval of this combination therapy in 2022, a second larger and longer multicenter placebo-controlled study was unable to show any significant benefit on primary or secondary endpoints.

As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.

Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.

vandenBerg_Frederick_UTRECHT_web.JPG

PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
 

ALSFRS-R Served as Primary Endpoint in Both Trials

In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).

The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.

In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.

For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.

Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.

As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
 

Differences Between Two Trials Were Evaluated

The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.

When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.

An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.

Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
 

‘Unfortunate’ Results

Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.

Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.

In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.

“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.

However, he believes that the study will still have value for better understanding ALS.

“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”

Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.