Multiple Sclerosis

Breastfeeding by women with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) who are taking monoclonal antibodies (mAbs) appears to be safe for infants, new research confirmed.

Registry data showed no differences in health or development in the first 3 years of life among infants exposed to natalizumab, ocrelizumab, rituximab, or ofatumumab, compared with unexposed infants.

“Most monoclonal antibody medications for multiple sclerosis are not currently approved for use while a mother is breastfeeding,” even though the disease can develop during a person’s reproductive years, study investigator Kerstin Hellwig, MD, with Ruhr University in Bochum, Germany, said in a news release.

“Our data show infants exposed to these medications through breastfeeding experienced no negative effects on health or development within the first 3 years of life,” Dr. Hellwig said.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Registry Data and Analysis

Using the German MS and Pregnancy Registry, researchers identified 183 infants born to mothers taking mAbs while breastfeeding — 180 with a diagnosis of MS and three with a diagnosis of NMOSD. The infants were matched to 183 unexposed infants (control group).

Exposure to mAbs during lactation started a median of 19 days postpartum and lasted for a median of 172 days. The most commonly used mAb during lactation was natalizumab (125 women), followed by ocrelizumab (34 women), rituximab (11 women), and ofatumumab (10 women).

Among the entire infant cohort, two were first exposed to natalizumab and then ocrelizumab; one was exposed to rituximab and then ocrelizumab; three had been previously breastfed on glatiramer acetate and two on interferons.

The primary outcomes were hospitalizations, antibiotic use, developmental delay, and weight during the first 3 years of life in mAb-exposed versus unexposed infants.

In adjusted regression analyses, mAb exposure during breastfeeding was not significantly associated with annual hospitalization (rate ratio [RR], 1.23; P = .473), annual systemic antibiotic use (RR, 1.55; P = .093), developmental delay (odds ratio, 1.16; P = .716), or weight.

A limitation of the study was that only about a third of the infants were followed for the full 3 years. Therefore, Dr. Hellwig said, the results for the third year of life are less meaningful than for years 1 and 2.
 

‘Reassuring’ Data

Reached for comment, Edith L. Graham, MD, Department of Neurology, Multiple Sclerosis and Neuroimmunology, Northwestern University, Chicago, Illinois, noted that this is the largest group of breastfed infants exposed to mAbs used to treat MS and said the data provide “reassuring infant outcomes with no increase in hospitalization, antibiotic use, or developmental delay.”

Dr. Graham noted that recent publications have reported more on the use of anti-CD20 mAbs (ocrelizumab/rituximab/ofatumumab) while breastfeeding, “and this study adds data for patients on natalizumab.”

“It will be important to know how infusion timing after birth impacts transfer of monoclonal antibodies depending on the milk stage as it transitions from colostrum to mature milk in the first month postpartum,” Dr. Graham said.

“While infection rates of infants are reassuring, data on allergies in the exposed infants would be interesting to look at as well,” she added. “While these infusions are not orally bioavailable, we do not know the full extent of impact on the neonatal gut microbiome.”

In addition, Dr. Graham said it would be important to know whether drugs administered monthly, such as natalizumab and ofatumumab, accumulate in the breast milk at higher levels than medications such as ocrelizumab and rituximab, which are administered twice a year.

The German MS and pregnancy registry was partly supported by the Innovation Fund of the Federal Joint Committee, Almirall Hermal GmbH, Biogen GmbH Germany, Hexal AG, Merck Serono GmbH, Novartis Pharma GmbH, Roche Deutschland GmbH, Sanofi Genzyme, and Teva GmbH. Dr. Hellwig and Dr. Graham had no relevant disclosures.

A version of this article appeared on Medscape.com.

Breastfeeding by women with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) who are taking monoclonal antibodies (mAbs) appears to be safe for infants, new research confirmed.

Registry data showed no differences in health or development in the first 3 years of life among infants exposed to natalizumab, ocrelizumab, rituximab, or ofatumumab, compared with unexposed infants.

“Most monoclonal antibody medications for multiple sclerosis are not currently approved for use while a mother is breastfeeding,” even though the disease can develop during a person’s reproductive years, study investigator Kerstin Hellwig, MD, with Ruhr University in Bochum, Germany, said in a news release.

“Our data show infants exposed to these medications through breastfeeding experienced no negative effects on health or development within the first 3 years of life,” Dr. Hellwig said.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Registry Data and Analysis

Using the German MS and Pregnancy Registry, researchers identified 183 infants born to mothers taking mAbs while breastfeeding — 180 with a diagnosis of MS and three with a diagnosis of NMOSD. The infants were matched to 183 unexposed infants (control group).

Exposure to mAbs during lactation started a median of 19 days postpartum and lasted for a median of 172 days. The most commonly used mAb during lactation was natalizumab (125 women), followed by ocrelizumab (34 women), rituximab (11 women), and ofatumumab (10 women).

Among the entire infant cohort, two were first exposed to natalizumab and then ocrelizumab; one was exposed to rituximab and then ocrelizumab; three had been previously breastfed on glatiramer acetate and two on interferons.

The primary outcomes were hospitalizations, antibiotic use, developmental delay, and weight during the first 3 years of life in mAb-exposed versus unexposed infants.

In adjusted regression analyses, mAb exposure during breastfeeding was not significantly associated with annual hospitalization (rate ratio [RR], 1.23; P = .473), annual systemic antibiotic use (RR, 1.55; P = .093), developmental delay (odds ratio, 1.16; P = .716), or weight.

A limitation of the study was that only about a third of the infants were followed for the full 3 years. Therefore, Dr. Hellwig said, the results for the third year of life are less meaningful than for years 1 and 2.
 

‘Reassuring’ Data

Reached for comment, Edith L. Graham, MD, Department of Neurology, Multiple Sclerosis and Neuroimmunology, Northwestern University, Chicago, Illinois, noted that this is the largest group of breastfed infants exposed to mAbs used to treat MS and said the data provide “reassuring infant outcomes with no increase in hospitalization, antibiotic use, or developmental delay.”

Dr. Graham noted that recent publications have reported more on the use of anti-CD20 mAbs (ocrelizumab/rituximab/ofatumumab) while breastfeeding, “and this study adds data for patients on natalizumab.”

“It will be important to know how infusion timing after birth impacts transfer of monoclonal antibodies depending on the milk stage as it transitions from colostrum to mature milk in the first month postpartum,” Dr. Graham said.

“While infection rates of infants are reassuring, data on allergies in the exposed infants would be interesting to look at as well,” she added. “While these infusions are not orally bioavailable, we do not know the full extent of impact on the neonatal gut microbiome.”

In addition, Dr. Graham said it would be important to know whether drugs administered monthly, such as natalizumab and ofatumumab, accumulate in the breast milk at higher levels than medications such as ocrelizumab and rituximab, which are administered twice a year.

The German MS and pregnancy registry was partly supported by the Innovation Fund of the Federal Joint Committee, Almirall Hermal GmbH, Biogen GmbH Germany, Hexal AG, Merck Serono GmbH, Novartis Pharma GmbH, Roche Deutschland GmbH, Sanofi Genzyme, and Teva GmbH. Dr. Hellwig and Dr. Graham had no relevant disclosures.

A version of this article appeared on Medscape.com.

Breastfeeding by women with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) who are taking monoclonal antibodies (mAbs) appears to be safe for infants, new research confirmed.

Registry data showed no differences in health or development in the first 3 years of life among infants exposed to natalizumab, ocrelizumab, rituximab, or ofatumumab, compared with unexposed infants.

“Most monoclonal antibody medications for multiple sclerosis are not currently approved for use while a mother is breastfeeding,” even though the disease can develop during a person’s reproductive years, study investigator Kerstin Hellwig, MD, with Ruhr University in Bochum, Germany, said in a news release.

“Our data show infants exposed to these medications through breastfeeding experienced no negative effects on health or development within the first 3 years of life,” Dr. Hellwig said.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Registry Data and Analysis

Using the German MS and Pregnancy Registry, researchers identified 183 infants born to mothers taking mAbs while breastfeeding — 180 with a diagnosis of MS and three with a diagnosis of NMOSD. The infants were matched to 183 unexposed infants (control group).

Exposure to mAbs during lactation started a median of 19 days postpartum and lasted for a median of 172 days. The most commonly used mAb during lactation was natalizumab (125 women), followed by ocrelizumab (34 women), rituximab (11 women), and ofatumumab (10 women).

Among the entire infant cohort, two were first exposed to natalizumab and then ocrelizumab; one was exposed to rituximab and then ocrelizumab; three had been previously breastfed on glatiramer acetate and two on interferons.

The primary outcomes were hospitalizations, antibiotic use, developmental delay, and weight during the first 3 years of life in mAb-exposed versus unexposed infants.

In adjusted regression analyses, mAb exposure during breastfeeding was not significantly associated with annual hospitalization (rate ratio [RR], 1.23; P = .473), annual systemic antibiotic use (RR, 1.55; P = .093), developmental delay (odds ratio, 1.16; P = .716), or weight.

A limitation of the study was that only about a third of the infants were followed for the full 3 years. Therefore, Dr. Hellwig said, the results for the third year of life are less meaningful than for years 1 and 2.
 

‘Reassuring’ Data

Reached for comment, Edith L. Graham, MD, Department of Neurology, Multiple Sclerosis and Neuroimmunology, Northwestern University, Chicago, Illinois, noted that this is the largest group of breastfed infants exposed to mAbs used to treat MS and said the data provide “reassuring infant outcomes with no increase in hospitalization, antibiotic use, or developmental delay.”

Dr. Graham noted that recent publications have reported more on the use of anti-CD20 mAbs (ocrelizumab/rituximab/ofatumumab) while breastfeeding, “and this study adds data for patients on natalizumab.”

“It will be important to know how infusion timing after birth impacts transfer of monoclonal antibodies depending on the milk stage as it transitions from colostrum to mature milk in the first month postpartum,” Dr. Graham said.

“While infection rates of infants are reassuring, data on allergies in the exposed infants would be interesting to look at as well,” she added. “While these infusions are not orally bioavailable, we do not know the full extent of impact on the neonatal gut microbiome.”

In addition, Dr. Graham said it would be important to know whether drugs administered monthly, such as natalizumab and ofatumumab, accumulate in the breast milk at higher levels than medications such as ocrelizumab and rituximab, which are administered twice a year.

The German MS and pregnancy registry was partly supported by the Innovation Fund of the Federal Joint Committee, Almirall Hermal GmbH, Biogen GmbH Germany, Hexal AG, Merck Serono GmbH, Novartis Pharma GmbH, Roche Deutschland GmbH, Sanofi Genzyme, and Teva GmbH. Dr. Hellwig and Dr. Graham had no relevant disclosures.

A version of this article appeared on Medscape.com.

Andrew Solomon, MD, from the University of Vermont in Burlington, highlights key findings presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.

Dr Solomon begins by discussing a study on the potential benefits of antipyretics to manage overheating associated with exercise, a common symptom among MS patients. Results showed that MS patients who took aspirin or acetaminophen had less increase in body temperature after a maximal exercise test than those who took placebo.

He next reports on a study that examined whether a combination of two imaging biomarkers specific for MS, namely the central vein sign and the paramagnetic rim lesion, could improve diagnostic specificity. This study found that the presence of at least one of the signs contributed to improved diagnosis.

Dr Solomon then discusses a post hoc analysis of the ULTIMATE I and II trials which reconsidered how to confirm relapses of MS. The study found that follow-up MRI could distinguish relapse from pseudoexacerbations.

Finally, he reports on a study that examined the feasibility and tolerability of low-field brain MRI in MS. The equipment is smaller, portable, and more cost-effective than standard MRI and has high acceptability from patients. Although the precision of these devices needs further testing, Dr Solomon suggests that portable MRI could make MS diagnosis and monitoring available to broader populations.

--

Andrew J. Solomon, MD, Professor, Neurological Sciences, Larner College of Medicine, University of Vermont; Division Chief, Multiple Sclerosis, University Health Center, Burlington, Vermont

Andrew J. Solomon, MD, has disclosed the following relevant financial relationships: Received research grant from: Bristol Myers Squibb

Andrew Solomon, MD, from the University of Vermont in Burlington, highlights key findings presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.

Dr Solomon begins by discussing a study on the potential benefits of antipyretics to manage overheating associated with exercise, a common symptom among MS patients. Results showed that MS patients who took aspirin or acetaminophen had less increase in body temperature after a maximal exercise test than those who took placebo.

He next reports on a study that examined whether a combination of two imaging biomarkers specific for MS, namely the central vein sign and the paramagnetic rim lesion, could improve diagnostic specificity. This study found that the presence of at least one of the signs contributed to improved diagnosis.

Dr Solomon then discusses a post hoc analysis of the ULTIMATE I and II trials which reconsidered how to confirm relapses of MS. The study found that follow-up MRI could distinguish relapse from pseudoexacerbations.

Finally, he reports on a study that examined the feasibility and tolerability of low-field brain MRI in MS. The equipment is smaller, portable, and more cost-effective than standard MRI and has high acceptability from patients. Although the precision of these devices needs further testing, Dr Solomon suggests that portable MRI could make MS diagnosis and monitoring available to broader populations.

--

Andrew J. Solomon, MD, Professor, Neurological Sciences, Larner College of Medicine, University of Vermont; Division Chief, Multiple Sclerosis, University Health Center, Burlington, Vermont

Andrew J. Solomon, MD, has disclosed the following relevant financial relationships: Received research grant from: Bristol Myers Squibb

Andrew Solomon, MD, from the University of Vermont in Burlington, highlights key findings presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.

Dr Solomon begins by discussing a study on the potential benefits of antipyretics to manage overheating associated with exercise, a common symptom among MS patients. Results showed that MS patients who took aspirin or acetaminophen had less increase in body temperature after a maximal exercise test than those who took placebo.

He next reports on a study that examined whether a combination of two imaging biomarkers specific for MS, namely the central vein sign and the paramagnetic rim lesion, could improve diagnostic specificity. This study found that the presence of at least one of the signs contributed to improved diagnosis.

Dr Solomon then discusses a post hoc analysis of the ULTIMATE I and II trials which reconsidered how to confirm relapses of MS. The study found that follow-up MRI could distinguish relapse from pseudoexacerbations.

Finally, he reports on a study that examined the feasibility and tolerability of low-field brain MRI in MS. The equipment is smaller, portable, and more cost-effective than standard MRI and has high acceptability from patients. Although the precision of these devices needs further testing, Dr Solomon suggests that portable MRI could make MS diagnosis and monitoring available to broader populations.

--

Andrew J. Solomon, MD, Professor, Neurological Sciences, Larner College of Medicine, University of Vermont; Division Chief, Multiple Sclerosis, University Health Center, Burlington, Vermont

Andrew J. Solomon, MD, has disclosed the following relevant financial relationships: Received research grant from: Bristol Myers Squibb

WEST PALM BEACH, FLORIDA — An over-the-counter antihistamine that had shown potential for treatment of multiple sclerosis (MS) in animal studies was linked to significant worsening of symptoms in humans, new trial data suggested.

Researchers halted an arm of a clinical trial of clemastine fumarate for MS after a fivefold increase in disease progression was reported in three participants, triggering “stoppage criteria,” investigators said.

The inexpensive antihistamine had been touted as a potential MS treatment following promising early findings, and some patients are reportedly taking it on an off-label basis. It was one of four approved drugs in an ongoing trial led by the National Institute of Allergy and Infectious Diseases (NIAID) to investigate the drugs’ efficacy in the treatment of MS.

“Most patients on the other drugs progressed much slower compared to their baseline,” said senior investigator Bibi Bielekova, MD, with NIAID. “When we compare the results in clemastine arm with all other patients treated with the remaining drugs, the probability that our patients progressed by chance is lower than 0.01%.”

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

TRAP-MS Trial

The OTC antihistamine clemastine has been available for decades under the brand names Tavist and Dayhist. In addition to findings from mouse studies, results from a small clinical trial reported in 2017 suggested that clemastine may promote myelin repair. Other animal studies and another small study with healthy volunteers also suggested the drug may reduce immune activity.

Clemastine fumarate is one of four drugs in the ongoing TRAP-MS phase 1/2 trial, which is sponsored by NIAID. The study is designed to determine what effects, if any, the drugs have on MS biomarkers either alone or in combination.

Other drugs in the study include the diabetes drug pioglitazone (Actos), the muscle relaxant dantrolene (Ryanodex, Revonto, and Dantrium), and the idiopathic pulmonary fibrosis drug pirfenidone (Pirespa).

An estimated 250 adults with MS were expected to be enrolled in the trial, which began in 2017 and is scheduled to reach its primary completion in 2025.

Per the study protocol, nine patients in the clemastine arm were assigned to receive 8 mg/d (divided into three doses of 2, 2, and 4 mg). Cerebrospinal fluid samples were collected at baseline and 6 months after clemastine treatment began.
 

Worsening Symptoms

The three patients whose worsening symptoms triggered stopping criteria when they demonstrated increased disability five times faster than their 18-month baseline, researchers reported.

These participants had increased levels of C-reactive protein and erythrocyte sedimentation rate and gained weight, which study authors said were “suggestive of systemic pro-inflammatory state.”

“We found that clemastine treatment causes significant changes in purinergic metabolism,” lead author Joanna Kocot, PhD, a NIAID fellow, said during the ACTRIMS presentation. “We also confirmed that this toxic effect of clemastine was because of pyroptosis,” a form of cell death.

None of the remaining 55 patients treated with other TRAP-MS therapies triggered safety criteria, which study authors said offered “evidence for clemastine toxicity.”

Demographic information was not provided, but the patients on clemastine with worsening symptoms were older, more disabled, and more obese than the other six patients in the clemastine arm, Dr. Bielekova said during the conference presentation.
 

‘Undesirable’ or ‘Premature’?

Commenting on the findings, Paul J. Tesar, PhD, professor of innovative therapeutics at Case Western Reserve University School of Medicine in Cleveland, said the findings are unexpected.

“Compared to previous trials, the TRAP-MS trial included different patient populations and treated them with clemastine for a longer time period, so it is hard to make direct comparisons,” said Dr. Tesar, who studies MS and did not take part in the new study. “From the limited data disclosed thus far, it does seem likely that clemastine is causing toxicity, possibly through increased inflammation, and accelerating disease progression.”

In the big picture, he said, “while clemastine trials have been important steps toward a first-in-class remyelinating drug, the promiscuous nature of clemastine — it binds to many protein targets — and its known side effects make it undesirable as a mainstay treatment for people with multiple sclerosis.”

Hundreds or perhaps thousands of patients with MS may already take the drug because of the early positive findings, said Ari Green, MD, medical director of the University of California at San Francisco Multiple Sclerosis Center and lead author of the initial 2017 clinical trial on clemastine and myelin repair.

Dr. Green, who was not involved in the new study, said he is skeptical of the findings.

“We can’t conclude much about an effect based on three patients, and the risk that this is a chance effect is extraordinarily high,” he said. “It’s premature to make any attribution of what they saw to clemastine itself.”

Dr. Bielekova disagreed, and said she stands by the findings.

The pyroptosis score, derived from CSF biomarkers, was elevated in MS and higher in progressive MS than in relapsing-remitting MS, she said, adding that pyroptosis correlates with how fast people with MS accumulate disability.

“From all drugs we tested, only clemastine increased this CSF pyroptosis score,” Dr. Bielekova said.

Regardless, Dr. Green urged caution when considering whether to use the drug.

“Nobody should take clemastine without the supervision of a doctor,” he said. “It’s actually best done in the context of clinical trials.”

NIAID funded the study, and the authors had no disclosures. Dr. Tesar is cofounder of Convelo Therapeutics, a biotechnology company developing remyelinating therapeutics for MS. Dr. Green said he is conducting studies related to clemastine, but they do not have industry funding.
 

A version of this article appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — An over-the-counter antihistamine that had shown potential for treatment of multiple sclerosis (MS) in animal studies was linked to significant worsening of symptoms in humans, new trial data suggested.

Researchers halted an arm of a clinical trial of clemastine fumarate for MS after a fivefold increase in disease progression was reported in three participants, triggering “stoppage criteria,” investigators said.

The inexpensive antihistamine had been touted as a potential MS treatment following promising early findings, and some patients are reportedly taking it on an off-label basis. It was one of four approved drugs in an ongoing trial led by the National Institute of Allergy and Infectious Diseases (NIAID) to investigate the drugs’ efficacy in the treatment of MS.

“Most patients on the other drugs progressed much slower compared to their baseline,” said senior investigator Bibi Bielekova, MD, with NIAID. “When we compare the results in clemastine arm with all other patients treated with the remaining drugs, the probability that our patients progressed by chance is lower than 0.01%.”

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

TRAP-MS Trial

The OTC antihistamine clemastine has been available for decades under the brand names Tavist and Dayhist. In addition to findings from mouse studies, results from a small clinical trial reported in 2017 suggested that clemastine may promote myelin repair. Other animal studies and another small study with healthy volunteers also suggested the drug may reduce immune activity.

Clemastine fumarate is one of four drugs in the ongoing TRAP-MS phase 1/2 trial, which is sponsored by NIAID. The study is designed to determine what effects, if any, the drugs have on MS biomarkers either alone or in combination.

Other drugs in the study include the diabetes drug pioglitazone (Actos), the muscle relaxant dantrolene (Ryanodex, Revonto, and Dantrium), and the idiopathic pulmonary fibrosis drug pirfenidone (Pirespa).

An estimated 250 adults with MS were expected to be enrolled in the trial, which began in 2017 and is scheduled to reach its primary completion in 2025.

Per the study protocol, nine patients in the clemastine arm were assigned to receive 8 mg/d (divided into three doses of 2, 2, and 4 mg). Cerebrospinal fluid samples were collected at baseline and 6 months after clemastine treatment began.
 

Worsening Symptoms

The three patients whose worsening symptoms triggered stopping criteria when they demonstrated increased disability five times faster than their 18-month baseline, researchers reported.

These participants had increased levels of C-reactive protein and erythrocyte sedimentation rate and gained weight, which study authors said were “suggestive of systemic pro-inflammatory state.”

“We found that clemastine treatment causes significant changes in purinergic metabolism,” lead author Joanna Kocot, PhD, a NIAID fellow, said during the ACTRIMS presentation. “We also confirmed that this toxic effect of clemastine was because of pyroptosis,” a form of cell death.

None of the remaining 55 patients treated with other TRAP-MS therapies triggered safety criteria, which study authors said offered “evidence for clemastine toxicity.”

Demographic information was not provided, but the patients on clemastine with worsening symptoms were older, more disabled, and more obese than the other six patients in the clemastine arm, Dr. Bielekova said during the conference presentation.
 

‘Undesirable’ or ‘Premature’?

Commenting on the findings, Paul J. Tesar, PhD, professor of innovative therapeutics at Case Western Reserve University School of Medicine in Cleveland, said the findings are unexpected.

“Compared to previous trials, the TRAP-MS trial included different patient populations and treated them with clemastine for a longer time period, so it is hard to make direct comparisons,” said Dr. Tesar, who studies MS and did not take part in the new study. “From the limited data disclosed thus far, it does seem likely that clemastine is causing toxicity, possibly through increased inflammation, and accelerating disease progression.”

In the big picture, he said, “while clemastine trials have been important steps toward a first-in-class remyelinating drug, the promiscuous nature of clemastine — it binds to many protein targets — and its known side effects make it undesirable as a mainstay treatment for people with multiple sclerosis.”

Hundreds or perhaps thousands of patients with MS may already take the drug because of the early positive findings, said Ari Green, MD, medical director of the University of California at San Francisco Multiple Sclerosis Center and lead author of the initial 2017 clinical trial on clemastine and myelin repair.

Dr. Green, who was not involved in the new study, said he is skeptical of the findings.

“We can’t conclude much about an effect based on three patients, and the risk that this is a chance effect is extraordinarily high,” he said. “It’s premature to make any attribution of what they saw to clemastine itself.”

Dr. Bielekova disagreed, and said she stands by the findings.

The pyroptosis score, derived from CSF biomarkers, was elevated in MS and higher in progressive MS than in relapsing-remitting MS, she said, adding that pyroptosis correlates with how fast people with MS accumulate disability.

“From all drugs we tested, only clemastine increased this CSF pyroptosis score,” Dr. Bielekova said.

Regardless, Dr. Green urged caution when considering whether to use the drug.

“Nobody should take clemastine without the supervision of a doctor,” he said. “It’s actually best done in the context of clinical trials.”

NIAID funded the study, and the authors had no disclosures. Dr. Tesar is cofounder of Convelo Therapeutics, a biotechnology company developing remyelinating therapeutics for MS. Dr. Green said he is conducting studies related to clemastine, but they do not have industry funding.
 

A version of this article appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — An over-the-counter antihistamine that had shown potential for treatment of multiple sclerosis (MS) in animal studies was linked to significant worsening of symptoms in humans, new trial data suggested.

Researchers halted an arm of a clinical trial of clemastine fumarate for MS after a fivefold increase in disease progression was reported in three participants, triggering “stoppage criteria,” investigators said.

The inexpensive antihistamine had been touted as a potential MS treatment following promising early findings, and some patients are reportedly taking it on an off-label basis. It was one of four approved drugs in an ongoing trial led by the National Institute of Allergy and Infectious Diseases (NIAID) to investigate the drugs’ efficacy in the treatment of MS.

“Most patients on the other drugs progressed much slower compared to their baseline,” said senior investigator Bibi Bielekova, MD, with NIAID. “When we compare the results in clemastine arm with all other patients treated with the remaining drugs, the probability that our patients progressed by chance is lower than 0.01%.”

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

TRAP-MS Trial

The OTC antihistamine clemastine has been available for decades under the brand names Tavist and Dayhist. In addition to findings from mouse studies, results from a small clinical trial reported in 2017 suggested that clemastine may promote myelin repair. Other animal studies and another small study with healthy volunteers also suggested the drug may reduce immune activity.

Clemastine fumarate is one of four drugs in the ongoing TRAP-MS phase 1/2 trial, which is sponsored by NIAID. The study is designed to determine what effects, if any, the drugs have on MS biomarkers either alone or in combination.

Other drugs in the study include the diabetes drug pioglitazone (Actos), the muscle relaxant dantrolene (Ryanodex, Revonto, and Dantrium), and the idiopathic pulmonary fibrosis drug pirfenidone (Pirespa).

An estimated 250 adults with MS were expected to be enrolled in the trial, which began in 2017 and is scheduled to reach its primary completion in 2025.

Per the study protocol, nine patients in the clemastine arm were assigned to receive 8 mg/d (divided into three doses of 2, 2, and 4 mg). Cerebrospinal fluid samples were collected at baseline and 6 months after clemastine treatment began.
 

Worsening Symptoms

The three patients whose worsening symptoms triggered stopping criteria when they demonstrated increased disability five times faster than their 18-month baseline, researchers reported.

These participants had increased levels of C-reactive protein and erythrocyte sedimentation rate and gained weight, which study authors said were “suggestive of systemic pro-inflammatory state.”

“We found that clemastine treatment causes significant changes in purinergic metabolism,” lead author Joanna Kocot, PhD, a NIAID fellow, said during the ACTRIMS presentation. “We also confirmed that this toxic effect of clemastine was because of pyroptosis,” a form of cell death.

None of the remaining 55 patients treated with other TRAP-MS therapies triggered safety criteria, which study authors said offered “evidence for clemastine toxicity.”

Demographic information was not provided, but the patients on clemastine with worsening symptoms were older, more disabled, and more obese than the other six patients in the clemastine arm, Dr. Bielekova said during the conference presentation.
 

‘Undesirable’ or ‘Premature’?

Commenting on the findings, Paul J. Tesar, PhD, professor of innovative therapeutics at Case Western Reserve University School of Medicine in Cleveland, said the findings are unexpected.

“Compared to previous trials, the TRAP-MS trial included different patient populations and treated them with clemastine for a longer time period, so it is hard to make direct comparisons,” said Dr. Tesar, who studies MS and did not take part in the new study. “From the limited data disclosed thus far, it does seem likely that clemastine is causing toxicity, possibly through increased inflammation, and accelerating disease progression.”

In the big picture, he said, “while clemastine trials have been important steps toward a first-in-class remyelinating drug, the promiscuous nature of clemastine — it binds to many protein targets — and its known side effects make it undesirable as a mainstay treatment for people with multiple sclerosis.”

Hundreds or perhaps thousands of patients with MS may already take the drug because of the early positive findings, said Ari Green, MD, medical director of the University of California at San Francisco Multiple Sclerosis Center and lead author of the initial 2017 clinical trial on clemastine and myelin repair.

Dr. Green, who was not involved in the new study, said he is skeptical of the findings.

“We can’t conclude much about an effect based on three patients, and the risk that this is a chance effect is extraordinarily high,” he said. “It’s premature to make any attribution of what they saw to clemastine itself.”

Dr. Bielekova disagreed, and said she stands by the findings.

The pyroptosis score, derived from CSF biomarkers, was elevated in MS and higher in progressive MS than in relapsing-remitting MS, she said, adding that pyroptosis correlates with how fast people with MS accumulate disability.

“From all drugs we tested, only clemastine increased this CSF pyroptosis score,” Dr. Bielekova said.

Regardless, Dr. Green urged caution when considering whether to use the drug.

“Nobody should take clemastine without the supervision of a doctor,” he said. “It’s actually best done in the context of clinical trials.”

NIAID funded the study, and the authors had no disclosures. Dr. Tesar is cofounder of Convelo Therapeutics, a biotechnology company developing remyelinating therapeutics for MS. Dr. Green said he is conducting studies related to clemastine, but they do not have industry funding.
 

A version of this article appeared on Medscape.com.

WEST PALM BEACH, CALIFORNIA — Aspirin and acetaminophen may offer an effective and inexpensive solution to exercise-induced heat sensitivity in relapsing-remitting multiple sclerosis (RRMS), results from a new phase 3 trial suggested.

The findings from the randomized, placebo-controlled, double-blind study could solve this common problem, known clinically as Uhthoff’s phenomenon, that causes temporary worsening of MS symptoms with heat exposure.

“This could be a game changer,” said study investigator Victoria M. Leavitt, PhD, assistant professor of neuropsychology of Columbia University Irving Medical Center in New York City. 

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and published online in the Journal of Neurology. 
 

A Common Condition

Research suggested that 60%-80% of MS patients experience heat sensitivity. However, while the exact cause is unknown, some evidence suggested it may be related to hypothalamic dysregulation or lesions of the hypothalamus.

Researchers have explored cooling strategies such as liquid-cooled clothing, but available tools can be hard to find, expensive, and cumbersome. Although aspirin has been linked to some symptom improvement in MS, its utility and that of acetaminophen for the condition has not been studied, Dr. Leavitt said. 

For the single-center study, researchers recruited 60 patients (81% female; average age, 42 years; 73% White individuals) between 2019 and 2022. Overall, 37 completed at least one study visit, and 29 completed two to three visits. The average disease duration was 6 years. 

Participants received oral administration of 650 mg aspirin, acetaminophen, or placebo at each of three study visits over 3 weeks, separated by at least 1 week. At each visit, they took part in a maximal exercise test conducted on a cycle ergometer and were asked to cycle at 50-60 revolutions/min for as long as possible. 

Compared with placebo, body temperature increase from baseline to exercise stoppage was significantly reduced with aspirin (0.006 °F vs 0.68 °F; P < .001) and with acetaminophen (0.31 °F vs 0.68 °F; P < .004) 

Neither medication was associated with a significant difference in time to exhaustion, and there were no serious adverse events.

“This is really nice because some people might have an adverse reaction to aspirin,” such as gastrointestinal issues. Acetaminophen has a different side-effect profile,” Dr. Leavitt said. 

Both medications are inexpensive and available over the counter. The 650-mg acetaminophen dose used in the study is available in an extended-release formula. Typically aspirin isn’t available in doses larger than 325 mg. The 650-mg dose used in the study is considered safe but large. 

Dr. Leavitt said she would like to study daily aspirin in people with MS to see if it can boost physical activity. “That’s the test of whether this will meaningfully affect the lives of people with MS,” she said. 
 

No Harm From Overheating

Commenting on the findings, Katherine Knox, MD, associate professor of physical medicine and rehabilitation at the University of Saskatchewan, Canada, noted that “the intervention maybe be initially helpful for the person fearful of getting weaker when they get ‘hot’ with exercise.” 

Dr. Knox, who wasn’t involved in the research, added that it’s important for patients with MS to overcome initial barriers and fears about exercise. 

“However, for most people the effects of being warm with exercise are less concerning for them after education that the weakness is temporary and does not cause harm if one takes the right precautions such as planning ahead to avoid a fall,” she said. Also, inexpensive interventions such as a fan or a wet cotton headband can be helpful, she said. 

The study “provides further evidence that the ‘overheating’ is not causing harm since the time to exhaustion was unchanged,” Dr. Knox added. 

The study was funded by the National Institutes of Health. The authors had no disclosures. Disclosure information for Dr. Knox was not available.
 

A version of this article appeared on Medscape.com.

WEST PALM BEACH, CALIFORNIA — Aspirin and acetaminophen may offer an effective and inexpensive solution to exercise-induced heat sensitivity in relapsing-remitting multiple sclerosis (RRMS), results from a new phase 3 trial suggested.

The findings from the randomized, placebo-controlled, double-blind study could solve this common problem, known clinically as Uhthoff’s phenomenon, that causes temporary worsening of MS symptoms with heat exposure.

“This could be a game changer,” said study investigator Victoria M. Leavitt, PhD, assistant professor of neuropsychology of Columbia University Irving Medical Center in New York City. 

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and published online in the Journal of Neurology. 
 

A Common Condition

Research suggested that 60%-80% of MS patients experience heat sensitivity. However, while the exact cause is unknown, some evidence suggested it may be related to hypothalamic dysregulation or lesions of the hypothalamus.

Researchers have explored cooling strategies such as liquid-cooled clothing, but available tools can be hard to find, expensive, and cumbersome. Although aspirin has been linked to some symptom improvement in MS, its utility and that of acetaminophen for the condition has not been studied, Dr. Leavitt said. 

For the single-center study, researchers recruited 60 patients (81% female; average age, 42 years; 73% White individuals) between 2019 and 2022. Overall, 37 completed at least one study visit, and 29 completed two to three visits. The average disease duration was 6 years. 

Participants received oral administration of 650 mg aspirin, acetaminophen, or placebo at each of three study visits over 3 weeks, separated by at least 1 week. At each visit, they took part in a maximal exercise test conducted on a cycle ergometer and were asked to cycle at 50-60 revolutions/min for as long as possible. 

Compared with placebo, body temperature increase from baseline to exercise stoppage was significantly reduced with aspirin (0.006 °F vs 0.68 °F; P < .001) and with acetaminophen (0.31 °F vs 0.68 °F; P < .004) 

Neither medication was associated with a significant difference in time to exhaustion, and there were no serious adverse events.

“This is really nice because some people might have an adverse reaction to aspirin,” such as gastrointestinal issues. Acetaminophen has a different side-effect profile,” Dr. Leavitt said. 

Both medications are inexpensive and available over the counter. The 650-mg acetaminophen dose used in the study is available in an extended-release formula. Typically aspirin isn’t available in doses larger than 325 mg. The 650-mg dose used in the study is considered safe but large. 

Dr. Leavitt said she would like to study daily aspirin in people with MS to see if it can boost physical activity. “That’s the test of whether this will meaningfully affect the lives of people with MS,” she said. 
 

No Harm From Overheating

Commenting on the findings, Katherine Knox, MD, associate professor of physical medicine and rehabilitation at the University of Saskatchewan, Canada, noted that “the intervention maybe be initially helpful for the person fearful of getting weaker when they get ‘hot’ with exercise.” 

Dr. Knox, who wasn’t involved in the research, added that it’s important for patients with MS to overcome initial barriers and fears about exercise. 

“However, for most people the effects of being warm with exercise are less concerning for them after education that the weakness is temporary and does not cause harm if one takes the right precautions such as planning ahead to avoid a fall,” she said. Also, inexpensive interventions such as a fan or a wet cotton headband can be helpful, she said. 

The study “provides further evidence that the ‘overheating’ is not causing harm since the time to exhaustion was unchanged,” Dr. Knox added. 

The study was funded by the National Institutes of Health. The authors had no disclosures. Disclosure information for Dr. Knox was not available.
 

A version of this article appeared on Medscape.com.

WEST PALM BEACH, CALIFORNIA — Aspirin and acetaminophen may offer an effective and inexpensive solution to exercise-induced heat sensitivity in relapsing-remitting multiple sclerosis (RRMS), results from a new phase 3 trial suggested.

The findings from the randomized, placebo-controlled, double-blind study could solve this common problem, known clinically as Uhthoff’s phenomenon, that causes temporary worsening of MS symptoms with heat exposure.

“This could be a game changer,” said study investigator Victoria M. Leavitt, PhD, assistant professor of neuropsychology of Columbia University Irving Medical Center in New York City. 

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and published online in the Journal of Neurology. 
 

A Common Condition

Research suggested that 60%-80% of MS patients experience heat sensitivity. However, while the exact cause is unknown, some evidence suggested it may be related to hypothalamic dysregulation or lesions of the hypothalamus.

Researchers have explored cooling strategies such as liquid-cooled clothing, but available tools can be hard to find, expensive, and cumbersome. Although aspirin has been linked to some symptom improvement in MS, its utility and that of acetaminophen for the condition has not been studied, Dr. Leavitt said. 

For the single-center study, researchers recruited 60 patients (81% female; average age, 42 years; 73% White individuals) between 2019 and 2022. Overall, 37 completed at least one study visit, and 29 completed two to three visits. The average disease duration was 6 years. 

Participants received oral administration of 650 mg aspirin, acetaminophen, or placebo at each of three study visits over 3 weeks, separated by at least 1 week. At each visit, they took part in a maximal exercise test conducted on a cycle ergometer and were asked to cycle at 50-60 revolutions/min for as long as possible. 

Compared with placebo, body temperature increase from baseline to exercise stoppage was significantly reduced with aspirin (0.006 °F vs 0.68 °F; P < .001) and with acetaminophen (0.31 °F vs 0.68 °F; P < .004) 

Neither medication was associated with a significant difference in time to exhaustion, and there were no serious adverse events.

“This is really nice because some people might have an adverse reaction to aspirin,” such as gastrointestinal issues. Acetaminophen has a different side-effect profile,” Dr. Leavitt said. 

Both medications are inexpensive and available over the counter. The 650-mg acetaminophen dose used in the study is available in an extended-release formula. Typically aspirin isn’t available in doses larger than 325 mg. The 650-mg dose used in the study is considered safe but large. 

Dr. Leavitt said she would like to study daily aspirin in people with MS to see if it can boost physical activity. “That’s the test of whether this will meaningfully affect the lives of people with MS,” she said. 
 

No Harm From Overheating

Commenting on the findings, Katherine Knox, MD, associate professor of physical medicine and rehabilitation at the University of Saskatchewan, Canada, noted that “the intervention maybe be initially helpful for the person fearful of getting weaker when they get ‘hot’ with exercise.” 

Dr. Knox, who wasn’t involved in the research, added that it’s important for patients with MS to overcome initial barriers and fears about exercise. 

“However, for most people the effects of being warm with exercise are less concerning for them after education that the weakness is temporary and does not cause harm if one takes the right precautions such as planning ahead to avoid a fall,” she said. Also, inexpensive interventions such as a fan or a wet cotton headband can be helpful, she said. 

The study “provides further evidence that the ‘overheating’ is not causing harm since the time to exhaustion was unchanged,” Dr. Knox added. 

The study was funded by the National Institutes of Health. The authors had no disclosures. Disclosure information for Dr. Knox was not available.
 

A version of this article appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — Top-line results of two phase 3 trials evaluating the BTK inhibitor evobrutinib for treatment of multiple sclerosis (MS) were negative when released several months ago, but the hope for a signal of benefit on secondary endpoints was dashed when the full results of the trials were presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum.

Based on prior drug development, including the promise seen in a phase 2 trial, “these negative results were quite disappointing,” reported Xavier Montalban, MD, director, department of neurology, Catalunya Center for Multiple Sclerosis, Hospital Universitario Vall d’Hebron, Barcelona, Spain.

In the evolutionRMS1 and 2 phase 3 trials, 2285 relapsing-remitting MS patients with active disease were randomized to 45 mg of twice-daily oral evobrutinib or 14 mg once-daily teriflunomide, a pyrimidine synthesis inhibitor already widely used for the treatment of MS. The trial, conducted in 52 countries, was double-blind and double-dummy.

Ted Bosworth/MDedge News

No Outcome Supported an Evobrutinib Advantage

Numerically, the mean number of T1 gadolinium-enhancing lesions was greater among those randomized to evobrutinib while the mean number of new or enlarging T2 lesions was lower. However, none of these differences in either study reached statistical significance.

The lower serum neurofilament light chain (sNfL) levels were significant (P = .032) in one of the two trials, but the difference was modest, and Dr. Montalban stated that the difference “was probably not clinically significant.”

Almost all of the patients had multiple relapses before being enrolled in the study, but only 36.5% had received a prior disease-modifying therapy. According to Dr. Montalban, the baseline characteristics of the patients enrolled were “nothing special,” in that they were very much “like the types of patients enrolled in trials like these.”

In general, both drugs were well tolerated with a comparable safety profile. The exception was a greater proportion of patients randomized to evobrutinib who developed elevated liver function tests, including a greater proportion with a level at least 5 times the upper limit of normal. All normalized after treatment was discontinued.

This is the first phase 3 trial of a BTK inhibitor in MS, according to Dr. Montalban, who pointed out that evobrutinib did perform as well as a highly active agent, even if it could not show superiority.

There is limited likelihood that further ongoing analyses will uncover meaningful activity not detected in the primary and secondary outcomes, but Dr. Montalban said that there is a possibility that a higher dose or a BTK inhibitor with different characteristics might still produce the types of clinical benefits hypothesized in this initial trial.

Asked to speculate about the results if the RM1 and RM2 trials had a noninferiority rather than a superiority design been employed, Dr. Montalban said that evobrutinib relative to teriflunomide appears to be “similar but more toxic.”

The recent excitement building for the potential of BTK inhibitors in MS was not helped by a second, but much smaller, late-breaker study that evaluated tolebrutinib. The primary endpoint of that study, conducted with just seven patients, was complete resolution of paramagnetic rim lesions (PRL), a prognostically important composition of macrophages, microglia, and iron seen in the central nervous system (CNS) on imaging.
 

No Resolution of CNS Lesions

Even after 48 weeks, none of the lesions had resolved, according to Maria I. Gaitán, MD, acting director of the Translational Neuroradiology Unit of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland.

Again, although these findings were disappointing, Dr. Gaitán said there are a number of explanations for the result that do not preclude a benefit from BTK inhibitors in future studies.

“Complete resolution of PRL might be a bar that was too high,” she said, noting that favorable changes in these lesions could have occurred even if the characteristic iron deposits persisted. She also suggested that dosing might not have been optimized to halt or reverse disease activity in the CNS. Like Dr. Montalban, she suggested that BTK inhibitors with different characteristics might succeed where tolebrutinib failed.

Dr. Freedman, current president of ACTRIMS, agreed that these data should not be interpreted as ruling out a clinical role for BTK inhibitors. Pointing to the substantial body of data supporting this mechanism for reversing inflammation in the CNS, he declared that “the story is not over.”

Dr. Montalban reported financial relationships with Actelion, Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Hoffman La Roche, Immunic, Janssen, Mylan, NervGen, Novartis, Sanofi-Genzyme, Teva, TG Therapeutics, and Merck, which provided funding for the RMS 1 and 2 trials. Dr. Freedman reported financial relationships with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Hoffman La Roche, Merck, Novartis, and Teva Canada Innovation. Dr. Gaitán reported no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — Top-line results of two phase 3 trials evaluating the BTK inhibitor evobrutinib for treatment of multiple sclerosis (MS) were negative when released several months ago, but the hope for a signal of benefit on secondary endpoints was dashed when the full results of the trials were presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum.

Based on prior drug development, including the promise seen in a phase 2 trial, “these negative results were quite disappointing,” reported Xavier Montalban, MD, director, department of neurology, Catalunya Center for Multiple Sclerosis, Hospital Universitario Vall d’Hebron, Barcelona, Spain.

In the evolutionRMS1 and 2 phase 3 trials, 2285 relapsing-remitting MS patients with active disease were randomized to 45 mg of twice-daily oral evobrutinib or 14 mg once-daily teriflunomide, a pyrimidine synthesis inhibitor already widely used for the treatment of MS. The trial, conducted in 52 countries, was double-blind and double-dummy.

Ted Bosworth/MDedge News

No Outcome Supported an Evobrutinib Advantage

Numerically, the mean number of T1 gadolinium-enhancing lesions was greater among those randomized to evobrutinib while the mean number of new or enlarging T2 lesions was lower. However, none of these differences in either study reached statistical significance.

The lower serum neurofilament light chain (sNfL) levels were significant (P = .032) in one of the two trials, but the difference was modest, and Dr. Montalban stated that the difference “was probably not clinically significant.”

Almost all of the patients had multiple relapses before being enrolled in the study, but only 36.5% had received a prior disease-modifying therapy. According to Dr. Montalban, the baseline characteristics of the patients enrolled were “nothing special,” in that they were very much “like the types of patients enrolled in trials like these.”

In general, both drugs were well tolerated with a comparable safety profile. The exception was a greater proportion of patients randomized to evobrutinib who developed elevated liver function tests, including a greater proportion with a level at least 5 times the upper limit of normal. All normalized after treatment was discontinued.

This is the first phase 3 trial of a BTK inhibitor in MS, according to Dr. Montalban, who pointed out that evobrutinib did perform as well as a highly active agent, even if it could not show superiority.

There is limited likelihood that further ongoing analyses will uncover meaningful activity not detected in the primary and secondary outcomes, but Dr. Montalban said that there is a possibility that a higher dose or a BTK inhibitor with different characteristics might still produce the types of clinical benefits hypothesized in this initial trial.

Asked to speculate about the results if the RM1 and RM2 trials had a noninferiority rather than a superiority design been employed, Dr. Montalban said that evobrutinib relative to teriflunomide appears to be “similar but more toxic.”

The recent excitement building for the potential of BTK inhibitors in MS was not helped by a second, but much smaller, late-breaker study that evaluated tolebrutinib. The primary endpoint of that study, conducted with just seven patients, was complete resolution of paramagnetic rim lesions (PRL), a prognostically important composition of macrophages, microglia, and iron seen in the central nervous system (CNS) on imaging.
 

No Resolution of CNS Lesions

Even after 48 weeks, none of the lesions had resolved, according to Maria I. Gaitán, MD, acting director of the Translational Neuroradiology Unit of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland.

Again, although these findings were disappointing, Dr. Gaitán said there are a number of explanations for the result that do not preclude a benefit from BTK inhibitors in future studies.

“Complete resolution of PRL might be a bar that was too high,” she said, noting that favorable changes in these lesions could have occurred even if the characteristic iron deposits persisted. She also suggested that dosing might not have been optimized to halt or reverse disease activity in the CNS. Like Dr. Montalban, she suggested that BTK inhibitors with different characteristics might succeed where tolebrutinib failed.

Dr. Freedman, current president of ACTRIMS, agreed that these data should not be interpreted as ruling out a clinical role for BTK inhibitors. Pointing to the substantial body of data supporting this mechanism for reversing inflammation in the CNS, he declared that “the story is not over.”

Dr. Montalban reported financial relationships with Actelion, Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Hoffman La Roche, Immunic, Janssen, Mylan, NervGen, Novartis, Sanofi-Genzyme, Teva, TG Therapeutics, and Merck, which provided funding for the RMS 1 and 2 trials. Dr. Freedman reported financial relationships with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Hoffman La Roche, Merck, Novartis, and Teva Canada Innovation. Dr. Gaitán reported no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — Top-line results of two phase 3 trials evaluating the BTK inhibitor evobrutinib for treatment of multiple sclerosis (MS) were negative when released several months ago, but the hope for a signal of benefit on secondary endpoints was dashed when the full results of the trials were presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum.

Based on prior drug development, including the promise seen in a phase 2 trial, “these negative results were quite disappointing,” reported Xavier Montalban, MD, director, department of neurology, Catalunya Center for Multiple Sclerosis, Hospital Universitario Vall d’Hebron, Barcelona, Spain.

In the evolutionRMS1 and 2 phase 3 trials, 2285 relapsing-remitting MS patients with active disease were randomized to 45 mg of twice-daily oral evobrutinib or 14 mg once-daily teriflunomide, a pyrimidine synthesis inhibitor already widely used for the treatment of MS. The trial, conducted in 52 countries, was double-blind and double-dummy.

Ted Bosworth/MDedge News

No Outcome Supported an Evobrutinib Advantage

Numerically, the mean number of T1 gadolinium-enhancing lesions was greater among those randomized to evobrutinib while the mean number of new or enlarging T2 lesions was lower. However, none of these differences in either study reached statistical significance.

The lower serum neurofilament light chain (sNfL) levels were significant (P = .032) in one of the two trials, but the difference was modest, and Dr. Montalban stated that the difference “was probably not clinically significant.”

Almost all of the patients had multiple relapses before being enrolled in the study, but only 36.5% had received a prior disease-modifying therapy. According to Dr. Montalban, the baseline characteristics of the patients enrolled were “nothing special,” in that they were very much “like the types of patients enrolled in trials like these.”

In general, both drugs were well tolerated with a comparable safety profile. The exception was a greater proportion of patients randomized to evobrutinib who developed elevated liver function tests, including a greater proportion with a level at least 5 times the upper limit of normal. All normalized after treatment was discontinued.

This is the first phase 3 trial of a BTK inhibitor in MS, according to Dr. Montalban, who pointed out that evobrutinib did perform as well as a highly active agent, even if it could not show superiority.

There is limited likelihood that further ongoing analyses will uncover meaningful activity not detected in the primary and secondary outcomes, but Dr. Montalban said that there is a possibility that a higher dose or a BTK inhibitor with different characteristics might still produce the types of clinical benefits hypothesized in this initial trial.

Asked to speculate about the results if the RM1 and RM2 trials had a noninferiority rather than a superiority design been employed, Dr. Montalban said that evobrutinib relative to teriflunomide appears to be “similar but more toxic.”

The recent excitement building for the potential of BTK inhibitors in MS was not helped by a second, but much smaller, late-breaker study that evaluated tolebrutinib. The primary endpoint of that study, conducted with just seven patients, was complete resolution of paramagnetic rim lesions (PRL), a prognostically important composition of macrophages, microglia, and iron seen in the central nervous system (CNS) on imaging.
 

No Resolution of CNS Lesions

Even after 48 weeks, none of the lesions had resolved, according to Maria I. Gaitán, MD, acting director of the Translational Neuroradiology Unit of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland.

Again, although these findings were disappointing, Dr. Gaitán said there are a number of explanations for the result that do not preclude a benefit from BTK inhibitors in future studies.

“Complete resolution of PRL might be a bar that was too high,” she said, noting that favorable changes in these lesions could have occurred even if the characteristic iron deposits persisted. She also suggested that dosing might not have been optimized to halt or reverse disease activity in the CNS. Like Dr. Montalban, she suggested that BTK inhibitors with different characteristics might succeed where tolebrutinib failed.

Dr. Freedman, current president of ACTRIMS, agreed that these data should not be interpreted as ruling out a clinical role for BTK inhibitors. Pointing to the substantial body of data supporting this mechanism for reversing inflammation in the CNS, he declared that “the story is not over.”

Dr. Montalban reported financial relationships with Actelion, Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Hoffman La Roche, Immunic, Janssen, Mylan, NervGen, Novartis, Sanofi-Genzyme, Teva, TG Therapeutics, and Merck, which provided funding for the RMS 1 and 2 trials. Dr. Freedman reported financial relationships with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Hoffman La Roche, Merck, Novartis, and Teva Canada Innovation. Dr. Gaitán reported no potential conflicts of interest.

Stroke, Alzheimer’s disease, and other neurological conditions are now the leading cause of health loss and disability around the world, affecting nearly half of the world’s population, a new comprehensive analysis showed.

In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.

Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.

“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release. 

The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.

The study was published online in The Lancet: Neurology.
 

The Top 10

The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.

Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.

In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.

The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.

“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.

The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.

Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.

“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.

“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
 

Prioritize Prevention

The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.

It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.

“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.

It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”

“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.

In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.

“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”

The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.

A version of this article appeared on Medscape.com.

Stroke, Alzheimer’s disease, and other neurological conditions are now the leading cause of health loss and disability around the world, affecting nearly half of the world’s population, a new comprehensive analysis showed.

In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.

Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.

“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release. 

The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.

The study was published online in The Lancet: Neurology.
 

The Top 10

The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.

Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.

In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.

The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.

“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.

The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.

Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.

“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.

“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
 

Prioritize Prevention

The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.

It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.

“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.

It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”

“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.

In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.

“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”

The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.

A version of this article appeared on Medscape.com.

Stroke, Alzheimer’s disease, and other neurological conditions are now the leading cause of health loss and disability around the world, affecting nearly half of the world’s population, a new comprehensive analysis showed.

In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.

Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.

“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release. 

The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.

The study was published online in The Lancet: Neurology.
 

The Top 10

The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.

Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.

In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.

The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.

“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.

The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.

Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.

“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.

“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
 

Prioritize Prevention

The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.

It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.

“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.

It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”

“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.

In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.

“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”

The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.

A version of this article appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — In an interim analysis of an extension study, intrathecal injection of autologous bone marrow-derived mesenchymal stem cells (MSC) has been associated with favorable effects on both symptoms and biomarkers in patients with progressive multiple sclerosis (MS), according to data presented as a late-breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

After at least 1 year of follow-up in 23 patients participating in the extension analysis, “there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration,” reported Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem.

Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomized to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.

A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an IV injection of MSCs harvested from their bone marrow.
 

No Disease Activity Seen in 60% at 1 Year

When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group. The intrathecal injection of MSCs, which was well tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.

Ted Bosworth/MDedge News

Forty of the patients in the initial study were enrolled in the extension. In the late-breaker presentation, Dr. Karussis provided interim results on 23, of which all had been followed for at least another additional year. These patients had been treated with one to three intrathecal injects of MSCs at intervals of 3 to 6 months.

Of further gains during the extension, Dr. Karussis described gains in cognitive function, represented by a 3-degree improvement in the Symbol Digit Modalities Test (SDMT), a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.

The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Dr. Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.

The 22% (P < .0004) reduction in GFAP, which Dr. Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments.

The safety and tolerability remained encouraging with longer follow-up. As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time-limited.

Although Dr. Karussis emphasized that these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides “an additional hint of possible neuroprotective and neurotrophic effects.”
 

Mechanism of MSC Benefit Incompletely Documented

In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far is unresolved.

Others evaluating MSCs in the experimental setting have shown that these “produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties,” said Jeffrey A. Cohen, MD, who was asked to comment on the findings. Dr. Cohen is director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis, Cleveland Clinic. He said that previous experimental work has encouraged clinical studies, including the work presented by Dr. Karussis.

While the late-breaker presentation provided data suggesting “persistent potent efficacy with good safety and tolerability,” Dr. Cohen pointed out that “the results from this group are substantially better than those reported by several other groups.” He called the difference in results “uncertain,” suggesting that more work is needed to prove that clinical benefit is reliably achieved.

“I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing,” Dr. Cohen said.

Dr. Karussis reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — In an interim analysis of an extension study, intrathecal injection of autologous bone marrow-derived mesenchymal stem cells (MSC) has been associated with favorable effects on both symptoms and biomarkers in patients with progressive multiple sclerosis (MS), according to data presented as a late-breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

After at least 1 year of follow-up in 23 patients participating in the extension analysis, “there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration,” reported Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem.

Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomized to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.

A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an IV injection of MSCs harvested from their bone marrow.
 

No Disease Activity Seen in 60% at 1 Year

When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group. The intrathecal injection of MSCs, which was well tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.

Ted Bosworth/MDedge News

Forty of the patients in the initial study were enrolled in the extension. In the late-breaker presentation, Dr. Karussis provided interim results on 23, of which all had been followed for at least another additional year. These patients had been treated with one to three intrathecal injects of MSCs at intervals of 3 to 6 months.

Of further gains during the extension, Dr. Karussis described gains in cognitive function, represented by a 3-degree improvement in the Symbol Digit Modalities Test (SDMT), a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.

The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Dr. Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.

The 22% (P < .0004) reduction in GFAP, which Dr. Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments.

The safety and tolerability remained encouraging with longer follow-up. As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time-limited.

Although Dr. Karussis emphasized that these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides “an additional hint of possible neuroprotective and neurotrophic effects.”
 

Mechanism of MSC Benefit Incompletely Documented

In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far is unresolved.

Others evaluating MSCs in the experimental setting have shown that these “produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties,” said Jeffrey A. Cohen, MD, who was asked to comment on the findings. Dr. Cohen is director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis, Cleveland Clinic. He said that previous experimental work has encouraged clinical studies, including the work presented by Dr. Karussis.

While the late-breaker presentation provided data suggesting “persistent potent efficacy with good safety and tolerability,” Dr. Cohen pointed out that “the results from this group are substantially better than those reported by several other groups.” He called the difference in results “uncertain,” suggesting that more work is needed to prove that clinical benefit is reliably achieved.

“I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing,” Dr. Cohen said.

Dr. Karussis reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — In an interim analysis of an extension study, intrathecal injection of autologous bone marrow-derived mesenchymal stem cells (MSC) has been associated with favorable effects on both symptoms and biomarkers in patients with progressive multiple sclerosis (MS), according to data presented as a late-breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

After at least 1 year of follow-up in 23 patients participating in the extension analysis, “there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration,” reported Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem.

Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomized to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.

A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an IV injection of MSCs harvested from their bone marrow.
 

No Disease Activity Seen in 60% at 1 Year

When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group. The intrathecal injection of MSCs, which was well tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.

Ted Bosworth/MDedge News

Forty of the patients in the initial study were enrolled in the extension. In the late-breaker presentation, Dr. Karussis provided interim results on 23, of which all had been followed for at least another additional year. These patients had been treated with one to three intrathecal injects of MSCs at intervals of 3 to 6 months.

Of further gains during the extension, Dr. Karussis described gains in cognitive function, represented by a 3-degree improvement in the Symbol Digit Modalities Test (SDMT), a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.

The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Dr. Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.

The 22% (P < .0004) reduction in GFAP, which Dr. Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments.

The safety and tolerability remained encouraging with longer follow-up. As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time-limited.

Although Dr. Karussis emphasized that these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides “an additional hint of possible neuroprotective and neurotrophic effects.”
 

Mechanism of MSC Benefit Incompletely Documented

In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far is unresolved.

Others evaluating MSCs in the experimental setting have shown that these “produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties,” said Jeffrey A. Cohen, MD, who was asked to comment on the findings. Dr. Cohen is director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis, Cleveland Clinic. He said that previous experimental work has encouraged clinical studies, including the work presented by Dr. Karussis.

While the late-breaker presentation provided data suggesting “persistent potent efficacy with good safety and tolerability,” Dr. Cohen pointed out that “the results from this group are substantially better than those reported by several other groups.” He called the difference in results “uncertain,” suggesting that more work is needed to prove that clinical benefit is reliably achieved.

“I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing,” Dr. Cohen said.

Dr. Karussis reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — Patient-reported outcomes (PROs) define the issues that matter to the patient, but their potential in multiple sclerosis (MS) is likely to remain unfulfilled until barriers, including a lack of incentives, are addressed systematically, according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
 

Potentially Useful Clinical Information

PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.

A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.

Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.

The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.

More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.

Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.

By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
 

A Path Forward

In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.

But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.

“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.

The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.

“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.

PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.

Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.

WEST PALM BEACH, FLORIDA — Patient-reported outcomes (PROs) define the issues that matter to the patient, but their potential in multiple sclerosis (MS) is likely to remain unfulfilled until barriers, including a lack of incentives, are addressed systematically, according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
 

Potentially Useful Clinical Information

PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.

A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.

Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.

The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.

More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.

Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.

By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
 

A Path Forward

In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.

But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.

“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.

The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.

“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.

PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.

Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.

WEST PALM BEACH, FLORIDA — Patient-reported outcomes (PROs) define the issues that matter to the patient, but their potential in multiple sclerosis (MS) is likely to remain unfulfilled until barriers, including a lack of incentives, are addressed systematically, according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
 

Potentially Useful Clinical Information

PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.

A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.

Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.

The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.

More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.

Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.

By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
 

A Path Forward

In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.

But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.

“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.

The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.

“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.

PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.

Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

Frexalimab (Sanofi), a novel, investigational second-generation inhibitor of the CD40 ligand, significantly reduced disease activity in relapsing multiple sclerosis (MS) and was well tolerated in a phase 2 study.

At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.

The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.

The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
 

‘Unambiguous Benefit’

Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.

“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.

The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.

Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).

All but four patients completed the 12-week double-blind period and entered the open-label period.

The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.

At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.

The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.

On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.

The effects were sustained over time across both active treatment groups.

Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
 

Phase 3 Trials Underway

The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.

There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.

No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.

Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.

Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
 

‘A High Bar for Any New Treatment’

In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”

If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”

Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”

“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”

“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.

While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.

The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
 

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

Frexalimab (Sanofi), a novel, investigational second-generation inhibitor of the CD40 ligand, significantly reduced disease activity in relapsing multiple sclerosis (MS) and was well tolerated in a phase 2 study.

At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.

The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.

The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
 

‘Unambiguous Benefit’

Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.

“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.

The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.

Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).

All but four patients completed the 12-week double-blind period and entered the open-label period.

The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.

At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.

The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.

On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.

The effects were sustained over time across both active treatment groups.

Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
 

Phase 3 Trials Underway

The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.

There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.

No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.

Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.

Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
 

‘A High Bar for Any New Treatment’

In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”

If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”

Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”

“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”

“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.

While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.

The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
 

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

Frexalimab (Sanofi), a novel, investigational second-generation inhibitor of the CD40 ligand, significantly reduced disease activity in relapsing multiple sclerosis (MS) and was well tolerated in a phase 2 study.

At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.

The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.

The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
 

‘Unambiguous Benefit’

Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.

“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.

The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.

Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).

All but four patients completed the 12-week double-blind period and entered the open-label period.

The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.

At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.

The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.

On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.

The effects were sustained over time across both active treatment groups.

Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
 

Phase 3 Trials Underway

The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.

There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.

No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.

Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.

Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
 

‘A High Bar for Any New Treatment’

In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”

If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”

Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”

“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”

“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.

While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.

The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
 

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