Ted Bosworth

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.

WEST PALM BEACH, FLORIDA — There is growing confidence that remyelinating agents will be a viable option in the treatment of multiple sclerosis (MS) in the not-too-distant future, according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.

Ted Bosworth/MDedge News

“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.

“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”

The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
 

Remyelinating Effect Documented at Multiple Sites

The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.

The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.

Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.

Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.

“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.

One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.

“We might need to provide drugs with a remyelinating effect very early in the process,” he said.

The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
 

Late-breaker: Two Remyelinating Drugs with Promise

Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).

Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.

The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.

“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.

He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.

Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — There is growing confidence that remyelinating agents will be a viable option in the treatment of multiple sclerosis (MS) in the not-too-distant future, according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.

Ted Bosworth/MDedge News

“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.

“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”

The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
 

Remyelinating Effect Documented at Multiple Sites

The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.

The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.

Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.

Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.

“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.

One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.

“We might need to provide drugs with a remyelinating effect very early in the process,” he said.

The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
 

Late-breaker: Two Remyelinating Drugs with Promise

Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).

Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.

The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.

“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.

He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.

Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — There is growing confidence that remyelinating agents will be a viable option in the treatment of multiple sclerosis (MS) in the not-too-distant future, according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.

Ted Bosworth/MDedge News

“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.

“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”

The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
 

Remyelinating Effect Documented at Multiple Sites

The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.

The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.

Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.

Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.

“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.

One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.

“We might need to provide drugs with a remyelinating effect very early in the process,” he said.

The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
 

Late-breaker: Two Remyelinating Drugs with Promise

Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).

Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.

The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.

“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.

He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.

Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.

SAN DIEGO — New guidelines for cutaneous melanoma have been issued by the National Comprehensive Cancer Network (NCCN), creating some new standards of practice that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.

Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.

Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time. 
 

Next AAD Guidelines More Than 1 Year Away

The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago. 

Ted Bosworth/MDedge News

More Than 50% Consensus Generally Required

The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.

Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website. 

Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.

Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.

There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
 

Best Margins for MIS Undefined

So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.

The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.

Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.

Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.

“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.

This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.

Dr. Swetter and Dr. Kim report no relevant financial relationships. 

A version of this article appeared on Medscape.com.

SAN DIEGO — New guidelines for cutaneous melanoma have been issued by the National Comprehensive Cancer Network (NCCN), creating some new standards of practice that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.

Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.

Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time. 
 

Next AAD Guidelines More Than 1 Year Away

The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago. 

Ted Bosworth/MDedge News

More Than 50% Consensus Generally Required

The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.

Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website. 

Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.

Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.

There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
 

Best Margins for MIS Undefined

So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.

The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.

Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.

Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.

“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.

This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.

Dr. Swetter and Dr. Kim report no relevant financial relationships. 

A version of this article appeared on Medscape.com.

SAN DIEGO — New guidelines for cutaneous melanoma have been issued by the National Comprehensive Cancer Network (NCCN), creating some new standards of practice that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.

Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.

Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time. 
 

Next AAD Guidelines More Than 1 Year Away

The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago. 

Ted Bosworth/MDedge News

More Than 50% Consensus Generally Required

The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.

Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website. 

Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.

Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.

There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
 

Best Margins for MIS Undefined

So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.

The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.

Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.

Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.

“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.

This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.

Dr. Swetter and Dr. Kim report no relevant financial relationships. 

A version of this article appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — Paramagnetic rim lesions (PRLs), which have been gaining attention as potentially useful prognostic biomarkers in multiple sclerosis (MS), predict accelerated cognitive loss, according to one of numerous PRL studies at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

“We think this supports other evidence that PRLs are going to be a useful biomarker for MS,” reported Susan Gauthier, DO, an associate professor of neurology and radiology at Weill Cornell University in New York City.

In a simple study, patients with PRLs at baseline were compared with patients without PRLs over a 4-year period, showing that baseline PRLs correlated with worse cognitive function over time.

Of the study cohort, with a median age of 42 years, 5 patients had clinically isolated syndrome (CIS), 81 had relapsing-remitting MS, and 5 had secondary progressive MS. On baseline MRI, 41% of patients had PRLs.

Cognitive function was tracked over time with the Brief International Cognitive Assessment for MS (BICAMS). The components include the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT).

Univariate linear model relationships were used to look for a relationship between baseline PRLs and cognitive function. Multiple linear models were performed “with all possible iterations” to further explore the most significant variables. At baseline, no differences were seen in any cognitive test between those with or without PRLs.
 

Cognitive Function Changes at 4 Years

Those with at least one PRL had significantly lower SDMT (P = 0.046) and BVLT (P = 0.0292) at 4 years. There was no significant difference for CVLT scores.

The findings are consistent with the potential for PRLs to serve “as an imaging marker to identify MS patients at risk for cognitive decline,” said Hannah Schwartz, BA, a mentee of Dr. Gauthier and senior clinical research coordinator in the Department of Neurology at Weill Cornell. Ms. Schwartz presented the data at ACTRIMS Forum Cutting Edge symposium.

Over the past 10 years, there has been a growing body of evidence that the presence of PRLs, which are generally described as a spot of demyelination in the central nervous system surrounded by a rim of iron-laden immune cells such as microglia and macrophages, are prognostically important. The sizable number of studies at the ACTRIMS meeting on PRLs, which so far appear to be unique to MS, suggests the field is maturing.
 

Routine Measurement of PRLs Is Feasible

One set of data from the CAVS-MS study suggest that routine measurement of this biomarker can be integrated into routine imaging. CAVS-MS is a 2-year international multicenter evaluation of MS biomarkers with 11 participating sites that has collected PRL data on 420 patients.

Overall, PRLs were identified in 39% of these patients. However, patients were divided by typical versus atypical presentation, defined by such factors as an uncharacteristic pattern of attacks, accelerated progression, or radiologically isolated lesions. Among the 201 patients with a typical presentation, at least 1 PRL was found in 53%. Among the 219 with atypical presentations, PRLs were seen in only 26%.

The greater rate of PRLs and the greater number of PRLs per positive patient in the typical presentation group (median 3 vs 2) were highly significant (both P < .0001), reported Brian Renner, MD, a research associate in the neuroimaging program, Department of Neurology, Cedars-Sinai Hospital, Los Angeles.

In this analysis, the PRLs were identified by a single experienced rater with T2- and T1-weighted imaging using 2024 North American Imaging in Multiple Sclerosis (NAIMS) criteria for PRL. These criteria were published earlier this year in Brain.

One message from this study is that “PRL measurement in a large multicenter cohort is feasible,” according to Dr. Renner. This is not only important based on the potential role of PRLs as a prognostic biomarker but also for diagnosis, given the fact that PRLs when present appear to confirm a diagnosis of MS.

Misdiagnosis of MS continues to be a problem, and Dr. Renner said that these appear “to be capable of differentiating MS lesions from non-MS disease mimics.” However, he stated that further validation studies are needed.
 

Can PRLs Be Prevented or Reversed?

The data on PRLs have generated interest in whether they can be prevented or reversed once they appear. This might be dependent on first determining who is at risk. Another study presented at ACTRIMS suggested that it might not be complex. Lesion size might be critical.

In this study, 233 images were evaluated in 64 patients participating in an observational study at the UMass Memorial Medical Center, Worcester, Massachusetts.

In a univariable analysis, a long list of patient factors, disease characteristics, and imaging characteristics correlated with an increased risk of develop PRLs. These included patient age, disease duration, lesion volume, enhancement pattern (ring vs nodular), and use of disease modifying therapies.

When a regression analysis of these factors was performed, “none of the predictive factors on the univariable analyses were significant after including lesion size in the model,” reported Mustafa Al Gburi, MD, a fellow in neuroimaging at UMass.

While his data did show that exposure to steroids did not appear to reduce risk of developing PRLs, he is now running follow-up to see if specific disease-modifying therapies are more or less preventive for the development of PRL. Because of the limited number of patients and follow-up, it is now too early to tell.

Overall, the risk of PRLs appears to grow substantially at a lesion size of greater than 11 mm, Dr. Al Gburi reported. He believes that this might be “a simple bedside marker to determine patients at future risk of chronic active lesions.”

PRLs might not just be a diagnostic and prognostic tool. Dr. Gauthier said that PRLs are at least a theoretical treatment target. While their immediate promise is in monitoring disease, she thinks the evidence would predict a benefit if PRLs could be prevented or reversed.

Dr. Gauthier reports financial relationships with Genentech, Sanofi-Genzyme, and Mallinckrodt. Dr. Renner and Dr. Al Gburi report no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — Paramagnetic rim lesions (PRLs), which have been gaining attention as potentially useful prognostic biomarkers in multiple sclerosis (MS), predict accelerated cognitive loss, according to one of numerous PRL studies at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

“We think this supports other evidence that PRLs are going to be a useful biomarker for MS,” reported Susan Gauthier, DO, an associate professor of neurology and radiology at Weill Cornell University in New York City.

In a simple study, patients with PRLs at baseline were compared with patients without PRLs over a 4-year period, showing that baseline PRLs correlated with worse cognitive function over time.

Of the study cohort, with a median age of 42 years, 5 patients had clinically isolated syndrome (CIS), 81 had relapsing-remitting MS, and 5 had secondary progressive MS. On baseline MRI, 41% of patients had PRLs.

Cognitive function was tracked over time with the Brief International Cognitive Assessment for MS (BICAMS). The components include the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT).

Univariate linear model relationships were used to look for a relationship between baseline PRLs and cognitive function. Multiple linear models were performed “with all possible iterations” to further explore the most significant variables. At baseline, no differences were seen in any cognitive test between those with or without PRLs.
 

Cognitive Function Changes at 4 Years

Those with at least one PRL had significantly lower SDMT (P = 0.046) and BVLT (P = 0.0292) at 4 years. There was no significant difference for CVLT scores.

The findings are consistent with the potential for PRLs to serve “as an imaging marker to identify MS patients at risk for cognitive decline,” said Hannah Schwartz, BA, a mentee of Dr. Gauthier and senior clinical research coordinator in the Department of Neurology at Weill Cornell. Ms. Schwartz presented the data at ACTRIMS Forum Cutting Edge symposium.

Over the past 10 years, there has been a growing body of evidence that the presence of PRLs, which are generally described as a spot of demyelination in the central nervous system surrounded by a rim of iron-laden immune cells such as microglia and macrophages, are prognostically important. The sizable number of studies at the ACTRIMS meeting on PRLs, which so far appear to be unique to MS, suggests the field is maturing.
 

Routine Measurement of PRLs Is Feasible

One set of data from the CAVS-MS study suggest that routine measurement of this biomarker can be integrated into routine imaging. CAVS-MS is a 2-year international multicenter evaluation of MS biomarkers with 11 participating sites that has collected PRL data on 420 patients.

Overall, PRLs were identified in 39% of these patients. However, patients were divided by typical versus atypical presentation, defined by such factors as an uncharacteristic pattern of attacks, accelerated progression, or radiologically isolated lesions. Among the 201 patients with a typical presentation, at least 1 PRL was found in 53%. Among the 219 with atypical presentations, PRLs were seen in only 26%.

The greater rate of PRLs and the greater number of PRLs per positive patient in the typical presentation group (median 3 vs 2) were highly significant (both P < .0001), reported Brian Renner, MD, a research associate in the neuroimaging program, Department of Neurology, Cedars-Sinai Hospital, Los Angeles.

In this analysis, the PRLs were identified by a single experienced rater with T2- and T1-weighted imaging using 2024 North American Imaging in Multiple Sclerosis (NAIMS) criteria for PRL. These criteria were published earlier this year in Brain.

One message from this study is that “PRL measurement in a large multicenter cohort is feasible,” according to Dr. Renner. This is not only important based on the potential role of PRLs as a prognostic biomarker but also for diagnosis, given the fact that PRLs when present appear to confirm a diagnosis of MS.

Misdiagnosis of MS continues to be a problem, and Dr. Renner said that these appear “to be capable of differentiating MS lesions from non-MS disease mimics.” However, he stated that further validation studies are needed.
 

Can PRLs Be Prevented or Reversed?

The data on PRLs have generated interest in whether they can be prevented or reversed once they appear. This might be dependent on first determining who is at risk. Another study presented at ACTRIMS suggested that it might not be complex. Lesion size might be critical.

In this study, 233 images were evaluated in 64 patients participating in an observational study at the UMass Memorial Medical Center, Worcester, Massachusetts.

In a univariable analysis, a long list of patient factors, disease characteristics, and imaging characteristics correlated with an increased risk of develop PRLs. These included patient age, disease duration, lesion volume, enhancement pattern (ring vs nodular), and use of disease modifying therapies.

When a regression analysis of these factors was performed, “none of the predictive factors on the univariable analyses were significant after including lesion size in the model,” reported Mustafa Al Gburi, MD, a fellow in neuroimaging at UMass.

While his data did show that exposure to steroids did not appear to reduce risk of developing PRLs, he is now running follow-up to see if specific disease-modifying therapies are more or less preventive for the development of PRL. Because of the limited number of patients and follow-up, it is now too early to tell.

Overall, the risk of PRLs appears to grow substantially at a lesion size of greater than 11 mm, Dr. Al Gburi reported. He believes that this might be “a simple bedside marker to determine patients at future risk of chronic active lesions.”

PRLs might not just be a diagnostic and prognostic tool. Dr. Gauthier said that PRLs are at least a theoretical treatment target. While their immediate promise is in monitoring disease, she thinks the evidence would predict a benefit if PRLs could be prevented or reversed.

Dr. Gauthier reports financial relationships with Genentech, Sanofi-Genzyme, and Mallinckrodt. Dr. Renner and Dr. Al Gburi report no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — Paramagnetic rim lesions (PRLs), which have been gaining attention as potentially useful prognostic biomarkers in multiple sclerosis (MS), predict accelerated cognitive loss, according to one of numerous PRL studies at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

“We think this supports other evidence that PRLs are going to be a useful biomarker for MS,” reported Susan Gauthier, DO, an associate professor of neurology and radiology at Weill Cornell University in New York City.

In a simple study, patients with PRLs at baseline were compared with patients without PRLs over a 4-year period, showing that baseline PRLs correlated with worse cognitive function over time.

Of the study cohort, with a median age of 42 years, 5 patients had clinically isolated syndrome (CIS), 81 had relapsing-remitting MS, and 5 had secondary progressive MS. On baseline MRI, 41% of patients had PRLs.

Cognitive function was tracked over time with the Brief International Cognitive Assessment for MS (BICAMS). The components include the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT).

Univariate linear model relationships were used to look for a relationship between baseline PRLs and cognitive function. Multiple linear models were performed “with all possible iterations” to further explore the most significant variables. At baseline, no differences were seen in any cognitive test between those with or without PRLs.
 

Cognitive Function Changes at 4 Years

Those with at least one PRL had significantly lower SDMT (P = 0.046) and BVLT (P = 0.0292) at 4 years. There was no significant difference for CVLT scores.

The findings are consistent with the potential for PRLs to serve “as an imaging marker to identify MS patients at risk for cognitive decline,” said Hannah Schwartz, BA, a mentee of Dr. Gauthier and senior clinical research coordinator in the Department of Neurology at Weill Cornell. Ms. Schwartz presented the data at ACTRIMS Forum Cutting Edge symposium.

Over the past 10 years, there has been a growing body of evidence that the presence of PRLs, which are generally described as a spot of demyelination in the central nervous system surrounded by a rim of iron-laden immune cells such as microglia and macrophages, are prognostically important. The sizable number of studies at the ACTRIMS meeting on PRLs, which so far appear to be unique to MS, suggests the field is maturing.
 

Routine Measurement of PRLs Is Feasible

One set of data from the CAVS-MS study suggest that routine measurement of this biomarker can be integrated into routine imaging. CAVS-MS is a 2-year international multicenter evaluation of MS biomarkers with 11 participating sites that has collected PRL data on 420 patients.

Overall, PRLs were identified in 39% of these patients. However, patients were divided by typical versus atypical presentation, defined by such factors as an uncharacteristic pattern of attacks, accelerated progression, or radiologically isolated lesions. Among the 201 patients with a typical presentation, at least 1 PRL was found in 53%. Among the 219 with atypical presentations, PRLs were seen in only 26%.

The greater rate of PRLs and the greater number of PRLs per positive patient in the typical presentation group (median 3 vs 2) were highly significant (both P < .0001), reported Brian Renner, MD, a research associate in the neuroimaging program, Department of Neurology, Cedars-Sinai Hospital, Los Angeles.

In this analysis, the PRLs were identified by a single experienced rater with T2- and T1-weighted imaging using 2024 North American Imaging in Multiple Sclerosis (NAIMS) criteria for PRL. These criteria were published earlier this year in Brain.

One message from this study is that “PRL measurement in a large multicenter cohort is feasible,” according to Dr. Renner. This is not only important based on the potential role of PRLs as a prognostic biomarker but also for diagnosis, given the fact that PRLs when present appear to confirm a diagnosis of MS.

Misdiagnosis of MS continues to be a problem, and Dr. Renner said that these appear “to be capable of differentiating MS lesions from non-MS disease mimics.” However, he stated that further validation studies are needed.
 

Can PRLs Be Prevented or Reversed?

The data on PRLs have generated interest in whether they can be prevented or reversed once they appear. This might be dependent on first determining who is at risk. Another study presented at ACTRIMS suggested that it might not be complex. Lesion size might be critical.

In this study, 233 images were evaluated in 64 patients participating in an observational study at the UMass Memorial Medical Center, Worcester, Massachusetts.

In a univariable analysis, a long list of patient factors, disease characteristics, and imaging characteristics correlated with an increased risk of develop PRLs. These included patient age, disease duration, lesion volume, enhancement pattern (ring vs nodular), and use of disease modifying therapies.

When a regression analysis of these factors was performed, “none of the predictive factors on the univariable analyses were significant after including lesion size in the model,” reported Mustafa Al Gburi, MD, a fellow in neuroimaging at UMass.

While his data did show that exposure to steroids did not appear to reduce risk of developing PRLs, he is now running follow-up to see if specific disease-modifying therapies are more or less preventive for the development of PRL. Because of the limited number of patients and follow-up, it is now too early to tell.

Overall, the risk of PRLs appears to grow substantially at a lesion size of greater than 11 mm, Dr. Al Gburi reported. He believes that this might be “a simple bedside marker to determine patients at future risk of chronic active lesions.”

PRLs might not just be a diagnostic and prognostic tool. Dr. Gauthier said that PRLs are at least a theoretical treatment target. While their immediate promise is in monitoring disease, she thinks the evidence would predict a benefit if PRLs could be prevented or reversed.

Dr. Gauthier reports financial relationships with Genentech, Sanofi-Genzyme, and Mallinckrodt. Dr. Renner and Dr. Al Gburi report no potential conflicts of interest.

Repairing patent foramen ovale (PFO) and other right-to-left shunt disorders for the prevention of migraine has generated mixed results, but the potential for these repairs also includes reducing the risk of stroke, according to a discussion at the 2023 Scottsdale Headache Symposium.

In two clinical trials evaluating whether PFO closure reduces migraine risk, the primary endpoints were not met, but a signal of benefit on secondary endpoints and the association between PFO, migraine, and stroke are among the reasons that PFO closure should be reevaluated, according to Andrew Charles MD, Director of the Goldberg Migraine Program, University of California, Los Angeles.

UCLA

One Intervention, Two Potential Benefits

Fixing these defects is therefore at least theoretically attractive for preventing both migraine and stroke, but Dr. Charles said the opportunity for preventing both migraine and stroke is most attractive in migraine patients who have additional stroke risk factors.

Use of oral contraceptives, which produce a hypercoagulable state, is an example.

“Are these the people we should really be thinking about if they have PFO and migraine, particularly migraine with aura?” Dr. Charles asked.

The association between right-to-left shunts and migraine is strong. Although PFO is common, presenting in 20%-25% of the adult population, it has been found in up to 50% of individuals who have migraine with aura. In patients with migraine but no aura, the prevalence of PFO has been estimated to be approximately 35% or still somewhat elevated relative to the general population.
 

Primary Endpoint Missed in Clinical Trials

The question of whether risk of migraine can be reduced with repair of PFO or other right-to-left shunts remains unresolved. In two high-quality randomized trials undertaken in PFO repair, neither met its primary endpoint. In one of these, called PRIMA, which was terminated early for slow enrollment, the reduction in mean headache attacks was not significant relative to medical therapy.

In the second, called PREMIUM, device closure of PFO also failed to significantly reduce migraine attacks over sham procedure although it was associated with complete migraine remission (10% vs 1%).

A pooled analysis of these two studies that was conducted subsequently concluded that PFO closure reduces mean monthly migraine days (-3.1 vs. -1.9 days; P = -.02) and increases the likelihood of complete migraine cessation (9% vs. 0.7%; P < .001), but Dr. Charles pointed out the primary endpoint was migraine attacks not migraine days, so other analyses can only be considered hypothesis-generating.

There are several reasons to relook at the relationship between migraine and PFO but the potential to prevent both migraine and stroke with PFO closure could be one of the most important.

Several years ago, Dr. Charles and his coinvestigators from UCLA evaluated more than 700 ischemic strokes. Of these, 127 strokes were characterized as cryptogenic because of lack of another identifiable etiology. While 59% of these patients had PFO, which is several times higher than the general population, the prevalence of PFO in patients with a cryptogenic stroke and a history of migraine was 79% in this published study.

“So, in this group of patients who did not have any other clear cause for a stroke, a diagnosis of PFO was very much overrepresented,” Dr. Charles said.
 

Migraine Days Might Be a Better Endpoint

For patients with migraine who have risk factors for stroke, this makes PFO closure an attractive intervention, but a positive randomized trial is needed. Several are underway. Importantly, the trials now enrolling are using migraine days, which was significantly reduced in both PREMIUM and PRIMA, rather than migraine attacks as the primary endpoint.

“Migraine days is now accepted by the Food and Drug Administration as a criterion of benefit,” reported Jonathan Tobis, MD, Research Director, Interventional Cardiology, UCLA David Geffen School of Medicine, Los Angeles.

He explained that the FDA insisted on migraine attacks as the endpoint for the PREMIUM trial, but this was a far more challenging endpoint on which to show a statistical benefit. He emphasized that a new set of trials will now test efficacy on the basis of migraine days.

One of these trials, called RELIEF, which is randomizing patients to device closure of PFO or a sham procedure. Both groups are receiving clopidogrel or prasugrel based on a previous observation that patients who respond to these drugs are also more likely to respond to PFO closure.

Another trial, called COMPETE-2, is comparing PFO closure with a device to aspirin plus a sham closure. This trial is ongoing in China.

Stroke is not being evaluated as an endpoint in either trial, but Dr. Charles suggested that this does warrant attention.

“I would also just put it out there that, apart from simply migraine, this is a therapeutic approach that we might actually think about in terms of helping to prevent stroke in our migraine patients,” he said.

Senior author of a recent meta-analysis of trials evaluating PFO closure and control of migraine, Ling Liu, MD, Department of Neurology, University of Sichuan, Chengdu, China, agreed that PFO closure for the treatment of migraine deserves “a reevaluation.”

In his meta-analysis of three randomized trials, one pooled study, and eight retrospective case series with 1,165 patients, PFO closure was associated with a nearly 75% reduction (odds ratio [OR], 0.259; P = .0048) reduction in migraine days and 50% increase in resolution of migraine in patients with a history of migraine with aura (OR, 1.586; P = .227).

The incidence of stroke was not evaluated in this meta-analysis, but Dr. Liu believes that the evidence of reducing the burden of migraine with PFO closure is compelling. Given the evidence from this meta-analysis that PFO closure is safe, Dr. Liu maintained that a definitive trial is needed “especially for migraine with frequent aura.”

As an interventional cardiologist, Dr. Tobis said that when PFO closures is performed for prevention of stroke in patients with migraine, it often leads to reduced migraine activity and, in some cases, elimination of migraine. Like others, he believes new analyses should be conducted.

“Everyone involved in this field believes there is something there,” Dr. Tobis said. The missing link is a clinical trial to confirm it.

Dr. Charles and Dr. Liu report no potential conflicts of interest. Dr. Tobis reports a financial relationship with Holistick Medical.

Repairing patent foramen ovale (PFO) and other right-to-left shunt disorders for the prevention of migraine has generated mixed results, but the potential for these repairs also includes reducing the risk of stroke, according to a discussion at the 2023 Scottsdale Headache Symposium.

In two clinical trials evaluating whether PFO closure reduces migraine risk, the primary endpoints were not met, but a signal of benefit on secondary endpoints and the association between PFO, migraine, and stroke are among the reasons that PFO closure should be reevaluated, according to Andrew Charles MD, Director of the Goldberg Migraine Program, University of California, Los Angeles.

UCLA

One Intervention, Two Potential Benefits

Fixing these defects is therefore at least theoretically attractive for preventing both migraine and stroke, but Dr. Charles said the opportunity for preventing both migraine and stroke is most attractive in migraine patients who have additional stroke risk factors.

Use of oral contraceptives, which produce a hypercoagulable state, is an example.

“Are these the people we should really be thinking about if they have PFO and migraine, particularly migraine with aura?” Dr. Charles asked.

The association between right-to-left shunts and migraine is strong. Although PFO is common, presenting in 20%-25% of the adult population, it has been found in up to 50% of individuals who have migraine with aura. In patients with migraine but no aura, the prevalence of PFO has been estimated to be approximately 35% or still somewhat elevated relative to the general population.
 

Primary Endpoint Missed in Clinical Trials

The question of whether risk of migraine can be reduced with repair of PFO or other right-to-left shunts remains unresolved. In two high-quality randomized trials undertaken in PFO repair, neither met its primary endpoint. In one of these, called PRIMA, which was terminated early for slow enrollment, the reduction in mean headache attacks was not significant relative to medical therapy.

In the second, called PREMIUM, device closure of PFO also failed to significantly reduce migraine attacks over sham procedure although it was associated with complete migraine remission (10% vs 1%).

A pooled analysis of these two studies that was conducted subsequently concluded that PFO closure reduces mean monthly migraine days (-3.1 vs. -1.9 days; P = -.02) and increases the likelihood of complete migraine cessation (9% vs. 0.7%; P < .001), but Dr. Charles pointed out the primary endpoint was migraine attacks not migraine days, so other analyses can only be considered hypothesis-generating.

There are several reasons to relook at the relationship between migraine and PFO but the potential to prevent both migraine and stroke with PFO closure could be one of the most important.

Several years ago, Dr. Charles and his coinvestigators from UCLA evaluated more than 700 ischemic strokes. Of these, 127 strokes were characterized as cryptogenic because of lack of another identifiable etiology. While 59% of these patients had PFO, which is several times higher than the general population, the prevalence of PFO in patients with a cryptogenic stroke and a history of migraine was 79% in this published study.

“So, in this group of patients who did not have any other clear cause for a stroke, a diagnosis of PFO was very much overrepresented,” Dr. Charles said.
 

Migraine Days Might Be a Better Endpoint

For patients with migraine who have risk factors for stroke, this makes PFO closure an attractive intervention, but a positive randomized trial is needed. Several are underway. Importantly, the trials now enrolling are using migraine days, which was significantly reduced in both PREMIUM and PRIMA, rather than migraine attacks as the primary endpoint.

“Migraine days is now accepted by the Food and Drug Administration as a criterion of benefit,” reported Jonathan Tobis, MD, Research Director, Interventional Cardiology, UCLA David Geffen School of Medicine, Los Angeles.

He explained that the FDA insisted on migraine attacks as the endpoint for the PREMIUM trial, but this was a far more challenging endpoint on which to show a statistical benefit. He emphasized that a new set of trials will now test efficacy on the basis of migraine days.

One of these trials, called RELIEF, which is randomizing patients to device closure of PFO or a sham procedure. Both groups are receiving clopidogrel or prasugrel based on a previous observation that patients who respond to these drugs are also more likely to respond to PFO closure.

Another trial, called COMPETE-2, is comparing PFO closure with a device to aspirin plus a sham closure. This trial is ongoing in China.

Stroke is not being evaluated as an endpoint in either trial, but Dr. Charles suggested that this does warrant attention.

“I would also just put it out there that, apart from simply migraine, this is a therapeutic approach that we might actually think about in terms of helping to prevent stroke in our migraine patients,” he said.

Senior author of a recent meta-analysis of trials evaluating PFO closure and control of migraine, Ling Liu, MD, Department of Neurology, University of Sichuan, Chengdu, China, agreed that PFO closure for the treatment of migraine deserves “a reevaluation.”

In his meta-analysis of three randomized trials, one pooled study, and eight retrospective case series with 1,165 patients, PFO closure was associated with a nearly 75% reduction (odds ratio [OR], 0.259; P = .0048) reduction in migraine days and 50% increase in resolution of migraine in patients with a history of migraine with aura (OR, 1.586; P = .227).

The incidence of stroke was not evaluated in this meta-analysis, but Dr. Liu believes that the evidence of reducing the burden of migraine with PFO closure is compelling. Given the evidence from this meta-analysis that PFO closure is safe, Dr. Liu maintained that a definitive trial is needed “especially for migraine with frequent aura.”

As an interventional cardiologist, Dr. Tobis said that when PFO closures is performed for prevention of stroke in patients with migraine, it often leads to reduced migraine activity and, in some cases, elimination of migraine. Like others, he believes new analyses should be conducted.

“Everyone involved in this field believes there is something there,” Dr. Tobis said. The missing link is a clinical trial to confirm it.

Dr. Charles and Dr. Liu report no potential conflicts of interest. Dr. Tobis reports a financial relationship with Holistick Medical.

Repairing patent foramen ovale (PFO) and other right-to-left shunt disorders for the prevention of migraine has generated mixed results, but the potential for these repairs also includes reducing the risk of stroke, according to a discussion at the 2023 Scottsdale Headache Symposium.

In two clinical trials evaluating whether PFO closure reduces migraine risk, the primary endpoints were not met, but a signal of benefit on secondary endpoints and the association between PFO, migraine, and stroke are among the reasons that PFO closure should be reevaluated, according to Andrew Charles MD, Director of the Goldberg Migraine Program, University of California, Los Angeles.

UCLA

One Intervention, Two Potential Benefits

Fixing these defects is therefore at least theoretically attractive for preventing both migraine and stroke, but Dr. Charles said the opportunity for preventing both migraine and stroke is most attractive in migraine patients who have additional stroke risk factors.

Use of oral contraceptives, which produce a hypercoagulable state, is an example.

“Are these the people we should really be thinking about if they have PFO and migraine, particularly migraine with aura?” Dr. Charles asked.

The association between right-to-left shunts and migraine is strong. Although PFO is common, presenting in 20%-25% of the adult population, it has been found in up to 50% of individuals who have migraine with aura. In patients with migraine but no aura, the prevalence of PFO has been estimated to be approximately 35% or still somewhat elevated relative to the general population.
 

Primary Endpoint Missed in Clinical Trials

The question of whether risk of migraine can be reduced with repair of PFO or other right-to-left shunts remains unresolved. In two high-quality randomized trials undertaken in PFO repair, neither met its primary endpoint. In one of these, called PRIMA, which was terminated early for slow enrollment, the reduction in mean headache attacks was not significant relative to medical therapy.

In the second, called PREMIUM, device closure of PFO also failed to significantly reduce migraine attacks over sham procedure although it was associated with complete migraine remission (10% vs 1%).

A pooled analysis of these two studies that was conducted subsequently concluded that PFO closure reduces mean monthly migraine days (-3.1 vs. -1.9 days; P = -.02) and increases the likelihood of complete migraine cessation (9% vs. 0.7%; P < .001), but Dr. Charles pointed out the primary endpoint was migraine attacks not migraine days, so other analyses can only be considered hypothesis-generating.

There are several reasons to relook at the relationship between migraine and PFO but the potential to prevent both migraine and stroke with PFO closure could be one of the most important.

Several years ago, Dr. Charles and his coinvestigators from UCLA evaluated more than 700 ischemic strokes. Of these, 127 strokes were characterized as cryptogenic because of lack of another identifiable etiology. While 59% of these patients had PFO, which is several times higher than the general population, the prevalence of PFO in patients with a cryptogenic stroke and a history of migraine was 79% in this published study.

“So, in this group of patients who did not have any other clear cause for a stroke, a diagnosis of PFO was very much overrepresented,” Dr. Charles said.
 

Migraine Days Might Be a Better Endpoint

For patients with migraine who have risk factors for stroke, this makes PFO closure an attractive intervention, but a positive randomized trial is needed. Several are underway. Importantly, the trials now enrolling are using migraine days, which was significantly reduced in both PREMIUM and PRIMA, rather than migraine attacks as the primary endpoint.

“Migraine days is now accepted by the Food and Drug Administration as a criterion of benefit,” reported Jonathan Tobis, MD, Research Director, Interventional Cardiology, UCLA David Geffen School of Medicine, Los Angeles.

He explained that the FDA insisted on migraine attacks as the endpoint for the PREMIUM trial, but this was a far more challenging endpoint on which to show a statistical benefit. He emphasized that a new set of trials will now test efficacy on the basis of migraine days.

One of these trials, called RELIEF, which is randomizing patients to device closure of PFO or a sham procedure. Both groups are receiving clopidogrel or prasugrel based on a previous observation that patients who respond to these drugs are also more likely to respond to PFO closure.

Another trial, called COMPETE-2, is comparing PFO closure with a device to aspirin plus a sham closure. This trial is ongoing in China.

Stroke is not being evaluated as an endpoint in either trial, but Dr. Charles suggested that this does warrant attention.

“I would also just put it out there that, apart from simply migraine, this is a therapeutic approach that we might actually think about in terms of helping to prevent stroke in our migraine patients,” he said.

Senior author of a recent meta-analysis of trials evaluating PFO closure and control of migraine, Ling Liu, MD, Department of Neurology, University of Sichuan, Chengdu, China, agreed that PFO closure for the treatment of migraine deserves “a reevaluation.”

In his meta-analysis of three randomized trials, one pooled study, and eight retrospective case series with 1,165 patients, PFO closure was associated with a nearly 75% reduction (odds ratio [OR], 0.259; P = .0048) reduction in migraine days and 50% increase in resolution of migraine in patients with a history of migraine with aura (OR, 1.586; P = .227).

The incidence of stroke was not evaluated in this meta-analysis, but Dr. Liu believes that the evidence of reducing the burden of migraine with PFO closure is compelling. Given the evidence from this meta-analysis that PFO closure is safe, Dr. Liu maintained that a definitive trial is needed “especially for migraine with frequent aura.”

As an interventional cardiologist, Dr. Tobis said that when PFO closures is performed for prevention of stroke in patients with migraine, it often leads to reduced migraine activity and, in some cases, elimination of migraine. Like others, he believes new analyses should be conducted.

“Everyone involved in this field believes there is something there,” Dr. Tobis said. The missing link is a clinical trial to confirm it.

Dr. Charles and Dr. Liu report no potential conflicts of interest. Dr. Tobis reports a financial relationship with Holistick Medical.

Drugs offered to treat the headache phase of migraine are not necessarily the best to abort the premonitory or prodromal phases, according to experts attempting to put these puzzle pieces together at the 2023 Scottsdale Headache Symposium.

As the details of the complex chain of molecular events become better understood, there is reason to believe that the targets for aborting events early in the process are not necessarily therapeutic at later stages or vice versa, according to Peter Goadsby, MBBS, MD, PhD, director of the National Institute for Health Research and professor of neurology, King’s College, London.

“I think this explains some of the frustration at trigger modulation. I think we are often trying to modulate a process that has already got started,” he said. The analogy might be closing the barn door after the animals have escaped.
 

Migraine phases might explain pathology

Given the progress in understanding each step that leads from one phase to the next in migraine onset, this premise is not surprising. Increased blood flow, trigeminal activation, and release of calcitonin gene–related peptide (CGRP) are early events in this process, according to Dr. Goadsby, but there is still uncertainty about the triggers of brainstem stimulation and cranial blood flow that precedes these events.

In his talk about the advances that led to the development of CGRP-targeted therapy, Dr. Goadsby explained how and why CGRP inhibition, along with triptans, pituitary adenylate cyclase–activating polypeptide (PACAP) inhibitors, and ditans, have been developed as treatment targets in migraine, while other once-promising targets, such as substance P inhibition and inducible nitric oxide synthase (INOS) inhibition, have not.

Much of this progress has been by trial and error through clinical studies in which efficacy has or has not been seen. Despite the progress in mapping the release of CGRP and its activity, Dr. Goadsby acknowledged that there is still much about its participation in migraine pathophysiology that remains poorly defined.

“Anyone who tells you that they know how CGRP works I think is blowing smoke, frankly,” Dr. Goadsby said. “Clearly these things are complex.”
 

CGRP is active in the CSF

This includes the site of action. Dr. Goadsby said that it is widely believed that CGRP inhibitors are active in the dura and not in the cerebrospinal fluid (CSF). However, Dr. Goadsby said that a study undertaken with monoclonal antibodies targeting CGRP have produced compelling evidence that CGRP is reduced in the CSF.

“They clearly get into the CSF,” said Dr. Goadsby, noting that the barrier between peripheral blood and the CSF “is different from the blood-brain barrier.”

Widely regarded as playing a pivotal role in the development of CGRP as a therapeutic target in migraine, Dr. Goadsby spent some time speculating about its potential for preventing the earliest steps in the process that leads from the premonitory state to allodynia, prodromal symptoms, migraine, and postdromal recovery.

Of triggers, “light is my favorite example,” he said. He noted that many patients are convinced that light initiates the subsequent steps that end in a migraine. This is fair assumption for those who have seen a sequence of events in which light in the absence of any other symptom always precedes prodromal symptoms and migraine.

“Why would you not think that?” he asked. “Unless you point out that the attack had already started and the reason that you are noticing the light is because of photophobia that started during the premonitory phase.”

It is increasingly clear that CGRP inhibition does have clinical benefit when started at early signs of a coming migraine, according to Dr. Goadsby. He cited a phase 3 study published just days before he spoke at the Scottsdale Headache Symposium. Called PRODROME, the study associated the CGRP receptor antagonist ubrogepant, which is already approved for treatment of migraine, with a significant reduction in the risk of moderate to severe headache relative to placebo when measured 24 hours after randomization (46% vs. 29%; P < .0001).


 

Brain activity monitoring supports phases

Citing imaging studies in his own laboratory, Todd J. Schwedt, MD, chair of neurology research, Mayo Clinic, Phoenix, substantiated several of the points made by Dr. Goadsby in a separate talk he made on migraine phases. By monitoring brain activity during each phase of migraine, he suggested his data support the role of CGRP in producing an inflammatory response as well as sensitizing the trigeminal cervical system in steps that appear to be important to the pain process.

Mitchel L. Zoler/MDedge News

Dr. Schwedt showed several pieces of evidence suggesting that CGRP is an early mediator even if it is not necessarily the first step in a process for every patient. However, like Dr. Goadsby, Dr. Schwedt also acknowledged that the interplay between events is complex and might differ between patients.

Yet, he says that brain activity on imaging is not the only evidence of the role of CGRP activation early in the process leading toward migraine.

“I am a little biased towards imaging, but it’s not just about imaging,” Dr. Schwedt said.

“If we look at preictal salivary CGRP levels and then follow them into the headache phase, we see the levels increase, but they go back to normal a couple of hours into the attack and then stay normal, presumably, until the patient gets closer to the next attack,” Dr. Schwedt said.

Despite progress there is more to be done to determine why CGRP is released and whether it can be inhibited early to abort migraine before the headache phase, but both Dr. Goadsby and Dr. Schwedt pointed to this as a very early event. This is not to say that others, such as cortical spreading depression, do not have an equally important role in the evolution of migraine, but each expert considers migraine phases to be useful divisions for tracing the sequence of pathogenic events.

The phase of a migraine attack and their corresponding symptoms “can be mapped to altered brain function and release of neuropeptides and neurotransmitters,” Dr. Schwedt said. The implication is that better targets for blocking migraine before it reaches the headache phase might be discovered in these early phases.

Dr. Goadsby and Dr. Schwedt listed more than 10 pharmaceutical companies to which they have financial relationships, but both claimed that none of these relationships posed a potential conflict of interest.

Drugs offered to treat the headache phase of migraine are not necessarily the best to abort the premonitory or prodromal phases, according to experts attempting to put these puzzle pieces together at the 2023 Scottsdale Headache Symposium.

As the details of the complex chain of molecular events become better understood, there is reason to believe that the targets for aborting events early in the process are not necessarily therapeutic at later stages or vice versa, according to Peter Goadsby, MBBS, MD, PhD, director of the National Institute for Health Research and professor of neurology, King’s College, London.

“I think this explains some of the frustration at trigger modulation. I think we are often trying to modulate a process that has already got started,” he said. The analogy might be closing the barn door after the animals have escaped.
 

Migraine phases might explain pathology

Given the progress in understanding each step that leads from one phase to the next in migraine onset, this premise is not surprising. Increased blood flow, trigeminal activation, and release of calcitonin gene–related peptide (CGRP) are early events in this process, according to Dr. Goadsby, but there is still uncertainty about the triggers of brainstem stimulation and cranial blood flow that precedes these events.

In his talk about the advances that led to the development of CGRP-targeted therapy, Dr. Goadsby explained how and why CGRP inhibition, along with triptans, pituitary adenylate cyclase–activating polypeptide (PACAP) inhibitors, and ditans, have been developed as treatment targets in migraine, while other once-promising targets, such as substance P inhibition and inducible nitric oxide synthase (INOS) inhibition, have not.

Much of this progress has been by trial and error through clinical studies in which efficacy has or has not been seen. Despite the progress in mapping the release of CGRP and its activity, Dr. Goadsby acknowledged that there is still much about its participation in migraine pathophysiology that remains poorly defined.

“Anyone who tells you that they know how CGRP works I think is blowing smoke, frankly,” Dr. Goadsby said. “Clearly these things are complex.”
 

CGRP is active in the CSF

This includes the site of action. Dr. Goadsby said that it is widely believed that CGRP inhibitors are active in the dura and not in the cerebrospinal fluid (CSF). However, Dr. Goadsby said that a study undertaken with monoclonal antibodies targeting CGRP have produced compelling evidence that CGRP is reduced in the CSF.

“They clearly get into the CSF,” said Dr. Goadsby, noting that the barrier between peripheral blood and the CSF “is different from the blood-brain barrier.”

Widely regarded as playing a pivotal role in the development of CGRP as a therapeutic target in migraine, Dr. Goadsby spent some time speculating about its potential for preventing the earliest steps in the process that leads from the premonitory state to allodynia, prodromal symptoms, migraine, and postdromal recovery.

Of triggers, “light is my favorite example,” he said. He noted that many patients are convinced that light initiates the subsequent steps that end in a migraine. This is fair assumption for those who have seen a sequence of events in which light in the absence of any other symptom always precedes prodromal symptoms and migraine.

“Why would you not think that?” he asked. “Unless you point out that the attack had already started and the reason that you are noticing the light is because of photophobia that started during the premonitory phase.”

It is increasingly clear that CGRP inhibition does have clinical benefit when started at early signs of a coming migraine, according to Dr. Goadsby. He cited a phase 3 study published just days before he spoke at the Scottsdale Headache Symposium. Called PRODROME, the study associated the CGRP receptor antagonist ubrogepant, which is already approved for treatment of migraine, with a significant reduction in the risk of moderate to severe headache relative to placebo when measured 24 hours after randomization (46% vs. 29%; P < .0001).


 

Brain activity monitoring supports phases

Citing imaging studies in his own laboratory, Todd J. Schwedt, MD, chair of neurology research, Mayo Clinic, Phoenix, substantiated several of the points made by Dr. Goadsby in a separate talk he made on migraine phases. By monitoring brain activity during each phase of migraine, he suggested his data support the role of CGRP in producing an inflammatory response as well as sensitizing the trigeminal cervical system in steps that appear to be important to the pain process.

Mitchel L. Zoler/MDedge News

Dr. Schwedt showed several pieces of evidence suggesting that CGRP is an early mediator even if it is not necessarily the first step in a process for every patient. However, like Dr. Goadsby, Dr. Schwedt also acknowledged that the interplay between events is complex and might differ between patients.

Yet, he says that brain activity on imaging is not the only evidence of the role of CGRP activation early in the process leading toward migraine.

“I am a little biased towards imaging, but it’s not just about imaging,” Dr. Schwedt said.

“If we look at preictal salivary CGRP levels and then follow them into the headache phase, we see the levels increase, but they go back to normal a couple of hours into the attack and then stay normal, presumably, until the patient gets closer to the next attack,” Dr. Schwedt said.

Despite progress there is more to be done to determine why CGRP is released and whether it can be inhibited early to abort migraine before the headache phase, but both Dr. Goadsby and Dr. Schwedt pointed to this as a very early event. This is not to say that others, such as cortical spreading depression, do not have an equally important role in the evolution of migraine, but each expert considers migraine phases to be useful divisions for tracing the sequence of pathogenic events.

The phase of a migraine attack and their corresponding symptoms “can be mapped to altered brain function and release of neuropeptides and neurotransmitters,” Dr. Schwedt said. The implication is that better targets for blocking migraine before it reaches the headache phase might be discovered in these early phases.

Dr. Goadsby and Dr. Schwedt listed more than 10 pharmaceutical companies to which they have financial relationships, but both claimed that none of these relationships posed a potential conflict of interest.

Drugs offered to treat the headache phase of migraine are not necessarily the best to abort the premonitory or prodromal phases, according to experts attempting to put these puzzle pieces together at the 2023 Scottsdale Headache Symposium.

As the details of the complex chain of molecular events become better understood, there is reason to believe that the targets for aborting events early in the process are not necessarily therapeutic at later stages or vice versa, according to Peter Goadsby, MBBS, MD, PhD, director of the National Institute for Health Research and professor of neurology, King’s College, London.

“I think this explains some of the frustration at trigger modulation. I think we are often trying to modulate a process that has already got started,” he said. The analogy might be closing the barn door after the animals have escaped.
 

Migraine phases might explain pathology

Given the progress in understanding each step that leads from one phase to the next in migraine onset, this premise is not surprising. Increased blood flow, trigeminal activation, and release of calcitonin gene–related peptide (CGRP) are early events in this process, according to Dr. Goadsby, but there is still uncertainty about the triggers of brainstem stimulation and cranial blood flow that precedes these events.

In his talk about the advances that led to the development of CGRP-targeted therapy, Dr. Goadsby explained how and why CGRP inhibition, along with triptans, pituitary adenylate cyclase–activating polypeptide (PACAP) inhibitors, and ditans, have been developed as treatment targets in migraine, while other once-promising targets, such as substance P inhibition and inducible nitric oxide synthase (INOS) inhibition, have not.

Much of this progress has been by trial and error through clinical studies in which efficacy has or has not been seen. Despite the progress in mapping the release of CGRP and its activity, Dr. Goadsby acknowledged that there is still much about its participation in migraine pathophysiology that remains poorly defined.

“Anyone who tells you that they know how CGRP works I think is blowing smoke, frankly,” Dr. Goadsby said. “Clearly these things are complex.”
 

CGRP is active in the CSF

This includes the site of action. Dr. Goadsby said that it is widely believed that CGRP inhibitors are active in the dura and not in the cerebrospinal fluid (CSF). However, Dr. Goadsby said that a study undertaken with monoclonal antibodies targeting CGRP have produced compelling evidence that CGRP is reduced in the CSF.

“They clearly get into the CSF,” said Dr. Goadsby, noting that the barrier between peripheral blood and the CSF “is different from the blood-brain barrier.”

Widely regarded as playing a pivotal role in the development of CGRP as a therapeutic target in migraine, Dr. Goadsby spent some time speculating about its potential for preventing the earliest steps in the process that leads from the premonitory state to allodynia, prodromal symptoms, migraine, and postdromal recovery.

Of triggers, “light is my favorite example,” he said. He noted that many patients are convinced that light initiates the subsequent steps that end in a migraine. This is fair assumption for those who have seen a sequence of events in which light in the absence of any other symptom always precedes prodromal symptoms and migraine.

“Why would you not think that?” he asked. “Unless you point out that the attack had already started and the reason that you are noticing the light is because of photophobia that started during the premonitory phase.”

It is increasingly clear that CGRP inhibition does have clinical benefit when started at early signs of a coming migraine, according to Dr. Goadsby. He cited a phase 3 study published just days before he spoke at the Scottsdale Headache Symposium. Called PRODROME, the study associated the CGRP receptor antagonist ubrogepant, which is already approved for treatment of migraine, with a significant reduction in the risk of moderate to severe headache relative to placebo when measured 24 hours after randomization (46% vs. 29%; P < .0001).


 

Brain activity monitoring supports phases

Citing imaging studies in his own laboratory, Todd J. Schwedt, MD, chair of neurology research, Mayo Clinic, Phoenix, substantiated several of the points made by Dr. Goadsby in a separate talk he made on migraine phases. By monitoring brain activity during each phase of migraine, he suggested his data support the role of CGRP in producing an inflammatory response as well as sensitizing the trigeminal cervical system in steps that appear to be important to the pain process.

Mitchel L. Zoler/MDedge News

Dr. Schwedt showed several pieces of evidence suggesting that CGRP is an early mediator even if it is not necessarily the first step in a process for every patient. However, like Dr. Goadsby, Dr. Schwedt also acknowledged that the interplay between events is complex and might differ between patients.

Yet, he says that brain activity on imaging is not the only evidence of the role of CGRP activation early in the process leading toward migraine.

“I am a little biased towards imaging, but it’s not just about imaging,” Dr. Schwedt said.

“If we look at preictal salivary CGRP levels and then follow them into the headache phase, we see the levels increase, but they go back to normal a couple of hours into the attack and then stay normal, presumably, until the patient gets closer to the next attack,” Dr. Schwedt said.

Despite progress there is more to be done to determine why CGRP is released and whether it can be inhibited early to abort migraine before the headache phase, but both Dr. Goadsby and Dr. Schwedt pointed to this as a very early event. This is not to say that others, such as cortical spreading depression, do not have an equally important role in the evolution of migraine, but each expert considers migraine phases to be useful divisions for tracing the sequence of pathogenic events.

The phase of a migraine attack and their corresponding symptoms “can be mapped to altered brain function and release of neuropeptides and neurotransmitters,” Dr. Schwedt said. The implication is that better targets for blocking migraine before it reaches the headache phase might be discovered in these early phases.

Dr. Goadsby and Dr. Schwedt listed more than 10 pharmaceutical companies to which they have financial relationships, but both claimed that none of these relationships posed a potential conflict of interest.

NEW YORK – From clinical trials to textbooks, patients with darker skin types who have psoriasis overall – and Black patients in particular – are underrepresented, which might at least partially explain why clinicians are slow to recognize nail involvement, even when the skin disease has already been diagnosed, according to Shari R. Lipner, MD.

In a recently published review of 45 randomized controlled trials of therapies for nail psoriasis, almost all included information about the gender of the patients enrolled, but only about 35% reported race and/or ethnicity, Dr. Lipner, associate professor of dermatology, Weill Cornell Medical College, New York, said at the Skin of Color Update 2023. The proportion climbed to 59% in trials that included at least one study site in the United States, although representation of non-White patients in studies conducted in the United States was not proportional to the population (13.4% vs. 39.9%), said Dr. Lipner, senior author of the review .
 

Black patients largely unrepresented in photos

When an Internet search was conducted for images of nail psoriasis, the proportion of images fell as the number of the Fitzpatrick scale increased. Fitzpatrick skin types 1 or 2 represented 70% of the images, skin types 3 to 4 represented about 27%, leaving just 3% represented by darker skin types, Dr. Lipner said.

Ted Bosworth/MDedge News

“Unfortunately, things are not much better if you look at the dermatology and nail-specific textbooks. In fact, the percentages we see are almost identical,” said Dr. Lipner, noting that her review of images suggested that only about 3% of images in textbooks are of Fitzpatrick skin types 5 or 6, an obstacle for clinicians learning to recognize nail involvement in skin of color patients with psoriasis.

“We have written a couple of papers on this topic, including a call to action” in a letter to the editor in the Journal of the American Academy of Dermatology, Dr. Lipner noted. “To ensure access to safe and effective treatments for all patient populations,” she and her coauthor wrote, “we advocate the prioritized enrollment of racial and ethnic minority groups in psoriasis, PsA [psoriatic arthritis], and NP [nail psoriasis] clinical trials.”

Data from the 2009-2010 U.S. National Health and Nutrition Examination Survey (NHANES) confirms that psoriasis is less common in Blacks (1.9%) and Hispanics (1.6%) than Whites (3.6%). But these lower numbers still translate into substantial numbers nationally. Of those with psoriasis, the lifetime incidence of nail involvement has been variously estimated between 80% and 90%, Dr. Lipner said.

In about 10% of patients with psoriasis, nail involvement is isolated, occurring in the absence of skin lesions, a proportion that appears to be similar in Blacks and Whites according to Dr. Lipner.
 

Patient characteristics similar by race

In a study conducted at her own center, many of the characteristics of psoriasis were similar when those with a Fitzpatrick skin type 4 or higher were compared to those of 3 or lower. This included male-female distribution, smoking history, and presence of accompanying psoriatic arthritis. There was one discrepancy between lighter and darker skin.

“The big difference was that it took almost 3 years longer [on average] for darker skin to be diagnosed, and there was worse severity of disease,” Dr. Lipner said.

Like cutaneous manifestations of psoriasis, there are differences in appearance in the nail, many of which are simply produced by how skin color alters the appearance, such as the brownish hue of erythema in darker versus lighter skin. Dr. Lipner also noted that many of the features, such as keratosis, can be more severe in patients with darker skin types, but this is likely because of the delay in diagnosis.

The problem with overlooking nail psoriasis in patients of any skin color is the significant and independent adverse impact imposed by nail disease on quality of life, she added. She recounted the case of a 22-year-old Black patient whose nail psoriasis was overlooked even as she was being treated for her skin lesions.

“The diagnosis of nail psoriasis was missed for 3 years,” said Dr. Lipner, noting that the nail involvement was not trivial. “She had trouble doing her daily activities of life, but also, she was very embarrassed by her nails, not surprisingly.”

The problem of underrepresentation of Blacks in photos depicting nail diseases is not going unnoticed.

“Recently, there has been a concerted effort on the part of authors and editors to include more images of skin of color patients in published articles and textbooks,” said Jane S. Bellet, MD, professor of dermatology, Duke University, Durham, N.C.

An expert in nail disorders, particularly in children, Dr. Bellet said in an interview that this trend “must continue and increase in volume.” She said that the need for more images of nail disease in skin of color is not restricted to textbooks but includes “other learning materials, such as online atlases.”

Dr. Lipner and Dr. Bellet reported no potential conflicts of interest relative to this topic.

NEW YORK – From clinical trials to textbooks, patients with darker skin types who have psoriasis overall – and Black patients in particular – are underrepresented, which might at least partially explain why clinicians are slow to recognize nail involvement, even when the skin disease has already been diagnosed, according to Shari R. Lipner, MD.

In a recently published review of 45 randomized controlled trials of therapies for nail psoriasis, almost all included information about the gender of the patients enrolled, but only about 35% reported race and/or ethnicity, Dr. Lipner, associate professor of dermatology, Weill Cornell Medical College, New York, said at the Skin of Color Update 2023. The proportion climbed to 59% in trials that included at least one study site in the United States, although representation of non-White patients in studies conducted in the United States was not proportional to the population (13.4% vs. 39.9%), said Dr. Lipner, senior author of the review .
 

Black patients largely unrepresented in photos

When an Internet search was conducted for images of nail psoriasis, the proportion of images fell as the number of the Fitzpatrick scale increased. Fitzpatrick skin types 1 or 2 represented 70% of the images, skin types 3 to 4 represented about 27%, leaving just 3% represented by darker skin types, Dr. Lipner said.

Ted Bosworth/MDedge News

“Unfortunately, things are not much better if you look at the dermatology and nail-specific textbooks. In fact, the percentages we see are almost identical,” said Dr. Lipner, noting that her review of images suggested that only about 3% of images in textbooks are of Fitzpatrick skin types 5 or 6, an obstacle for clinicians learning to recognize nail involvement in skin of color patients with psoriasis.

“We have written a couple of papers on this topic, including a call to action” in a letter to the editor in the Journal of the American Academy of Dermatology, Dr. Lipner noted. “To ensure access to safe and effective treatments for all patient populations,” she and her coauthor wrote, “we advocate the prioritized enrollment of racial and ethnic minority groups in psoriasis, PsA [psoriatic arthritis], and NP [nail psoriasis] clinical trials.”

Data from the 2009-2010 U.S. National Health and Nutrition Examination Survey (NHANES) confirms that psoriasis is less common in Blacks (1.9%) and Hispanics (1.6%) than Whites (3.6%). But these lower numbers still translate into substantial numbers nationally. Of those with psoriasis, the lifetime incidence of nail involvement has been variously estimated between 80% and 90%, Dr. Lipner said.

In about 10% of patients with psoriasis, nail involvement is isolated, occurring in the absence of skin lesions, a proportion that appears to be similar in Blacks and Whites according to Dr. Lipner.
 

Patient characteristics similar by race

In a study conducted at her own center, many of the characteristics of psoriasis were similar when those with a Fitzpatrick skin type 4 or higher were compared to those of 3 or lower. This included male-female distribution, smoking history, and presence of accompanying psoriatic arthritis. There was one discrepancy between lighter and darker skin.

“The big difference was that it took almost 3 years longer [on average] for darker skin to be diagnosed, and there was worse severity of disease,” Dr. Lipner said.

Like cutaneous manifestations of psoriasis, there are differences in appearance in the nail, many of which are simply produced by how skin color alters the appearance, such as the brownish hue of erythema in darker versus lighter skin. Dr. Lipner also noted that many of the features, such as keratosis, can be more severe in patients with darker skin types, but this is likely because of the delay in diagnosis.

The problem with overlooking nail psoriasis in patients of any skin color is the significant and independent adverse impact imposed by nail disease on quality of life, she added. She recounted the case of a 22-year-old Black patient whose nail psoriasis was overlooked even as she was being treated for her skin lesions.

“The diagnosis of nail psoriasis was missed for 3 years,” said Dr. Lipner, noting that the nail involvement was not trivial. “She had trouble doing her daily activities of life, but also, she was very embarrassed by her nails, not surprisingly.”

The problem of underrepresentation of Blacks in photos depicting nail diseases is not going unnoticed.

“Recently, there has been a concerted effort on the part of authors and editors to include more images of skin of color patients in published articles and textbooks,” said Jane S. Bellet, MD, professor of dermatology, Duke University, Durham, N.C.

An expert in nail disorders, particularly in children, Dr. Bellet said in an interview that this trend “must continue and increase in volume.” She said that the need for more images of nail disease in skin of color is not restricted to textbooks but includes “other learning materials, such as online atlases.”

Dr. Lipner and Dr. Bellet reported no potential conflicts of interest relative to this topic.

NEW YORK – From clinical trials to textbooks, patients with darker skin types who have psoriasis overall – and Black patients in particular – are underrepresented, which might at least partially explain why clinicians are slow to recognize nail involvement, even when the skin disease has already been diagnosed, according to Shari R. Lipner, MD.

In a recently published review of 45 randomized controlled trials of therapies for nail psoriasis, almost all included information about the gender of the patients enrolled, but only about 35% reported race and/or ethnicity, Dr. Lipner, associate professor of dermatology, Weill Cornell Medical College, New York, said at the Skin of Color Update 2023. The proportion climbed to 59% in trials that included at least one study site in the United States, although representation of non-White patients in studies conducted in the United States was not proportional to the population (13.4% vs. 39.9%), said Dr. Lipner, senior author of the review .
 

Black patients largely unrepresented in photos

When an Internet search was conducted for images of nail psoriasis, the proportion of images fell as the number of the Fitzpatrick scale increased. Fitzpatrick skin types 1 or 2 represented 70% of the images, skin types 3 to 4 represented about 27%, leaving just 3% represented by darker skin types, Dr. Lipner said.

Ted Bosworth/MDedge News

“Unfortunately, things are not much better if you look at the dermatology and nail-specific textbooks. In fact, the percentages we see are almost identical,” said Dr. Lipner, noting that her review of images suggested that only about 3% of images in textbooks are of Fitzpatrick skin types 5 or 6, an obstacle for clinicians learning to recognize nail involvement in skin of color patients with psoriasis.

“We have written a couple of papers on this topic, including a call to action” in a letter to the editor in the Journal of the American Academy of Dermatology, Dr. Lipner noted. “To ensure access to safe and effective treatments for all patient populations,” she and her coauthor wrote, “we advocate the prioritized enrollment of racial and ethnic minority groups in psoriasis, PsA [psoriatic arthritis], and NP [nail psoriasis] clinical trials.”

Data from the 2009-2010 U.S. National Health and Nutrition Examination Survey (NHANES) confirms that psoriasis is less common in Blacks (1.9%) and Hispanics (1.6%) than Whites (3.6%). But these lower numbers still translate into substantial numbers nationally. Of those with psoriasis, the lifetime incidence of nail involvement has been variously estimated between 80% and 90%, Dr. Lipner said.

In about 10% of patients with psoriasis, nail involvement is isolated, occurring in the absence of skin lesions, a proportion that appears to be similar in Blacks and Whites according to Dr. Lipner.
 

Patient characteristics similar by race

In a study conducted at her own center, many of the characteristics of psoriasis were similar when those with a Fitzpatrick skin type 4 or higher were compared to those of 3 or lower. This included male-female distribution, smoking history, and presence of accompanying psoriatic arthritis. There was one discrepancy between lighter and darker skin.

“The big difference was that it took almost 3 years longer [on average] for darker skin to be diagnosed, and there was worse severity of disease,” Dr. Lipner said.

Like cutaneous manifestations of psoriasis, there are differences in appearance in the nail, many of which are simply produced by how skin color alters the appearance, such as the brownish hue of erythema in darker versus lighter skin. Dr. Lipner also noted that many of the features, such as keratosis, can be more severe in patients with darker skin types, but this is likely because of the delay in diagnosis.

The problem with overlooking nail psoriasis in patients of any skin color is the significant and independent adverse impact imposed by nail disease on quality of life, she added. She recounted the case of a 22-year-old Black patient whose nail psoriasis was overlooked even as she was being treated for her skin lesions.

“The diagnosis of nail psoriasis was missed for 3 years,” said Dr. Lipner, noting that the nail involvement was not trivial. “She had trouble doing her daily activities of life, but also, she was very embarrassed by her nails, not surprisingly.”

The problem of underrepresentation of Blacks in photos depicting nail diseases is not going unnoticed.

“Recently, there has been a concerted effort on the part of authors and editors to include more images of skin of color patients in published articles and textbooks,” said Jane S. Bellet, MD, professor of dermatology, Duke University, Durham, N.C.

An expert in nail disorders, particularly in children, Dr. Bellet said in an interview that this trend “must continue and increase in volume.” She said that the need for more images of nail disease in skin of color is not restricted to textbooks but includes “other learning materials, such as online atlases.”

Dr. Lipner and Dr. Bellet reported no potential conflicts of interest relative to this topic.

BERLIN – The open-label extension trials of deuruxolitinib for alopecia areata in adults show a persistent climb in response with the majority of patients achieving complete or near complete hair regrowth by 52 weeks, according to data presented at the annual congress of the European Academy of Dermatology and Venereology.

With response curves still climbing at follow-up to date, the results are “truly, truly remarkable,” said Brett King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

Deuruxolitinib is a JAK inhibitor that has specificity for the 1 and 2 subtypes. At 24 weeks in the phase 3 THRIVE-AA1 and THRIVE-AA2 trials, presented at the American Academy of Dermatology annual meeting earlier this year, about 40% of those on the 12-mg twice-daily dose and 32% of those on the 8-mg twice-daily dose achieved a Severity of Alopecia Tool (SALT) score of ≤ 20%, signifying 80% or greater hair regrowth at 24 weeks. The placebo response was 0%.

Ted Bosworth/MDedge News

There were 741 patients available at 52 weeks for this on-going analysis. The mean SALT scores at entry exceeded 80%, meaning complete or near complete hair loss. The substantial proportion of patients who met the primary endpoint of SALT ≤ 20 at the end of the blinded period was encouraging, but Dr. King said that the 52-week results are important, not only showing the response was sustained, but that greater regrowth occurs over time.

“Alopecia takes time to treat,” said Dr. King, summarizing the lesson from these data. Moreover, he added that the long-term data are likely to under represent the absolute benefit even if no further growth is achieved with even longer follow-up. One reason is that missing long-term data were accounted for with a last-observation-carried-forward approach.

In other words, “this is the floor when considering response at 52 weeks,” Dr. King said. “In the real world, where adjunctive measures such as intralesional Kenalog [triamcinolone acetonide] or topical treatments are added, we are likely to do even better,” he added.
 

Adverse events remained low

Treatment-emergent adverse events remained low with “nothing particularly surprising,” Dr. King said. The rate of serious adverse events over 52 weeks was less than 2% on either dose of deuruxolitinib. The proportion of patients who discontinued treatment because of an adverse event was 0.7% in the 8-mg twice-daily arm and 1.1% in the 12-mg twice-daily arm.

Most approved oral JAK inhibitors carry a boxed warning based on a trial conducted with the relatively nonspecific tofacitinib. The trial enrolled older patients with rheumatoid arthritis at risk for thrombotic events, raising questions about its relevance to selective JAK inhibitors employed for other indications. There was only one thrombosis observed in the 52-week alopecia areata follow-up in a patient on deuruxolitinib. Dr. King noted that this patient, who was obese and was on the higher of the two doses, had multiple comorbidities, including systemic lupus erythematosus.

There were no major adverse cardiac events reported in long-term follow-up or cases of tuberculosis. The rate of opportunistic infections was 0.1% in the 8-mg twice-daily arm and 0.2% in the 12-mg twice-daily arm. Serious infections were observed in 0.6% and 0.4% of these two arms, respectively. There were four malignancies (0.5%) in each of the two study arms.

Of the side effects likely to be related to deuruxolitinib, acne was observed in about 10% of patients on either dose. The mechanism is unclear, but Dr. King reported this has been commonly observed with other JAK inhibitors.

Asked his opinion about the optimal starting dose of deuruxolitinib, Dr. King said, “in my mind, the efficacy of 8 mg is so impressive that I would not struggle at all in starting there,” noting that the higher dose could be considered with a slow or inadequate response.
 

Two JAK inhibitors are already approved

If approved for alopecia areata, deuruxolitinib will be the third JAK inhibitor available for this indication, following the recent approvals of baricitinib and ritlecitinib.

Calling JAK inhibitors “a major advance in the treatment of alopecia areata, particularly for those patients with severe, refractory disease,” Lynne Goldberg, MD, professor of dermatology at Boston University, and director of the hair clinic, Boston Medical Center, said that the proportion of patients with SALT scores ≤ 20 at 52-weeks is “huge.”

She is generally comfortable with the safety of the JAK inhibitors for alopecia areata.

“I believe that, in general, these medications are well tolerated in the alopecia areata population, particularly in otherwise healthy, young patients,” she said, indicating the benefit-to-risk ratio is particularly acceptable when disease is severe.

“This disease has tremendous emotional and functional implications, and many patients with severe or recurrent disease are willing to chance the side effects to live with a full head of hair,” she said. She added that well-informed patients can “make their own, individual assessment.”

Dr. King has financial relationships with approximately 20 pharmaceutical companies, including Concert Pharmaceuticals, which makes deuruxolitinib and provided funding for this study. Dr. Goldberg reports no financial conflicts relevant to this topic.

BERLIN – The open-label extension trials of deuruxolitinib for alopecia areata in adults show a persistent climb in response with the majority of patients achieving complete or near complete hair regrowth by 52 weeks, according to data presented at the annual congress of the European Academy of Dermatology and Venereology.

With response curves still climbing at follow-up to date, the results are “truly, truly remarkable,” said Brett King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

Deuruxolitinib is a JAK inhibitor that has specificity for the 1 and 2 subtypes. At 24 weeks in the phase 3 THRIVE-AA1 and THRIVE-AA2 trials, presented at the American Academy of Dermatology annual meeting earlier this year, about 40% of those on the 12-mg twice-daily dose and 32% of those on the 8-mg twice-daily dose achieved a Severity of Alopecia Tool (SALT) score of ≤ 20%, signifying 80% or greater hair regrowth at 24 weeks. The placebo response was 0%.

Ted Bosworth/MDedge News

There were 741 patients available at 52 weeks for this on-going analysis. The mean SALT scores at entry exceeded 80%, meaning complete or near complete hair loss. The substantial proportion of patients who met the primary endpoint of SALT ≤ 20 at the end of the blinded period was encouraging, but Dr. King said that the 52-week results are important, not only showing the response was sustained, but that greater regrowth occurs over time.

“Alopecia takes time to treat,” said Dr. King, summarizing the lesson from these data. Moreover, he added that the long-term data are likely to under represent the absolute benefit even if no further growth is achieved with even longer follow-up. One reason is that missing long-term data were accounted for with a last-observation-carried-forward approach.

In other words, “this is the floor when considering response at 52 weeks,” Dr. King said. “In the real world, where adjunctive measures such as intralesional Kenalog [triamcinolone acetonide] or topical treatments are added, we are likely to do even better,” he added.
 

Adverse events remained low

Treatment-emergent adverse events remained low with “nothing particularly surprising,” Dr. King said. The rate of serious adverse events over 52 weeks was less than 2% on either dose of deuruxolitinib. The proportion of patients who discontinued treatment because of an adverse event was 0.7% in the 8-mg twice-daily arm and 1.1% in the 12-mg twice-daily arm.

Most approved oral JAK inhibitors carry a boxed warning based on a trial conducted with the relatively nonspecific tofacitinib. The trial enrolled older patients with rheumatoid arthritis at risk for thrombotic events, raising questions about its relevance to selective JAK inhibitors employed for other indications. There was only one thrombosis observed in the 52-week alopecia areata follow-up in a patient on deuruxolitinib. Dr. King noted that this patient, who was obese and was on the higher of the two doses, had multiple comorbidities, including systemic lupus erythematosus.

There were no major adverse cardiac events reported in long-term follow-up or cases of tuberculosis. The rate of opportunistic infections was 0.1% in the 8-mg twice-daily arm and 0.2% in the 12-mg twice-daily arm. Serious infections were observed in 0.6% and 0.4% of these two arms, respectively. There were four malignancies (0.5%) in each of the two study arms.

Of the side effects likely to be related to deuruxolitinib, acne was observed in about 10% of patients on either dose. The mechanism is unclear, but Dr. King reported this has been commonly observed with other JAK inhibitors.

Asked his opinion about the optimal starting dose of deuruxolitinib, Dr. King said, “in my mind, the efficacy of 8 mg is so impressive that I would not struggle at all in starting there,” noting that the higher dose could be considered with a slow or inadequate response.
 

Two JAK inhibitors are already approved

If approved for alopecia areata, deuruxolitinib will be the third JAK inhibitor available for this indication, following the recent approvals of baricitinib and ritlecitinib.

Calling JAK inhibitors “a major advance in the treatment of alopecia areata, particularly for those patients with severe, refractory disease,” Lynne Goldberg, MD, professor of dermatology at Boston University, and director of the hair clinic, Boston Medical Center, said that the proportion of patients with SALT scores ≤ 20 at 52-weeks is “huge.”

She is generally comfortable with the safety of the JAK inhibitors for alopecia areata.

“I believe that, in general, these medications are well tolerated in the alopecia areata population, particularly in otherwise healthy, young patients,” she said, indicating the benefit-to-risk ratio is particularly acceptable when disease is severe.

“This disease has tremendous emotional and functional implications, and many patients with severe or recurrent disease are willing to chance the side effects to live with a full head of hair,” she said. She added that well-informed patients can “make their own, individual assessment.”

Dr. King has financial relationships with approximately 20 pharmaceutical companies, including Concert Pharmaceuticals, which makes deuruxolitinib and provided funding for this study. Dr. Goldberg reports no financial conflicts relevant to this topic.

BERLIN – The open-label extension trials of deuruxolitinib for alopecia areata in adults show a persistent climb in response with the majority of patients achieving complete or near complete hair regrowth by 52 weeks, according to data presented at the annual congress of the European Academy of Dermatology and Venereology.

With response curves still climbing at follow-up to date, the results are “truly, truly remarkable,” said Brett King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

Deuruxolitinib is a JAK inhibitor that has specificity for the 1 and 2 subtypes. At 24 weeks in the phase 3 THRIVE-AA1 and THRIVE-AA2 trials, presented at the American Academy of Dermatology annual meeting earlier this year, about 40% of those on the 12-mg twice-daily dose and 32% of those on the 8-mg twice-daily dose achieved a Severity of Alopecia Tool (SALT) score of ≤ 20%, signifying 80% or greater hair regrowth at 24 weeks. The placebo response was 0%.

Ted Bosworth/MDedge News

There were 741 patients available at 52 weeks for this on-going analysis. The mean SALT scores at entry exceeded 80%, meaning complete or near complete hair loss. The substantial proportion of patients who met the primary endpoint of SALT ≤ 20 at the end of the blinded period was encouraging, but Dr. King said that the 52-week results are important, not only showing the response was sustained, but that greater regrowth occurs over time.

“Alopecia takes time to treat,” said Dr. King, summarizing the lesson from these data. Moreover, he added that the long-term data are likely to under represent the absolute benefit even if no further growth is achieved with even longer follow-up. One reason is that missing long-term data were accounted for with a last-observation-carried-forward approach.

In other words, “this is the floor when considering response at 52 weeks,” Dr. King said. “In the real world, where adjunctive measures such as intralesional Kenalog [triamcinolone acetonide] or topical treatments are added, we are likely to do even better,” he added.
 

Adverse events remained low

Treatment-emergent adverse events remained low with “nothing particularly surprising,” Dr. King said. The rate of serious adverse events over 52 weeks was less than 2% on either dose of deuruxolitinib. The proportion of patients who discontinued treatment because of an adverse event was 0.7% in the 8-mg twice-daily arm and 1.1% in the 12-mg twice-daily arm.

Most approved oral JAK inhibitors carry a boxed warning based on a trial conducted with the relatively nonspecific tofacitinib. The trial enrolled older patients with rheumatoid arthritis at risk for thrombotic events, raising questions about its relevance to selective JAK inhibitors employed for other indications. There was only one thrombosis observed in the 52-week alopecia areata follow-up in a patient on deuruxolitinib. Dr. King noted that this patient, who was obese and was on the higher of the two doses, had multiple comorbidities, including systemic lupus erythematosus.

There were no major adverse cardiac events reported in long-term follow-up or cases of tuberculosis. The rate of opportunistic infections was 0.1% in the 8-mg twice-daily arm and 0.2% in the 12-mg twice-daily arm. Serious infections were observed in 0.6% and 0.4% of these two arms, respectively. There were four malignancies (0.5%) in each of the two study arms.

Of the side effects likely to be related to deuruxolitinib, acne was observed in about 10% of patients on either dose. The mechanism is unclear, but Dr. King reported this has been commonly observed with other JAK inhibitors.

Asked his opinion about the optimal starting dose of deuruxolitinib, Dr. King said, “in my mind, the efficacy of 8 mg is so impressive that I would not struggle at all in starting there,” noting that the higher dose could be considered with a slow or inadequate response.
 

Two JAK inhibitors are already approved

If approved for alopecia areata, deuruxolitinib will be the third JAK inhibitor available for this indication, following the recent approvals of baricitinib and ritlecitinib.

Calling JAK inhibitors “a major advance in the treatment of alopecia areata, particularly for those patients with severe, refractory disease,” Lynne Goldberg, MD, professor of dermatology at Boston University, and director of the hair clinic, Boston Medical Center, said that the proportion of patients with SALT scores ≤ 20 at 52-weeks is “huge.”

She is generally comfortable with the safety of the JAK inhibitors for alopecia areata.

“I believe that, in general, these medications are well tolerated in the alopecia areata population, particularly in otherwise healthy, young patients,” she said, indicating the benefit-to-risk ratio is particularly acceptable when disease is severe.

“This disease has tremendous emotional and functional implications, and many patients with severe or recurrent disease are willing to chance the side effects to live with a full head of hair,” she said. She added that well-informed patients can “make their own, individual assessment.”

Dr. King has financial relationships with approximately 20 pharmaceutical companies, including Concert Pharmaceuticals, which makes deuruxolitinib and provided funding for this study. Dr. Goldberg reports no financial conflicts relevant to this topic.

BERLIN – Tapinarof cream is highly effective, safe, and well tolerated for the treatment of atopic dermatitis (AD) in adults as well as children as young as 2 years of age, according to results of two pivotal trials presented at the at the annual congress of the European Academy of Dermatology and Venereology.

If approved for AD, one advantage of tapinarof cream relative to topical corticosteroids is potential use “without restrictions on duration, extent, or site of application,” reported Jonathan I. Silverberg, MD, PhD, MPH, director of clinical research, George Washington University, Washington.

Tapinarof cream, 1%, an aryl hydrocarbon receptor agonist, was approved in 2022 for treating plaque psoriasis in adults.

In the two phase 3 trials, ADORING 1 and ADORING 2, which were presented together at the meeting, the primary endpoint was Validated Investigator Global Assessment (vIGA) for AD of 0 (clear) or 1 (almost clear) at 8 weeks. For this endpoint and all secondary endpoints, the relative advantage of the active cream over the vehicle alone was about the same in both studies.

For example, the vIGA clear or almost clear response was met by 45.4% and 46.4% of those in the experimental arm of ADORING 1 and 2, respectively, but only 13.9% and 18.0% in the control arms (P < .0001 for both).

For the secondary endpoint of Eczema Area and Severity Index (EASI75), signifying 75% clearance of skin lesions, the response rates were 55.8% and 59.1% in the two trials, but only 22.9% and 24.1% in the respective control arms (P < .0001 for both).

The two identically designed trials randomized patients with moderate to severe AD in a 2:1 ratio to tapinarof cream or vehicle alone. There were 407 patients ages 2-81 years in ADORING I and 406 in ADORING 2. Patients were instructed to apply the active cream or vehicle once per day.

The safety data for tapinarof in these studies was generally consistent with the experience with this agent in plaque psoriasis. According to Dr. Silverberg, there was a modest increase in reports of headache early in this study, but these were transient. Follicular events were also more common on tapinarof than on its vehicle, but Dr. Silverberg said that the rate of discontinuations for adverse events, although low in both arms, was numerically lower in the active treatment arm in both trials.

“There were reports of contact dermatitis in the psoriasis studies, but we have not seen this in the AD trials,” Dr. Silverberg said.
 

Itch control evaluated

In a separate presentation of ADORING 1 and 2 results, Eric Simpson, MD, professor of dermatology, Oregon Health & Science University, Portland, provided detailed information about itch control, which was evaluated with the Peak Pruritus–Numerical Rating Scale (PP-NRS).

Ted Bosworth/MDedge News

“The PP-NRS considers a person’s worst itch over the past 24 hours based on an 11-point scale,” explained Dr. Simpson, who said that patients scored itch daily with comparisons made at weeks 1, 2, 4, and 8.

Over time, pruritus scores fell in both groups, but reductions were far steeper among those in the active treatment arms.

“In ADORING 1, there were greater reductions in itch as early as day 1,” Dr. Simpson reported. Although the differences in itch were not detected until day 2 in ADORING 2, the differences were already significant and clinically meaningful in both studies by the end of the first week.

By week 8, the mean reductions in PP-NRS scores were 2.6 and 2.4 in the vehicle arms of ADORING 1 and 2, respectively. In the treatment arm, the reduction was 4.1 points in both arms (P < .0001 for both studies).
 

Forty-eight–week follow-up planned

More than 90% of patients in both studies have rolled over into the open-label extension ADORING 3 trial, with a planned follow-up of 48 weeks, according to Dr. Silverberg, who said that those in the placebo arm have been crossed over to tapinarof.

The response and the safety appear to be similar in adults and children, although Dr. Silverberg said that further analyses of outcomes by age are planned. He noted that there is also an ongoing study of tapinarof in children with plaque psoriasis.

In AD in particular, Dr. Silverberg said there is “an unmet need” for a topical nonsteroidal anti-inflammatory. While topical corticosteroids are a mainstay of AD therapy in children as well as adults, he noted the limitations of these drugs, including that they can only be applied for limited periods.

Tapinarof binds to the aryl hydrocarbon receptor (AhR), which regulates immune function in the skin and is expressed in many skin cell types. By inhibiting AhR, tapinarof blocks cytokine activation and has an antioxidant effect.

Adelaide A. Hebert, MD, professor and director of pediatric dermatology, McGovern Medical School at UTHealth, Houston, has participated in clinical studies of tapinarof for AD, and said she has been impressed with its efficacy and tolerability in children as well as adults. In the case of children, parents, as well as patients, “valued the rapid onset of disease control, the once-daily application regimen, and the itch control,” she said in an interview after the meeting.

If approved, Dr. Hebert said, “this novel steroid-free medication has the potential to change the management arena for pediatric and adult patients with moderate to severe atopic dermatitis.”

The recent introduction of new systemic therapies for AD, such as JAK inhibitors, has increased options for AD control, but “we still need effective and safe topical therapies, especially in children and young adults,” said Sonja Ständer, MD, head of the Interdisciplinary Center for Chronic Pruritus, University of Münster (Germany). Author of a comprehensive review article on AD in the New England Journal of Medicine 2 years ago, Dr. Ständer said results from the phase 3 topical tapinarof trials, as well as the phase 3 topical ruxolitinib trials, which were also presented as late breakers at the 2023 EADV meeting, provide “hope that an alternative to topical steroids will soon be available.”

Based on their safety and rapid control of itch in children with AD, “these will complement our current portfolio of topical therapies very well and have the potential to replace topical steroids early in therapy or to replace them altogether,” she told this news organization.

Dermavant Sciences, manufacturer of tapinarof, anticipates filing for Food and Drug Administration approval for AD in the first quarter of 2024, according to a company statement.

Dr. Silverberg and Dr. Simpson reported financial relationships with multiple pharmaceutical companies, including Dermavant, which provided funding for the ADORING trials. Dr. Hebert has financial relationship with more than 15 pharmaceutical companies, including Dermavent and other companies that have or are developing therapies for AD. Dr. Ständer reported financial relationships with Beiersdorf, Eli Lilly, Galderma, Kiniksa, Pfizer, and Sanofi.

BERLIN – Tapinarof cream is highly effective, safe, and well tolerated for the treatment of atopic dermatitis (AD) in adults as well as children as young as 2 years of age, according to results of two pivotal trials presented at the at the annual congress of the European Academy of Dermatology and Venereology.

If approved for AD, one advantage of tapinarof cream relative to topical corticosteroids is potential use “without restrictions on duration, extent, or site of application,” reported Jonathan I. Silverberg, MD, PhD, MPH, director of clinical research, George Washington University, Washington.

Tapinarof cream, 1%, an aryl hydrocarbon receptor agonist, was approved in 2022 for treating plaque psoriasis in adults.

In the two phase 3 trials, ADORING 1 and ADORING 2, which were presented together at the meeting, the primary endpoint was Validated Investigator Global Assessment (vIGA) for AD of 0 (clear) or 1 (almost clear) at 8 weeks. For this endpoint and all secondary endpoints, the relative advantage of the active cream over the vehicle alone was about the same in both studies.

For example, the vIGA clear or almost clear response was met by 45.4% and 46.4% of those in the experimental arm of ADORING 1 and 2, respectively, but only 13.9% and 18.0% in the control arms (P < .0001 for both).

For the secondary endpoint of Eczema Area and Severity Index (EASI75), signifying 75% clearance of skin lesions, the response rates were 55.8% and 59.1% in the two trials, but only 22.9% and 24.1% in the respective control arms (P < .0001 for both).

The two identically designed trials randomized patients with moderate to severe AD in a 2:1 ratio to tapinarof cream or vehicle alone. There were 407 patients ages 2-81 years in ADORING I and 406 in ADORING 2. Patients were instructed to apply the active cream or vehicle once per day.

The safety data for tapinarof in these studies was generally consistent with the experience with this agent in plaque psoriasis. According to Dr. Silverberg, there was a modest increase in reports of headache early in this study, but these were transient. Follicular events were also more common on tapinarof than on its vehicle, but Dr. Silverberg said that the rate of discontinuations for adverse events, although low in both arms, was numerically lower in the active treatment arm in both trials.

“There were reports of contact dermatitis in the psoriasis studies, but we have not seen this in the AD trials,” Dr. Silverberg said.
 

Itch control evaluated

In a separate presentation of ADORING 1 and 2 results, Eric Simpson, MD, professor of dermatology, Oregon Health & Science University, Portland, provided detailed information about itch control, which was evaluated with the Peak Pruritus–Numerical Rating Scale (PP-NRS).

Ted Bosworth/MDedge News

“The PP-NRS considers a person’s worst itch over the past 24 hours based on an 11-point scale,” explained Dr. Simpson, who said that patients scored itch daily with comparisons made at weeks 1, 2, 4, and 8.

Over time, pruritus scores fell in both groups, but reductions were far steeper among those in the active treatment arms.

“In ADORING 1, there were greater reductions in itch as early as day 1,” Dr. Simpson reported. Although the differences in itch were not detected until day 2 in ADORING 2, the differences were already significant and clinically meaningful in both studies by the end of the first week.

By week 8, the mean reductions in PP-NRS scores were 2.6 and 2.4 in the vehicle arms of ADORING 1 and 2, respectively. In the treatment arm, the reduction was 4.1 points in both arms (P < .0001 for both studies).
 

Forty-eight–week follow-up planned

More than 90% of patients in both studies have rolled over into the open-label extension ADORING 3 trial, with a planned follow-up of 48 weeks, according to Dr. Silverberg, who said that those in the placebo arm have been crossed over to tapinarof.

The response and the safety appear to be similar in adults and children, although Dr. Silverberg said that further analyses of outcomes by age are planned. He noted that there is also an ongoing study of tapinarof in children with plaque psoriasis.

In AD in particular, Dr. Silverberg said there is “an unmet need” for a topical nonsteroidal anti-inflammatory. While topical corticosteroids are a mainstay of AD therapy in children as well as adults, he noted the limitations of these drugs, including that they can only be applied for limited periods.

Tapinarof binds to the aryl hydrocarbon receptor (AhR), which regulates immune function in the skin and is expressed in many skin cell types. By inhibiting AhR, tapinarof blocks cytokine activation and has an antioxidant effect.

Adelaide A. Hebert, MD, professor and director of pediatric dermatology, McGovern Medical School at UTHealth, Houston, has participated in clinical studies of tapinarof for AD, and said she has been impressed with its efficacy and tolerability in children as well as adults. In the case of children, parents, as well as patients, “valued the rapid onset of disease control, the once-daily application regimen, and the itch control,” she said in an interview after the meeting.

If approved, Dr. Hebert said, “this novel steroid-free medication has the potential to change the management arena for pediatric and adult patients with moderate to severe atopic dermatitis.”

The recent introduction of new systemic therapies for AD, such as JAK inhibitors, has increased options for AD control, but “we still need effective and safe topical therapies, especially in children and young adults,” said Sonja Ständer, MD, head of the Interdisciplinary Center for Chronic Pruritus, University of Münster (Germany). Author of a comprehensive review article on AD in the New England Journal of Medicine 2 years ago, Dr. Ständer said results from the phase 3 topical tapinarof trials, as well as the phase 3 topical ruxolitinib trials, which were also presented as late breakers at the 2023 EADV meeting, provide “hope that an alternative to topical steroids will soon be available.”

Based on their safety and rapid control of itch in children with AD, “these will complement our current portfolio of topical therapies very well and have the potential to replace topical steroids early in therapy or to replace them altogether,” she told this news organization.

Dermavant Sciences, manufacturer of tapinarof, anticipates filing for Food and Drug Administration approval for AD in the first quarter of 2024, according to a company statement.

Dr. Silverberg and Dr. Simpson reported financial relationships with multiple pharmaceutical companies, including Dermavant, which provided funding for the ADORING trials. Dr. Hebert has financial relationship with more than 15 pharmaceutical companies, including Dermavent and other companies that have or are developing therapies for AD. Dr. Ständer reported financial relationships with Beiersdorf, Eli Lilly, Galderma, Kiniksa, Pfizer, and Sanofi.

BERLIN – Tapinarof cream is highly effective, safe, and well tolerated for the treatment of atopic dermatitis (AD) in adults as well as children as young as 2 years of age, according to results of two pivotal trials presented at the at the annual congress of the European Academy of Dermatology and Venereology.

If approved for AD, one advantage of tapinarof cream relative to topical corticosteroids is potential use “without restrictions on duration, extent, or site of application,” reported Jonathan I. Silverberg, MD, PhD, MPH, director of clinical research, George Washington University, Washington.

Tapinarof cream, 1%, an aryl hydrocarbon receptor agonist, was approved in 2022 for treating plaque psoriasis in adults.

In the two phase 3 trials, ADORING 1 and ADORING 2, which were presented together at the meeting, the primary endpoint was Validated Investigator Global Assessment (vIGA) for AD of 0 (clear) or 1 (almost clear) at 8 weeks. For this endpoint and all secondary endpoints, the relative advantage of the active cream over the vehicle alone was about the same in both studies.

For example, the vIGA clear or almost clear response was met by 45.4% and 46.4% of those in the experimental arm of ADORING 1 and 2, respectively, but only 13.9% and 18.0% in the control arms (P < .0001 for both).

For the secondary endpoint of Eczema Area and Severity Index (EASI75), signifying 75% clearance of skin lesions, the response rates were 55.8% and 59.1% in the two trials, but only 22.9% and 24.1% in the respective control arms (P < .0001 for both).

The two identically designed trials randomized patients with moderate to severe AD in a 2:1 ratio to tapinarof cream or vehicle alone. There were 407 patients ages 2-81 years in ADORING I and 406 in ADORING 2. Patients were instructed to apply the active cream or vehicle once per day.

The safety data for tapinarof in these studies was generally consistent with the experience with this agent in plaque psoriasis. According to Dr. Silverberg, there was a modest increase in reports of headache early in this study, but these were transient. Follicular events were also more common on tapinarof than on its vehicle, but Dr. Silverberg said that the rate of discontinuations for adverse events, although low in both arms, was numerically lower in the active treatment arm in both trials.

“There were reports of contact dermatitis in the psoriasis studies, but we have not seen this in the AD trials,” Dr. Silverberg said.
 

Itch control evaluated

In a separate presentation of ADORING 1 and 2 results, Eric Simpson, MD, professor of dermatology, Oregon Health & Science University, Portland, provided detailed information about itch control, which was evaluated with the Peak Pruritus–Numerical Rating Scale (PP-NRS).

Ted Bosworth/MDedge News

“The PP-NRS considers a person’s worst itch over the past 24 hours based on an 11-point scale,” explained Dr. Simpson, who said that patients scored itch daily with comparisons made at weeks 1, 2, 4, and 8.

Over time, pruritus scores fell in both groups, but reductions were far steeper among those in the active treatment arms.

“In ADORING 1, there were greater reductions in itch as early as day 1,” Dr. Simpson reported. Although the differences in itch were not detected until day 2 in ADORING 2, the differences were already significant and clinically meaningful in both studies by the end of the first week.

By week 8, the mean reductions in PP-NRS scores were 2.6 and 2.4 in the vehicle arms of ADORING 1 and 2, respectively. In the treatment arm, the reduction was 4.1 points in both arms (P < .0001 for both studies).
 

Forty-eight–week follow-up planned

More than 90% of patients in both studies have rolled over into the open-label extension ADORING 3 trial, with a planned follow-up of 48 weeks, according to Dr. Silverberg, who said that those in the placebo arm have been crossed over to tapinarof.

The response and the safety appear to be similar in adults and children, although Dr. Silverberg said that further analyses of outcomes by age are planned. He noted that there is also an ongoing study of tapinarof in children with plaque psoriasis.

In AD in particular, Dr. Silverberg said there is “an unmet need” for a topical nonsteroidal anti-inflammatory. While topical corticosteroids are a mainstay of AD therapy in children as well as adults, he noted the limitations of these drugs, including that they can only be applied for limited periods.

Tapinarof binds to the aryl hydrocarbon receptor (AhR), which regulates immune function in the skin and is expressed in many skin cell types. By inhibiting AhR, tapinarof blocks cytokine activation and has an antioxidant effect.

Adelaide A. Hebert, MD, professor and director of pediatric dermatology, McGovern Medical School at UTHealth, Houston, has participated in clinical studies of tapinarof for AD, and said she has been impressed with its efficacy and tolerability in children as well as adults. In the case of children, parents, as well as patients, “valued the rapid onset of disease control, the once-daily application regimen, and the itch control,” she said in an interview after the meeting.

If approved, Dr. Hebert said, “this novel steroid-free medication has the potential to change the management arena for pediatric and adult patients with moderate to severe atopic dermatitis.”

The recent introduction of new systemic therapies for AD, such as JAK inhibitors, has increased options for AD control, but “we still need effective and safe topical therapies, especially in children and young adults,” said Sonja Ständer, MD, head of the Interdisciplinary Center for Chronic Pruritus, University of Münster (Germany). Author of a comprehensive review article on AD in the New England Journal of Medicine 2 years ago, Dr. Ständer said results from the phase 3 topical tapinarof trials, as well as the phase 3 topical ruxolitinib trials, which were also presented as late breakers at the 2023 EADV meeting, provide “hope that an alternative to topical steroids will soon be available.”

Based on their safety and rapid control of itch in children with AD, “these will complement our current portfolio of topical therapies very well and have the potential to replace topical steroids early in therapy or to replace them altogether,” she told this news organization.

Dermavant Sciences, manufacturer of tapinarof, anticipates filing for Food and Drug Administration approval for AD in the first quarter of 2024, according to a company statement.

Dr. Silverberg and Dr. Simpson reported financial relationships with multiple pharmaceutical companies, including Dermavant, which provided funding for the ADORING trials. Dr. Hebert has financial relationship with more than 15 pharmaceutical companies, including Dermavent and other companies that have or are developing therapies for AD. Dr. Ständer reported financial relationships with Beiersdorf, Eli Lilly, Galderma, Kiniksa, Pfizer, and Sanofi.

BERLIN – In separate trials conducted in patients with hidradenitis suppurativa (HS), two biologics that inhibit the activity of interleukin-17A (IL-17A) and IL-17F were associated with highly encouraging rates of control.

One of the trials evaluated a nanobody inhibitor, sonelokimab, a molecule with a substantially smaller size than traditional monoclonal antibodies (40 kilodaltons vs. 150 kilodaltons). After 24 weeks of treatment, the most effective of the two study doses almost doubled the proportion of patients with complete resolution of draining tunnels (41.1% vs. 23.8%; P < .05) relative to placebo.

“I think the size of sonelokimab is important,” Brian Kirby, MD, a consultant dermatologist at St. Vincent’s Hospital, Dublin, said at the annual congress of the European Academy of Dermatology and Venereology. “We think the smaller size results in better penetration of inflamed tissue,” he added, noting that penetration of abscesses, fistulae, and tunnels has been recognized in the past as a potential weakness of the larger monoclonal antibodies.

Ted Bosworth/MDedge News

The other set of anti-17-A/F set of data were generated by a pooled 48-week maintenance from the BE HEARD I and II trials with bimekizumab. The 16-week data from these two trials were presented at the annual meeting of the American Academy of Dermatology earlier this year.
 

IL-17A/F trials

Both the 16-week phase 2 data with sonelokimab and the 48-week pooled phase 3 maintenance data with bimekizumab were presented as late-breakers at the EADV Congress.

In the sonelokimab trial, called MIRA, 234 adults with HS were randomized in a 2:2:2:1 ratio to one of the two experimental arms, placebo, or a reference arm with the tumor necrosis factor (TNF) inhibitor adalimumab. Nearly 64% had Hurley stage II HS.

The primary endpoint was a 75% or greater reduction in total abscesses and nodules with no increase in draining tunnel count (HiSCR75) from baseline. Dr. Kirby said that this is more rigorous than the HiSCR50 endpoint more commonly used in HS clinical trials. Treatments were administered every 2 weeks for the first 8 weeks of a planned follow-up of 24 weeks and then every 4 weeks thereafter.

At 16 weeks, according to the data Dr. Kirby presented, both doses of sonelokimab were more active than placebo, but Dr. Kirby reported that the lower dose performed better for most objective endpoints.

For example, the HiSCR75 was reached by 43.3% of those randomized to the 120-mg dose (P < .001 vs. placebo), 34.8% of those randomized to the 240-mg dose (P <.01), and 14.7% of those randomized to placebo.

For HiSCR50, response rates were 65.7%, 53.0%, and 27.9%, for the 120-mg, 240-mg, and placebo arms, respectively. Again, both the lower dose (P < .001) and the higher dose (P < .01) were significantly superior to placebo.

On the International Hidradenitis Suppurativa Severity Score System (IHS4), which counts nodules and abscesses, score reductions were 19.3, 14.5, and 7.9 for the lower dose, higher dose, and placebo, respectively, with a greater statistical advantage for the lower relative to the higher dose over placebo (P <.001 vs. P <.01).

However, patient-focused outcomes were not necessarily greater for the lower dose. For the patient-completed measure, the Numerical Rating Scale 50% reduction in skin pain (NRS50), the proportion of patients responding at 12 weeks was numerically greater for the 240-mg dose (41.3%) than with the 120-mg dose (32.0%), although both reached the same statistical advantage (P < .001) over the 4.3% who reached this level of response on placebo.

For the Dermatology Life Quality Index (DLQI) and the Patient Global Impression of Severity (PGI-S), improvements from baseline were similar for the lower and higher dose, although there was a modest numerical and statistical advantage for the higher dose over placebo (P < .001 vs. P <.01).

The HiSCR50 (57.6%) and HiSCR75 (36.4%) responses were both lower for those randomized to the TNF inhibitor adalimumab relative to sonelokimab, but the smaller number of patients in this arm prohibited a statistical comparison.

Although oral candidiasis was more common among patients receiving either dose of sonelokimab than placebo, these were of mild to moderate severity. Dr. Kirby said that there were no unexpected safety issues, and sonelokimab was generally well tolerated.

The results are encouraging, but Dr. Kirby acknowledged that data are now needed to confirm that resolution of tunnels and fistulae is greater with a nanobody inhibitor of IL-17A/F than other targeted therapies. Even if this is validated, he said studies are needed to prove that the small relative molecule size is the reason behind the benefits.
 

Forty-eight–week bimekizumab data

From the pooled BE HEARD I and BE HEARD II maintenance data, the major message is that the robust responses observed at 16 weeks versus placebo were maintained at 48 weeks. More than 75% of patients retained a HiSCR50 response and more than 55% achieved a HiSCR75 response at the 48-week follow-up. The durable response was also reflected in other measures, according to Christos C. Zouboulis, MD, PhD, director of the department of dermatology, Brandenburg Medical School, Neuruppin, Germany.

“Improvements in disease severity were seen over time,” Dr. Zouboulis reported. “The majority of patients with severe HS at baseline shifted to mild to moderate disease according to the IHS4 classification.”

To the degree that both sonelokimab and bimekizumab target IL-17A/F, these data are mutually reinforcing. Dr. Kirby said that there is a sizable body of data implicating IL-17A/F in driving HS, and the activity of inhibitors in support the clinical value of IL-17A/F suppression.

On Oct. 18, shortly after the EADV meeting concluded, the Food and Drug Administration approved bimekizumab for treating moderate to severe plaque psoriasis, the first approved indication in the United States. In the European Union, it was approved for psoriasis in 2021, and for psoriatic arthritis and ankylosing spondylitis in June 2023.

Dr. Kirby has financial relationships with more than 10 pharmaceutical companies, including MoonLake, which is developing sonelokimab and sponsored the MIRA trial. Dr. Christos, president of the European HS Foundation, has financial relationships with multiple pharmaceutical companies, including UCB, which makes bimekizumab and provided funding for the BE HEARD I and II trials.

BERLIN – In separate trials conducted in patients with hidradenitis suppurativa (HS), two biologics that inhibit the activity of interleukin-17A (IL-17A) and IL-17F were associated with highly encouraging rates of control.

One of the trials evaluated a nanobody inhibitor, sonelokimab, a molecule with a substantially smaller size than traditional monoclonal antibodies (40 kilodaltons vs. 150 kilodaltons). After 24 weeks of treatment, the most effective of the two study doses almost doubled the proportion of patients with complete resolution of draining tunnels (41.1% vs. 23.8%; P < .05) relative to placebo.

“I think the size of sonelokimab is important,” Brian Kirby, MD, a consultant dermatologist at St. Vincent’s Hospital, Dublin, said at the annual congress of the European Academy of Dermatology and Venereology. “We think the smaller size results in better penetration of inflamed tissue,” he added, noting that penetration of abscesses, fistulae, and tunnels has been recognized in the past as a potential weakness of the larger monoclonal antibodies.

Ted Bosworth/MDedge News

The other set of anti-17-A/F set of data were generated by a pooled 48-week maintenance from the BE HEARD I and II trials with bimekizumab. The 16-week data from these two trials were presented at the annual meeting of the American Academy of Dermatology earlier this year.
 

IL-17A/F trials

Both the 16-week phase 2 data with sonelokimab and the 48-week pooled phase 3 maintenance data with bimekizumab were presented as late-breakers at the EADV Congress.

In the sonelokimab trial, called MIRA, 234 adults with HS were randomized in a 2:2:2:1 ratio to one of the two experimental arms, placebo, or a reference arm with the tumor necrosis factor (TNF) inhibitor adalimumab. Nearly 64% had Hurley stage II HS.

The primary endpoint was a 75% or greater reduction in total abscesses and nodules with no increase in draining tunnel count (HiSCR75) from baseline. Dr. Kirby said that this is more rigorous than the HiSCR50 endpoint more commonly used in HS clinical trials. Treatments were administered every 2 weeks for the first 8 weeks of a planned follow-up of 24 weeks and then every 4 weeks thereafter.

At 16 weeks, according to the data Dr. Kirby presented, both doses of sonelokimab were more active than placebo, but Dr. Kirby reported that the lower dose performed better for most objective endpoints.

For example, the HiSCR75 was reached by 43.3% of those randomized to the 120-mg dose (P < .001 vs. placebo), 34.8% of those randomized to the 240-mg dose (P <.01), and 14.7% of those randomized to placebo.

For HiSCR50, response rates were 65.7%, 53.0%, and 27.9%, for the 120-mg, 240-mg, and placebo arms, respectively. Again, both the lower dose (P < .001) and the higher dose (P < .01) were significantly superior to placebo.

On the International Hidradenitis Suppurativa Severity Score System (IHS4), which counts nodules and abscesses, score reductions were 19.3, 14.5, and 7.9 for the lower dose, higher dose, and placebo, respectively, with a greater statistical advantage for the lower relative to the higher dose over placebo (P <.001 vs. P <.01).

However, patient-focused outcomes were not necessarily greater for the lower dose. For the patient-completed measure, the Numerical Rating Scale 50% reduction in skin pain (NRS50), the proportion of patients responding at 12 weeks was numerically greater for the 240-mg dose (41.3%) than with the 120-mg dose (32.0%), although both reached the same statistical advantage (P < .001) over the 4.3% who reached this level of response on placebo.

For the Dermatology Life Quality Index (DLQI) and the Patient Global Impression of Severity (PGI-S), improvements from baseline were similar for the lower and higher dose, although there was a modest numerical and statistical advantage for the higher dose over placebo (P < .001 vs. P <.01).

The HiSCR50 (57.6%) and HiSCR75 (36.4%) responses were both lower for those randomized to the TNF inhibitor adalimumab relative to sonelokimab, but the smaller number of patients in this arm prohibited a statistical comparison.

Although oral candidiasis was more common among patients receiving either dose of sonelokimab than placebo, these were of mild to moderate severity. Dr. Kirby said that there were no unexpected safety issues, and sonelokimab was generally well tolerated.

The results are encouraging, but Dr. Kirby acknowledged that data are now needed to confirm that resolution of tunnels and fistulae is greater with a nanobody inhibitor of IL-17A/F than other targeted therapies. Even if this is validated, he said studies are needed to prove that the small relative molecule size is the reason behind the benefits.
 

Forty-eight–week bimekizumab data

From the pooled BE HEARD I and BE HEARD II maintenance data, the major message is that the robust responses observed at 16 weeks versus placebo were maintained at 48 weeks. More than 75% of patients retained a HiSCR50 response and more than 55% achieved a HiSCR75 response at the 48-week follow-up. The durable response was also reflected in other measures, according to Christos C. Zouboulis, MD, PhD, director of the department of dermatology, Brandenburg Medical School, Neuruppin, Germany.

“Improvements in disease severity were seen over time,” Dr. Zouboulis reported. “The majority of patients with severe HS at baseline shifted to mild to moderate disease according to the IHS4 classification.”

To the degree that both sonelokimab and bimekizumab target IL-17A/F, these data are mutually reinforcing. Dr. Kirby said that there is a sizable body of data implicating IL-17A/F in driving HS, and the activity of inhibitors in support the clinical value of IL-17A/F suppression.

On Oct. 18, shortly after the EADV meeting concluded, the Food and Drug Administration approved bimekizumab for treating moderate to severe plaque psoriasis, the first approved indication in the United States. In the European Union, it was approved for psoriasis in 2021, and for psoriatic arthritis and ankylosing spondylitis in June 2023.

Dr. Kirby has financial relationships with more than 10 pharmaceutical companies, including MoonLake, which is developing sonelokimab and sponsored the MIRA trial. Dr. Christos, president of the European HS Foundation, has financial relationships with multiple pharmaceutical companies, including UCB, which makes bimekizumab and provided funding for the BE HEARD I and II trials.

BERLIN – In separate trials conducted in patients with hidradenitis suppurativa (HS), two biologics that inhibit the activity of interleukin-17A (IL-17A) and IL-17F were associated with highly encouraging rates of control.

One of the trials evaluated a nanobody inhibitor, sonelokimab, a molecule with a substantially smaller size than traditional monoclonal antibodies (40 kilodaltons vs. 150 kilodaltons). After 24 weeks of treatment, the most effective of the two study doses almost doubled the proportion of patients with complete resolution of draining tunnels (41.1% vs. 23.8%; P < .05) relative to placebo.

“I think the size of sonelokimab is important,” Brian Kirby, MD, a consultant dermatologist at St. Vincent’s Hospital, Dublin, said at the annual congress of the European Academy of Dermatology and Venereology. “We think the smaller size results in better penetration of inflamed tissue,” he added, noting that penetration of abscesses, fistulae, and tunnels has been recognized in the past as a potential weakness of the larger monoclonal antibodies.

Ted Bosworth/MDedge News

The other set of anti-17-A/F set of data were generated by a pooled 48-week maintenance from the BE HEARD I and II trials with bimekizumab. The 16-week data from these two trials were presented at the annual meeting of the American Academy of Dermatology earlier this year.
 

IL-17A/F trials

Both the 16-week phase 2 data with sonelokimab and the 48-week pooled phase 3 maintenance data with bimekizumab were presented as late-breakers at the EADV Congress.

In the sonelokimab trial, called MIRA, 234 adults with HS were randomized in a 2:2:2:1 ratio to one of the two experimental arms, placebo, or a reference arm with the tumor necrosis factor (TNF) inhibitor adalimumab. Nearly 64% had Hurley stage II HS.

The primary endpoint was a 75% or greater reduction in total abscesses and nodules with no increase in draining tunnel count (HiSCR75) from baseline. Dr. Kirby said that this is more rigorous than the HiSCR50 endpoint more commonly used in HS clinical trials. Treatments were administered every 2 weeks for the first 8 weeks of a planned follow-up of 24 weeks and then every 4 weeks thereafter.

At 16 weeks, according to the data Dr. Kirby presented, both doses of sonelokimab were more active than placebo, but Dr. Kirby reported that the lower dose performed better for most objective endpoints.

For example, the HiSCR75 was reached by 43.3% of those randomized to the 120-mg dose (P < .001 vs. placebo), 34.8% of those randomized to the 240-mg dose (P <.01), and 14.7% of those randomized to placebo.

For HiSCR50, response rates were 65.7%, 53.0%, and 27.9%, for the 120-mg, 240-mg, and placebo arms, respectively. Again, both the lower dose (P < .001) and the higher dose (P < .01) were significantly superior to placebo.

On the International Hidradenitis Suppurativa Severity Score System (IHS4), which counts nodules and abscesses, score reductions were 19.3, 14.5, and 7.9 for the lower dose, higher dose, and placebo, respectively, with a greater statistical advantage for the lower relative to the higher dose over placebo (P <.001 vs. P <.01).

However, patient-focused outcomes were not necessarily greater for the lower dose. For the patient-completed measure, the Numerical Rating Scale 50% reduction in skin pain (NRS50), the proportion of patients responding at 12 weeks was numerically greater for the 240-mg dose (41.3%) than with the 120-mg dose (32.0%), although both reached the same statistical advantage (P < .001) over the 4.3% who reached this level of response on placebo.

For the Dermatology Life Quality Index (DLQI) and the Patient Global Impression of Severity (PGI-S), improvements from baseline were similar for the lower and higher dose, although there was a modest numerical and statistical advantage for the higher dose over placebo (P < .001 vs. P <.01).

The HiSCR50 (57.6%) and HiSCR75 (36.4%) responses were both lower for those randomized to the TNF inhibitor adalimumab relative to sonelokimab, but the smaller number of patients in this arm prohibited a statistical comparison.

Although oral candidiasis was more common among patients receiving either dose of sonelokimab than placebo, these were of mild to moderate severity. Dr. Kirby said that there were no unexpected safety issues, and sonelokimab was generally well tolerated.

The results are encouraging, but Dr. Kirby acknowledged that data are now needed to confirm that resolution of tunnels and fistulae is greater with a nanobody inhibitor of IL-17A/F than other targeted therapies. Even if this is validated, he said studies are needed to prove that the small relative molecule size is the reason behind the benefits.
 

Forty-eight–week bimekizumab data

From the pooled BE HEARD I and BE HEARD II maintenance data, the major message is that the robust responses observed at 16 weeks versus placebo were maintained at 48 weeks. More than 75% of patients retained a HiSCR50 response and more than 55% achieved a HiSCR75 response at the 48-week follow-up. The durable response was also reflected in other measures, according to Christos C. Zouboulis, MD, PhD, director of the department of dermatology, Brandenburg Medical School, Neuruppin, Germany.

“Improvements in disease severity were seen over time,” Dr. Zouboulis reported. “The majority of patients with severe HS at baseline shifted to mild to moderate disease according to the IHS4 classification.”

To the degree that both sonelokimab and bimekizumab target IL-17A/F, these data are mutually reinforcing. Dr. Kirby said that there is a sizable body of data implicating IL-17A/F in driving HS, and the activity of inhibitors in support the clinical value of IL-17A/F suppression.

On Oct. 18, shortly after the EADV meeting concluded, the Food and Drug Administration approved bimekizumab for treating moderate to severe plaque psoriasis, the first approved indication in the United States. In the European Union, it was approved for psoriasis in 2021, and for psoriatic arthritis and ankylosing spondylitis in June 2023.

Dr. Kirby has financial relationships with more than 10 pharmaceutical companies, including MoonLake, which is developing sonelokimab and sponsored the MIRA trial. Dr. Christos, president of the European HS Foundation, has financial relationships with multiple pharmaceutical companies, including UCB, which makes bimekizumab and provided funding for the BE HEARD I and II trials.