Ted Bosworth

AMSTERDAM — A proteomics study designed to determine why some patients with atopic dermatitis (AD) respond quickly to dupilumab, others respond more slowly, and the remainder do not respond at all demonstrated that molecular responses in these three groups are very different.

A discovery that could lead to personalizing therapies, the data identified “distinct systemic biomarker profiles,” according to Ester Del Duca, MD, an instructor in the Laboratory of Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai, New York City.

The study was conducted with 67 patients with AD and 16 healthy controls. Serum was collected at two timepoints: An average of 20 weeks after starting dupilumab, then at a mean interval of about 9 months later. At these timepoints, called follow-up 1 and 2, a panel of more than 600 proteins, including unique markers for immunologic, cardiovascular, and neurologic activity, were evaluated.

The criterion for differentiating the three response groups was an Investigator Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (or at least a 2-point IGA reduction from baseline). Early responders were those who met the criterion at both follow-ups, late responders were those who met this criterion only at the second follow-up, and nonresponders never met the criterion.

“There were no significant differences at baseline in clinical severity, past medical history, or patient characteristics,” said Del Duca, who presented these data in a late breaking news session at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.

Of the 67 patients with AD, 39 were early responders, 11 were late responders, and 17 were nonresponders.

The differences in proteomics were marked. For early responders, there was an early normalization of the proteome, reported Del Duca, illustrating the differences in the proteome of the three groups with a color-coded chart of protein up-regulation and down-regulation relative to healthy controls. The normalization of the proteome persisted in early responders when assessed at the second follow-up.

In the late responders, the proteome dysregulation was substantial relative to healthy controls at the first follow-up, but there was considerable improvement by the second follow-up. Although the change at the second follow-up was still not as robust as that seen in the early responders at either follow-up, Del Duca described the proteomic profile as a 45% improvement from the first follow-up.

In contrast, nonresponders showed worsening in their blood proteome from follow-up 1 to 2. Nonresponders at first follow-up showed up-regulation relative to healthy controls for many proteins associated with the Th1 response, such as interferon gamma, CXCL9, and CXCL10, and Th2 response, such as interleukin-4 and Th17/22, and these did not normalize or worsen by the second follow-up.

“Uniquely to nonresponders, key Th1 biomarkers remained significantly up-regulated relative to controls at both follow-up 1 and 2,” with a P value < .05, Del Duca reported.

To achieve normalization of the proteome as defined by healthy controls, both up-regulation and down-regulation of protein activity were required, although more up-regulations than down-regulations were observed.

When evaluating the proteome changes most implicated in immunoregulation, the investigators were able to show a correlation between worsening in the proteome and greater severity of AD as defined by IGA, Eczema Area and Severity Index, and body surface area involvement.

“Spearman analysis revealed strong and positive correlations between improvements in biomarkers at follow-up 1 and 2 with improvements in clinical markers,” Del Duca said. As examples, she noted favorable changes in biomarkers specifically associated with T cells, dendritic cells, and natural killer cells as clinical outcomes improved.

Conversely, the worsening in T-cell activation among nonresponders, particularly Th1 biomarkers, also tracked with increasing AD symptoms over time.

The implications of the research are broad, and most importantly, it shows that therapeutic targets are likely to differ between patients with AD, according to Del Duca. Although proteomic studies have not yet been conducted with other treatments, these might provide further insight about how patients with AD differ in response across other drugs.

This is important work, according to Brigitte Dréno, MD, PhD, head of the Department of Dermatology, Nantes University Hospital in France. As moderator of the late-breaking news session, she suggested that there are many potential messages from these data, not least that treatment of AD likely involves targeting cytokines beyond those affected by dupilumab in at least some patients.

When Dréno asked Del Duca about what could be surmised about changes from baseline before treatment to the first follow-up, Del Duca said that the study was retrospective, so baseline data were not available.

This is an important missing piece of this investigation, according to Dréno.

“As you move this work forward,” she said that it would be “very important” to determine “if there are predictive markers for evaluating which patients will respond.”

This is a small study with many additional variables to consider in order to develop a clinically useful tool, Del Duca noted. However, this work not only has the potential to guide treatment selection but the biomarkers up-regulated in nonresponders are already “suggesting potential targets for refining therapeutic strategies,” she said.

The study received funding from Bristol-Myers Squibb. Del Duca reported no financial relationships with industry. Dréno reported financial relationships with La Roche–Posay, Pierre Fabré, and Galderma.

A version of this article appeared on Medscape.com.

AMSTERDAM — A proteomics study designed to determine why some patients with atopic dermatitis (AD) respond quickly to dupilumab, others respond more slowly, and the remainder do not respond at all demonstrated that molecular responses in these three groups are very different.

A discovery that could lead to personalizing therapies, the data identified “distinct systemic biomarker profiles,” according to Ester Del Duca, MD, an instructor in the Laboratory of Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai, New York City.

The study was conducted with 67 patients with AD and 16 healthy controls. Serum was collected at two timepoints: An average of 20 weeks after starting dupilumab, then at a mean interval of about 9 months later. At these timepoints, called follow-up 1 and 2, a panel of more than 600 proteins, including unique markers for immunologic, cardiovascular, and neurologic activity, were evaluated.

The criterion for differentiating the three response groups was an Investigator Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (or at least a 2-point IGA reduction from baseline). Early responders were those who met the criterion at both follow-ups, late responders were those who met this criterion only at the second follow-up, and nonresponders never met the criterion.

“There were no significant differences at baseline in clinical severity, past medical history, or patient characteristics,” said Del Duca, who presented these data in a late breaking news session at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.

Of the 67 patients with AD, 39 were early responders, 11 were late responders, and 17 were nonresponders.

The differences in proteomics were marked. For early responders, there was an early normalization of the proteome, reported Del Duca, illustrating the differences in the proteome of the three groups with a color-coded chart of protein up-regulation and down-regulation relative to healthy controls. The normalization of the proteome persisted in early responders when assessed at the second follow-up.

In the late responders, the proteome dysregulation was substantial relative to healthy controls at the first follow-up, but there was considerable improvement by the second follow-up. Although the change at the second follow-up was still not as robust as that seen in the early responders at either follow-up, Del Duca described the proteomic profile as a 45% improvement from the first follow-up.

In contrast, nonresponders showed worsening in their blood proteome from follow-up 1 to 2. Nonresponders at first follow-up showed up-regulation relative to healthy controls for many proteins associated with the Th1 response, such as interferon gamma, CXCL9, and CXCL10, and Th2 response, such as interleukin-4 and Th17/22, and these did not normalize or worsen by the second follow-up.

“Uniquely to nonresponders, key Th1 biomarkers remained significantly up-regulated relative to controls at both follow-up 1 and 2,” with a P value < .05, Del Duca reported.

To achieve normalization of the proteome as defined by healthy controls, both up-regulation and down-regulation of protein activity were required, although more up-regulations than down-regulations were observed.

When evaluating the proteome changes most implicated in immunoregulation, the investigators were able to show a correlation between worsening in the proteome and greater severity of AD as defined by IGA, Eczema Area and Severity Index, and body surface area involvement.

“Spearman analysis revealed strong and positive correlations between improvements in biomarkers at follow-up 1 and 2 with improvements in clinical markers,” Del Duca said. As examples, she noted favorable changes in biomarkers specifically associated with T cells, dendritic cells, and natural killer cells as clinical outcomes improved.

Conversely, the worsening in T-cell activation among nonresponders, particularly Th1 biomarkers, also tracked with increasing AD symptoms over time.

The implications of the research are broad, and most importantly, it shows that therapeutic targets are likely to differ between patients with AD, according to Del Duca. Although proteomic studies have not yet been conducted with other treatments, these might provide further insight about how patients with AD differ in response across other drugs.

This is important work, according to Brigitte Dréno, MD, PhD, head of the Department of Dermatology, Nantes University Hospital in France. As moderator of the late-breaking news session, she suggested that there are many potential messages from these data, not least that treatment of AD likely involves targeting cytokines beyond those affected by dupilumab in at least some patients.

When Dréno asked Del Duca about what could be surmised about changes from baseline before treatment to the first follow-up, Del Duca said that the study was retrospective, so baseline data were not available.

This is an important missing piece of this investigation, according to Dréno.

“As you move this work forward,” she said that it would be “very important” to determine “if there are predictive markers for evaluating which patients will respond.”

This is a small study with many additional variables to consider in order to develop a clinically useful tool, Del Duca noted. However, this work not only has the potential to guide treatment selection but the biomarkers up-regulated in nonresponders are already “suggesting potential targets for refining therapeutic strategies,” she said.

The study received funding from Bristol-Myers Squibb. Del Duca reported no financial relationships with industry. Dréno reported financial relationships with La Roche–Posay, Pierre Fabré, and Galderma.

A version of this article appeared on Medscape.com.

AMSTERDAM — A proteomics study designed to determine why some patients with atopic dermatitis (AD) respond quickly to dupilumab, others respond more slowly, and the remainder do not respond at all demonstrated that molecular responses in these three groups are very different.

A discovery that could lead to personalizing therapies, the data identified “distinct systemic biomarker profiles,” according to Ester Del Duca, MD, an instructor in the Laboratory of Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai, New York City.

The study was conducted with 67 patients with AD and 16 healthy controls. Serum was collected at two timepoints: An average of 20 weeks after starting dupilumab, then at a mean interval of about 9 months later. At these timepoints, called follow-up 1 and 2, a panel of more than 600 proteins, including unique markers for immunologic, cardiovascular, and neurologic activity, were evaluated.

The criterion for differentiating the three response groups was an Investigator Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (or at least a 2-point IGA reduction from baseline). Early responders were those who met the criterion at both follow-ups, late responders were those who met this criterion only at the second follow-up, and nonresponders never met the criterion.

“There were no significant differences at baseline in clinical severity, past medical history, or patient characteristics,” said Del Duca, who presented these data in a late breaking news session at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.

Of the 67 patients with AD, 39 were early responders, 11 were late responders, and 17 were nonresponders.

The differences in proteomics were marked. For early responders, there was an early normalization of the proteome, reported Del Duca, illustrating the differences in the proteome of the three groups with a color-coded chart of protein up-regulation and down-regulation relative to healthy controls. The normalization of the proteome persisted in early responders when assessed at the second follow-up.

In the late responders, the proteome dysregulation was substantial relative to healthy controls at the first follow-up, but there was considerable improvement by the second follow-up. Although the change at the second follow-up was still not as robust as that seen in the early responders at either follow-up, Del Duca described the proteomic profile as a 45% improvement from the first follow-up.

In contrast, nonresponders showed worsening in their blood proteome from follow-up 1 to 2. Nonresponders at first follow-up showed up-regulation relative to healthy controls for many proteins associated with the Th1 response, such as interferon gamma, CXCL9, and CXCL10, and Th2 response, such as interleukin-4 and Th17/22, and these did not normalize or worsen by the second follow-up.

“Uniquely to nonresponders, key Th1 biomarkers remained significantly up-regulated relative to controls at both follow-up 1 and 2,” with a P value < .05, Del Duca reported.

To achieve normalization of the proteome as defined by healthy controls, both up-regulation and down-regulation of protein activity were required, although more up-regulations than down-regulations were observed.

When evaluating the proteome changes most implicated in immunoregulation, the investigators were able to show a correlation between worsening in the proteome and greater severity of AD as defined by IGA, Eczema Area and Severity Index, and body surface area involvement.

“Spearman analysis revealed strong and positive correlations between improvements in biomarkers at follow-up 1 and 2 with improvements in clinical markers,” Del Duca said. As examples, she noted favorable changes in biomarkers specifically associated with T cells, dendritic cells, and natural killer cells as clinical outcomes improved.

Conversely, the worsening in T-cell activation among nonresponders, particularly Th1 biomarkers, also tracked with increasing AD symptoms over time.

The implications of the research are broad, and most importantly, it shows that therapeutic targets are likely to differ between patients with AD, according to Del Duca. Although proteomic studies have not yet been conducted with other treatments, these might provide further insight about how patients with AD differ in response across other drugs.

This is important work, according to Brigitte Dréno, MD, PhD, head of the Department of Dermatology, Nantes University Hospital in France. As moderator of the late-breaking news session, she suggested that there are many potential messages from these data, not least that treatment of AD likely involves targeting cytokines beyond those affected by dupilumab in at least some patients.

When Dréno asked Del Duca about what could be surmised about changes from baseline before treatment to the first follow-up, Del Duca said that the study was retrospective, so baseline data were not available.

This is an important missing piece of this investigation, according to Dréno.

“As you move this work forward,” she said that it would be “very important” to determine “if there are predictive markers for evaluating which patients will respond.”

This is a small study with many additional variables to consider in order to develop a clinically useful tool, Del Duca noted. However, this work not only has the potential to guide treatment selection but the biomarkers up-regulated in nonresponders are already “suggesting potential targets for refining therapeutic strategies,” she said.

The study received funding from Bristol-Myers Squibb. Del Duca reported no financial relationships with industry. Dréno reported financial relationships with La Roche–Posay, Pierre Fabré, and Galderma.

A version of this article appeared on Medscape.com.

AMSTERDAM — Following the report of results from a randomized trial in which a topically applied Janus kinase (JAK) inhibitor was highly active in patients with mild to moderate hidradenitis suppurativa (HS), an open-label extension showed that 16 more weeks of treatment on as-needed basis provided complete or near complete clearance of lesions in up to 38.5% of patients.

“Ruxolitinib cream may be a novel approach to address an unmet medical need in the treatment of milder HS for which there are no currently approved treatments,” reported Martina L. Porter, MD, assistant professor of dermatology, Harvard Medical School, and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.

In the earlier 16-week, double-blind, randomized period of this phase 2b study, 69 adults with mild to moderate HS were randomized to 1.5% ruxolitinib cream or vehicle, applied twice daily for 16 weeks. The new results are from the open-label extension period, where those on the vehicle were crossed over to topical ruxolitinib and treatment was continued for another 16 weeks.
 

Over 80% Meet Primary Endpoint at 32 Weeks

Entry criteria for the study included Hurley stage I or II HS with no draining tunnels. Hurley stage III patients were not eligible. Patients had to have an abscess or inflammatory nodule (AN) count of 3 lesions concentrated in a single anatomic area or up to 10 lesions if disseminated. The median AN count of those enrolled was 5.4. 

In the randomized portion of the study and in the open-label extension, the recommendation for application was to apply the medication to nodules and a 1-cm area of surrounding skin. As-needed treatment was only recommended in the extension portion of the study and rescue medication was not allowed.

The goal of the open-label extension was to evaluate how long the improvements were sustained, according to Dr. Porter, who presented the results at the 2024 European Academy of Dermatology and Venereology (EADV) meeting.

The primary endpoints of AN50, signaling at least a 50% reduction in AN count from baseline, among those initially randomized to ruxolitinib cream climbed slightly from 79.2% at the end of 16 weeks to 81.0% at the end of 32 weeks.

This shows that the benefits recorded in the randomized phase of the trial were sustained during the open-label extension, Dr. Porter said. 

For those randomized to vehicle, there was a substantial response of 56.3% for AN50 during the randomized portion of the study, but catchup in the vehicle group to those on active therapy occurred rapidly over the open-label extension. By the end of 32 weeks, the score among the crossover patients slightly exceeded that of those on continuous therapy (88.5% vs 81.0%).

AN75 responses at week 32 were 66.7% and 61.5% in the continuous arm and crossover arm, respectively. The proportion of patients reaching an AN90 or AN100 response, meaning clear or almost clear, were 19% and 38.5%, in continuous treatment and crossover arms, respectively.

One of the secondary endpoints was the HS Clinical Response 50, indicating at least a 50% reduction in the AN count with no increase in abscesses or draining fistulae. At 32 weeks, the proportions of patients who met this endpoint were 81.0% and 88.5% in the continuous treatment and crossover arms, respectively. 

The mean reduction in International HS Severity Scoring System scores from baseline were 4.1 and 4.5 in the continuous treatment and crossover arms, respectively. 
 

Patients in the Study Mostly Women, 42% Black Individuals

Most (94%) of the participants were women; about 45% and 42% were White and Black individuals, respectively. Most of the remaining patients were Asian individuals. The median age at entry was 29 years, and the mean body mass index was approximately 34 kg/m². A substantial proportion of patients had systemic comorbidities, according to Dr. Porter, who noted that about 25% had anxiety, depression, or both.

“This phenotype — a high proportion of women with nodules but no draining tunnels and a substantial number of comorbidities — is one we often see in patients with mild HS,” Dr. Porter said.

The safety and tolerability profile of ruxolitinib cream was quite good, according to Dr. Porter, who noted that there were fewer treatment-related adverse events in the open-label extension. Overall, the number of treatment-related adverse events (3.6%), including application site reactions leading to discontinuation (1.8%) was low. 

Although there is a growing list of therapies now approved for HS, Dr. Porter emphasized that all have been developed for moderate to severe disease. She suggested that there is a sizable group of patients with mild disease for whom such therapies as biologics might not be warranted even if symptom relief is needed.

Given this unmet need, she said phase 3 trials are warranted to confirm the benefits and the safety of a topical therapy that can be used as needed to control intermittent HS flares.

Asked to comment, the lead author of a recently published review article on the “evolving treatment landscape” of HS, James G. Krueger, MD, professor in clinical investigation at Rockefeller University, New York City, agreed that there is an unmet need for effective and safe therapies in milder HS.

“I agree with the premise,” said Dr. Krueger, indicating that phase 3 data will be essential to confirm the promise of this approach. Dr. Krueger, who did not hear the results presented at the EADV meeting, listed several JAK inhibitors in his review that have shown promising efficacy as oral agents and support JAK signaling as a target of HS treatment. 

Topical ruxolitinib (Opzelura) is currently approved in the United States for treating nonsegmental vitiligo in patients aged ≥ 12 years and for mild to moderate atopic dermatitis in patients aged ≥ 12 years. In Europe, it is approved for treatment of nonsegmental vitiligo with facial involvement in patients aged ≥ 12 years. 

Dr. Porter reported no potential conflicts of interest. Dr. Krueger reported financial relationships with more than 25 pharmaceutical companies not including Incyte, which is developing ruxolitinib cream.

A version of this article appeared on Medscape.com.

AMSTERDAM — Following the report of results from a randomized trial in which a topically applied Janus kinase (JAK) inhibitor was highly active in patients with mild to moderate hidradenitis suppurativa (HS), an open-label extension showed that 16 more weeks of treatment on as-needed basis provided complete or near complete clearance of lesions in up to 38.5% of patients.

“Ruxolitinib cream may be a novel approach to address an unmet medical need in the treatment of milder HS for which there are no currently approved treatments,” reported Martina L. Porter, MD, assistant professor of dermatology, Harvard Medical School, and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.

In the earlier 16-week, double-blind, randomized period of this phase 2b study, 69 adults with mild to moderate HS were randomized to 1.5% ruxolitinib cream or vehicle, applied twice daily for 16 weeks. The new results are from the open-label extension period, where those on the vehicle were crossed over to topical ruxolitinib and treatment was continued for another 16 weeks.
 

Over 80% Meet Primary Endpoint at 32 Weeks

Entry criteria for the study included Hurley stage I or II HS with no draining tunnels. Hurley stage III patients were not eligible. Patients had to have an abscess or inflammatory nodule (AN) count of 3 lesions concentrated in a single anatomic area or up to 10 lesions if disseminated. The median AN count of those enrolled was 5.4. 

In the randomized portion of the study and in the open-label extension, the recommendation for application was to apply the medication to nodules and a 1-cm area of surrounding skin. As-needed treatment was only recommended in the extension portion of the study and rescue medication was not allowed.

The goal of the open-label extension was to evaluate how long the improvements were sustained, according to Dr. Porter, who presented the results at the 2024 European Academy of Dermatology and Venereology (EADV) meeting.

The primary endpoints of AN50, signaling at least a 50% reduction in AN count from baseline, among those initially randomized to ruxolitinib cream climbed slightly from 79.2% at the end of 16 weeks to 81.0% at the end of 32 weeks.

This shows that the benefits recorded in the randomized phase of the trial were sustained during the open-label extension, Dr. Porter said. 

For those randomized to vehicle, there was a substantial response of 56.3% for AN50 during the randomized portion of the study, but catchup in the vehicle group to those on active therapy occurred rapidly over the open-label extension. By the end of 32 weeks, the score among the crossover patients slightly exceeded that of those on continuous therapy (88.5% vs 81.0%).

AN75 responses at week 32 were 66.7% and 61.5% in the continuous arm and crossover arm, respectively. The proportion of patients reaching an AN90 or AN100 response, meaning clear or almost clear, were 19% and 38.5%, in continuous treatment and crossover arms, respectively.

One of the secondary endpoints was the HS Clinical Response 50, indicating at least a 50% reduction in the AN count with no increase in abscesses or draining fistulae. At 32 weeks, the proportions of patients who met this endpoint were 81.0% and 88.5% in the continuous treatment and crossover arms, respectively. 

The mean reduction in International HS Severity Scoring System scores from baseline were 4.1 and 4.5 in the continuous treatment and crossover arms, respectively. 
 

Patients in the Study Mostly Women, 42% Black Individuals

Most (94%) of the participants were women; about 45% and 42% were White and Black individuals, respectively. Most of the remaining patients were Asian individuals. The median age at entry was 29 years, and the mean body mass index was approximately 34 kg/m². A substantial proportion of patients had systemic comorbidities, according to Dr. Porter, who noted that about 25% had anxiety, depression, or both.

“This phenotype — a high proportion of women with nodules but no draining tunnels and a substantial number of comorbidities — is one we often see in patients with mild HS,” Dr. Porter said.

The safety and tolerability profile of ruxolitinib cream was quite good, according to Dr. Porter, who noted that there were fewer treatment-related adverse events in the open-label extension. Overall, the number of treatment-related adverse events (3.6%), including application site reactions leading to discontinuation (1.8%) was low. 

Although there is a growing list of therapies now approved for HS, Dr. Porter emphasized that all have been developed for moderate to severe disease. She suggested that there is a sizable group of patients with mild disease for whom such therapies as biologics might not be warranted even if symptom relief is needed.

Given this unmet need, she said phase 3 trials are warranted to confirm the benefits and the safety of a topical therapy that can be used as needed to control intermittent HS flares.

Asked to comment, the lead author of a recently published review article on the “evolving treatment landscape” of HS, James G. Krueger, MD, professor in clinical investigation at Rockefeller University, New York City, agreed that there is an unmet need for effective and safe therapies in milder HS.

“I agree with the premise,” said Dr. Krueger, indicating that phase 3 data will be essential to confirm the promise of this approach. Dr. Krueger, who did not hear the results presented at the EADV meeting, listed several JAK inhibitors in his review that have shown promising efficacy as oral agents and support JAK signaling as a target of HS treatment. 

Topical ruxolitinib (Opzelura) is currently approved in the United States for treating nonsegmental vitiligo in patients aged ≥ 12 years and for mild to moderate atopic dermatitis in patients aged ≥ 12 years. In Europe, it is approved for treatment of nonsegmental vitiligo with facial involvement in patients aged ≥ 12 years. 

Dr. Porter reported no potential conflicts of interest. Dr. Krueger reported financial relationships with more than 25 pharmaceutical companies not including Incyte, which is developing ruxolitinib cream.

A version of this article appeared on Medscape.com.

AMSTERDAM — Following the report of results from a randomized trial in which a topically applied Janus kinase (JAK) inhibitor was highly active in patients with mild to moderate hidradenitis suppurativa (HS), an open-label extension showed that 16 more weeks of treatment on as-needed basis provided complete or near complete clearance of lesions in up to 38.5% of patients.

“Ruxolitinib cream may be a novel approach to address an unmet medical need in the treatment of milder HS for which there are no currently approved treatments,” reported Martina L. Porter, MD, assistant professor of dermatology, Harvard Medical School, and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.

In the earlier 16-week, double-blind, randomized period of this phase 2b study, 69 adults with mild to moderate HS were randomized to 1.5% ruxolitinib cream or vehicle, applied twice daily for 16 weeks. The new results are from the open-label extension period, where those on the vehicle were crossed over to topical ruxolitinib and treatment was continued for another 16 weeks.
 

Over 80% Meet Primary Endpoint at 32 Weeks

Entry criteria for the study included Hurley stage I or II HS with no draining tunnels. Hurley stage III patients were not eligible. Patients had to have an abscess or inflammatory nodule (AN) count of 3 lesions concentrated in a single anatomic area or up to 10 lesions if disseminated. The median AN count of those enrolled was 5.4. 

In the randomized portion of the study and in the open-label extension, the recommendation for application was to apply the medication to nodules and a 1-cm area of surrounding skin. As-needed treatment was only recommended in the extension portion of the study and rescue medication was not allowed.

The goal of the open-label extension was to evaluate how long the improvements were sustained, according to Dr. Porter, who presented the results at the 2024 European Academy of Dermatology and Venereology (EADV) meeting.

The primary endpoints of AN50, signaling at least a 50% reduction in AN count from baseline, among those initially randomized to ruxolitinib cream climbed slightly from 79.2% at the end of 16 weeks to 81.0% at the end of 32 weeks.

This shows that the benefits recorded in the randomized phase of the trial were sustained during the open-label extension, Dr. Porter said. 

For those randomized to vehicle, there was a substantial response of 56.3% for AN50 during the randomized portion of the study, but catchup in the vehicle group to those on active therapy occurred rapidly over the open-label extension. By the end of 32 weeks, the score among the crossover patients slightly exceeded that of those on continuous therapy (88.5% vs 81.0%).

AN75 responses at week 32 were 66.7% and 61.5% in the continuous arm and crossover arm, respectively. The proportion of patients reaching an AN90 or AN100 response, meaning clear or almost clear, were 19% and 38.5%, in continuous treatment and crossover arms, respectively.

One of the secondary endpoints was the HS Clinical Response 50, indicating at least a 50% reduction in the AN count with no increase in abscesses or draining fistulae. At 32 weeks, the proportions of patients who met this endpoint were 81.0% and 88.5% in the continuous treatment and crossover arms, respectively. 

The mean reduction in International HS Severity Scoring System scores from baseline were 4.1 and 4.5 in the continuous treatment and crossover arms, respectively. 
 

Patients in the Study Mostly Women, 42% Black Individuals

Most (94%) of the participants were women; about 45% and 42% were White and Black individuals, respectively. Most of the remaining patients were Asian individuals. The median age at entry was 29 years, and the mean body mass index was approximately 34 kg/m². A substantial proportion of patients had systemic comorbidities, according to Dr. Porter, who noted that about 25% had anxiety, depression, or both.

“This phenotype — a high proportion of women with nodules but no draining tunnels and a substantial number of comorbidities — is one we often see in patients with mild HS,” Dr. Porter said.

The safety and tolerability profile of ruxolitinib cream was quite good, according to Dr. Porter, who noted that there were fewer treatment-related adverse events in the open-label extension. Overall, the number of treatment-related adverse events (3.6%), including application site reactions leading to discontinuation (1.8%) was low. 

Although there is a growing list of therapies now approved for HS, Dr. Porter emphasized that all have been developed for moderate to severe disease. She suggested that there is a sizable group of patients with mild disease for whom such therapies as biologics might not be warranted even if symptom relief is needed.

Given this unmet need, she said phase 3 trials are warranted to confirm the benefits and the safety of a topical therapy that can be used as needed to control intermittent HS flares.

Asked to comment, the lead author of a recently published review article on the “evolving treatment landscape” of HS, James G. Krueger, MD, professor in clinical investigation at Rockefeller University, New York City, agreed that there is an unmet need for effective and safe therapies in milder HS.

“I agree with the premise,” said Dr. Krueger, indicating that phase 3 data will be essential to confirm the promise of this approach. Dr. Krueger, who did not hear the results presented at the EADV meeting, listed several JAK inhibitors in his review that have shown promising efficacy as oral agents and support JAK signaling as a target of HS treatment. 

Topical ruxolitinib (Opzelura) is currently approved in the United States for treating nonsegmental vitiligo in patients aged ≥ 12 years and for mild to moderate atopic dermatitis in patients aged ≥ 12 years. In Europe, it is approved for treatment of nonsegmental vitiligo with facial involvement in patients aged ≥ 12 years. 

Dr. Porter reported no potential conflicts of interest. Dr. Krueger reported financial relationships with more than 25 pharmaceutical companies not including Incyte, which is developing ruxolitinib cream.

A version of this article appeared on Medscape.com.

COPENHAGEN — Serum glial fibrillary acidic protein (sGFAP) is quickly maturing as a biomarker to predict disability in patients with multiple sclerosis (MS), but it will add information to, not compete with, serum neurofilament light chain (sNFl) levels, according to multiple independent studies.

The basic consensus is that “elevated sNFl levels predict inflammatory-associated worsening, while sGFAP values correlate with progression independent of inflammation,” said Enric Monreal, MD, Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.

This key message was repeated by several researchers presenting data at the 2024 ECTRIMS 2004 meeting, including one delivered as a latebreaker. There was also general agreement that sGFAP will eventually be a routine prognostic tool even if more data are needed to validate how it will be used in routine MS management.
 

A New Biomarker for MS Disability Progression

Although apparently reliable for predicting MS disability, “sGFAP is about 5 years behind where we are with sNFl,” said Evan Madill, MD, a clinical research fellow at the Brigham Multiple Sclerosis Research Center, Harvard Medical School, Boston. He does think, however, that it is coming to clinical practice.

In the study he presented, 744 patients from the Brigham MS Research Center database were evaluated retrospectively for sGFAP levels and subsequent disability progression. Among this cohort, for which sGFAP levels were collected at baseline and over time, 46.5% had 6-month confirmed disability progression (CDP) over follow-up.

On univariate analysis, sGFAP levels correlated with and predicted CDP, need for a new ambulatory aid, and conversion to secondary progressive MS (SPMS). For patients less than 60 years of age, all of these correlations were highly significant (P ≤ .002). On multivariate analysis, the significance was preserved for CDP (P = .032) and for need of a new ambulatory aid (P = .007), but it was lost for SPMS conversion.

Notably, his data suggest that a one-time baseline measurement of sGFAP was more useful than change in sGFAP as a predictor.

It is unclear why sGFAP is less predictive in older individuals, but Dr. Madill speculated that non-MS phenomena might play a role at older ages. Treatment did not influence sGFAP levels in this study, but Dr. Madill said most of the data were collected before anti-CD20 monoclonal antibodies were widely available.

The observational study data presented by Dr. Monreal involved 725 patients drawn from 13 European hospitals. sGFAP and sNFl levels were evaluated from blood drawn within 12 months of MS onset. Over time these biomarkers had overlapping but different predictive strengths.

Consistent with previously published studies, which link elevations in sNFl to neuronal damage and elevations in sGFAP to astrogliosis, sGFAP was found to be more useful for predicting progression independent of relapse activity (PIRA), particularly in patients with low sNFl levels.

Increases in sNFl were associated with an increased risk of both PIRA and relapse-associated worsening (RAW), but sNFl was more closely associated with RAW in untreated patients. The risk of PIRA and RAW were similar across GFAP and sNFl levels in those patients treated with high-efficacy disease-modifying therapies (DMT).

Overall, when stratifying the cohort into three groups, those with both low sNFl and low GFAP, those with high sNFl with low GFAP, and those with high GFAP and low sNFl, the relative risks of disability associated with PIRA and RAW diverged, suggesting these biomarkers correlate with different processes of progression.
 

Comparing sGFAP and sNFl

This same principle was explored further in the latebreaking presentation by Ahmed Abdelhak, MD, a clinical instructor, Weill Institute for Neurosciences, University of California, San Francisco. The objective of his study was to compare sGFAP and sNFl for predicting PIRA in patients on treatment.

The study included 212 patients from the Swiss Multiple Sclerosis Cohort who were started on fingolimod or on B-cell depleting therapies like rituximab. After correcting for sex, age at onset, baseline Expanded Disability Status Scale (EDSS) scores, and other variables, Dr. Abdelhak also reported that the predictive values for PIRA were different for sGFAP relative to sNFl at least on the group level.

However, in this study, unlike the analysis of the Brigham MS Research Center data, changes in sGFAP over time when on treatment did have prognostic value, and there was a relationship between sGFAP levels and treatment. Although reductions in GFAP predicted less disability progression whether patients were treated with fingolimod B-cell depleting therapies, that patterns were different. Dr. Abdelhak, like the other investigators speaking at ECTRIMS, also said the data so far favor sGFAP over sNFl for predicting PIRA.

Each z-score unit change in sGFAP corresponded to a 47% lower risk of PIRA in follow-up over 6.8 years, Dr. Abdelhak reported, adding that the predictive value of sGFAP was “numerically stronger than the corresponding relation for sNFl.”

So far, clinical utility of sGFAP remains speculative. Most of the correlations he presented were on a group rather than the individual level. Moreover, Dr. Abdelhak cautioned that these correlations, based on observational data, do not necessarily reflect causation.

Nonetheless, remarking on the parallels of his data on sGFAP and sNFl with other studies presented at the ECTRIMS meeting, Dr. Abdelhak foresees a time when GFAP will be a prognostic tool, offering relative simplicity and lower cost than the current standard of imaging. He also sees a role in clinical research.

“Monitoring of sGFAP dynamics following DMT initiation could be used to prognosticate long-term PIRA risk and provide insights valuable for design and interpretation of trial outcomes,” he said.

Dr. Monreal reported financial relationships with Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Dr. Madill and Dr. Abdelhak reported no potential conflicts of interest.

COPENHAGEN — Serum glial fibrillary acidic protein (sGFAP) is quickly maturing as a biomarker to predict disability in patients with multiple sclerosis (MS), but it will add information to, not compete with, serum neurofilament light chain (sNFl) levels, according to multiple independent studies.

The basic consensus is that “elevated sNFl levels predict inflammatory-associated worsening, while sGFAP values correlate with progression independent of inflammation,” said Enric Monreal, MD, Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.

This key message was repeated by several researchers presenting data at the 2024 ECTRIMS 2004 meeting, including one delivered as a latebreaker. There was also general agreement that sGFAP will eventually be a routine prognostic tool even if more data are needed to validate how it will be used in routine MS management.
 

A New Biomarker for MS Disability Progression

Although apparently reliable for predicting MS disability, “sGFAP is about 5 years behind where we are with sNFl,” said Evan Madill, MD, a clinical research fellow at the Brigham Multiple Sclerosis Research Center, Harvard Medical School, Boston. He does think, however, that it is coming to clinical practice.

In the study he presented, 744 patients from the Brigham MS Research Center database were evaluated retrospectively for sGFAP levels and subsequent disability progression. Among this cohort, for which sGFAP levels were collected at baseline and over time, 46.5% had 6-month confirmed disability progression (CDP) over follow-up.

On univariate analysis, sGFAP levels correlated with and predicted CDP, need for a new ambulatory aid, and conversion to secondary progressive MS (SPMS). For patients less than 60 years of age, all of these correlations were highly significant (P ≤ .002). On multivariate analysis, the significance was preserved for CDP (P = .032) and for need of a new ambulatory aid (P = .007), but it was lost for SPMS conversion.

Notably, his data suggest that a one-time baseline measurement of sGFAP was more useful than change in sGFAP as a predictor.

It is unclear why sGFAP is less predictive in older individuals, but Dr. Madill speculated that non-MS phenomena might play a role at older ages. Treatment did not influence sGFAP levels in this study, but Dr. Madill said most of the data were collected before anti-CD20 monoclonal antibodies were widely available.

The observational study data presented by Dr. Monreal involved 725 patients drawn from 13 European hospitals. sGFAP and sNFl levels were evaluated from blood drawn within 12 months of MS onset. Over time these biomarkers had overlapping but different predictive strengths.

Consistent with previously published studies, which link elevations in sNFl to neuronal damage and elevations in sGFAP to astrogliosis, sGFAP was found to be more useful for predicting progression independent of relapse activity (PIRA), particularly in patients with low sNFl levels.

Increases in sNFl were associated with an increased risk of both PIRA and relapse-associated worsening (RAW), but sNFl was more closely associated with RAW in untreated patients. The risk of PIRA and RAW were similar across GFAP and sNFl levels in those patients treated with high-efficacy disease-modifying therapies (DMT).

Overall, when stratifying the cohort into three groups, those with both low sNFl and low GFAP, those with high sNFl with low GFAP, and those with high GFAP and low sNFl, the relative risks of disability associated with PIRA and RAW diverged, suggesting these biomarkers correlate with different processes of progression.
 

Comparing sGFAP and sNFl

This same principle was explored further in the latebreaking presentation by Ahmed Abdelhak, MD, a clinical instructor, Weill Institute for Neurosciences, University of California, San Francisco. The objective of his study was to compare sGFAP and sNFl for predicting PIRA in patients on treatment.

The study included 212 patients from the Swiss Multiple Sclerosis Cohort who were started on fingolimod or on B-cell depleting therapies like rituximab. After correcting for sex, age at onset, baseline Expanded Disability Status Scale (EDSS) scores, and other variables, Dr. Abdelhak also reported that the predictive values for PIRA were different for sGFAP relative to sNFl at least on the group level.

However, in this study, unlike the analysis of the Brigham MS Research Center data, changes in sGFAP over time when on treatment did have prognostic value, and there was a relationship between sGFAP levels and treatment. Although reductions in GFAP predicted less disability progression whether patients were treated with fingolimod B-cell depleting therapies, that patterns were different. Dr. Abdelhak, like the other investigators speaking at ECTRIMS, also said the data so far favor sGFAP over sNFl for predicting PIRA.

Each z-score unit change in sGFAP corresponded to a 47% lower risk of PIRA in follow-up over 6.8 years, Dr. Abdelhak reported, adding that the predictive value of sGFAP was “numerically stronger than the corresponding relation for sNFl.”

So far, clinical utility of sGFAP remains speculative. Most of the correlations he presented were on a group rather than the individual level. Moreover, Dr. Abdelhak cautioned that these correlations, based on observational data, do not necessarily reflect causation.

Nonetheless, remarking on the parallels of his data on sGFAP and sNFl with other studies presented at the ECTRIMS meeting, Dr. Abdelhak foresees a time when GFAP will be a prognostic tool, offering relative simplicity and lower cost than the current standard of imaging. He also sees a role in clinical research.

“Monitoring of sGFAP dynamics following DMT initiation could be used to prognosticate long-term PIRA risk and provide insights valuable for design and interpretation of trial outcomes,” he said.

Dr. Monreal reported financial relationships with Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Dr. Madill and Dr. Abdelhak reported no potential conflicts of interest.

COPENHAGEN — Serum glial fibrillary acidic protein (sGFAP) is quickly maturing as a biomarker to predict disability in patients with multiple sclerosis (MS), but it will add information to, not compete with, serum neurofilament light chain (sNFl) levels, according to multiple independent studies.

The basic consensus is that “elevated sNFl levels predict inflammatory-associated worsening, while sGFAP values correlate with progression independent of inflammation,” said Enric Monreal, MD, Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.

This key message was repeated by several researchers presenting data at the 2024 ECTRIMS 2004 meeting, including one delivered as a latebreaker. There was also general agreement that sGFAP will eventually be a routine prognostic tool even if more data are needed to validate how it will be used in routine MS management.
 

A New Biomarker for MS Disability Progression

Although apparently reliable for predicting MS disability, “sGFAP is about 5 years behind where we are with sNFl,” said Evan Madill, MD, a clinical research fellow at the Brigham Multiple Sclerosis Research Center, Harvard Medical School, Boston. He does think, however, that it is coming to clinical practice.

In the study he presented, 744 patients from the Brigham MS Research Center database were evaluated retrospectively for sGFAP levels and subsequent disability progression. Among this cohort, for which sGFAP levels were collected at baseline and over time, 46.5% had 6-month confirmed disability progression (CDP) over follow-up.

On univariate analysis, sGFAP levels correlated with and predicted CDP, need for a new ambulatory aid, and conversion to secondary progressive MS (SPMS). For patients less than 60 years of age, all of these correlations were highly significant (P ≤ .002). On multivariate analysis, the significance was preserved for CDP (P = .032) and for need of a new ambulatory aid (P = .007), but it was lost for SPMS conversion.

Notably, his data suggest that a one-time baseline measurement of sGFAP was more useful than change in sGFAP as a predictor.

It is unclear why sGFAP is less predictive in older individuals, but Dr. Madill speculated that non-MS phenomena might play a role at older ages. Treatment did not influence sGFAP levels in this study, but Dr. Madill said most of the data were collected before anti-CD20 monoclonal antibodies were widely available.

The observational study data presented by Dr. Monreal involved 725 patients drawn from 13 European hospitals. sGFAP and sNFl levels were evaluated from blood drawn within 12 months of MS onset. Over time these biomarkers had overlapping but different predictive strengths.

Consistent with previously published studies, which link elevations in sNFl to neuronal damage and elevations in sGFAP to astrogliosis, sGFAP was found to be more useful for predicting progression independent of relapse activity (PIRA), particularly in patients with low sNFl levels.

Increases in sNFl were associated with an increased risk of both PIRA and relapse-associated worsening (RAW), but sNFl was more closely associated with RAW in untreated patients. The risk of PIRA and RAW were similar across GFAP and sNFl levels in those patients treated with high-efficacy disease-modifying therapies (DMT).

Overall, when stratifying the cohort into three groups, those with both low sNFl and low GFAP, those with high sNFl with low GFAP, and those with high GFAP and low sNFl, the relative risks of disability associated with PIRA and RAW diverged, suggesting these biomarkers correlate with different processes of progression.
 

Comparing sGFAP and sNFl

This same principle was explored further in the latebreaking presentation by Ahmed Abdelhak, MD, a clinical instructor, Weill Institute for Neurosciences, University of California, San Francisco. The objective of his study was to compare sGFAP and sNFl for predicting PIRA in patients on treatment.

The study included 212 patients from the Swiss Multiple Sclerosis Cohort who were started on fingolimod or on B-cell depleting therapies like rituximab. After correcting for sex, age at onset, baseline Expanded Disability Status Scale (EDSS) scores, and other variables, Dr. Abdelhak also reported that the predictive values for PIRA were different for sGFAP relative to sNFl at least on the group level.

However, in this study, unlike the analysis of the Brigham MS Research Center data, changes in sGFAP over time when on treatment did have prognostic value, and there was a relationship between sGFAP levels and treatment. Although reductions in GFAP predicted less disability progression whether patients were treated with fingolimod B-cell depleting therapies, that patterns were different. Dr. Abdelhak, like the other investigators speaking at ECTRIMS, also said the data so far favor sGFAP over sNFl for predicting PIRA.

Each z-score unit change in sGFAP corresponded to a 47% lower risk of PIRA in follow-up over 6.8 years, Dr. Abdelhak reported, adding that the predictive value of sGFAP was “numerically stronger than the corresponding relation for sNFl.”

So far, clinical utility of sGFAP remains speculative. Most of the correlations he presented were on a group rather than the individual level. Moreover, Dr. Abdelhak cautioned that these correlations, based on observational data, do not necessarily reflect causation.

Nonetheless, remarking on the parallels of his data on sGFAP and sNFl with other studies presented at the ECTRIMS meeting, Dr. Abdelhak foresees a time when GFAP will be a prognostic tool, offering relative simplicity and lower cost than the current standard of imaging. He also sees a role in clinical research.

“Monitoring of sGFAP dynamics following DMT initiation could be used to prognosticate long-term PIRA risk and provide insights valuable for design and interpretation of trial outcomes,” he said.

Dr. Monreal reported financial relationships with Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Dr. Madill and Dr. Abdelhak reported no potential conflicts of interest.

AMSTERDAM — There is a mountain of evidence that atopic dermatitis (AD) exerts a large negative impact on quality of life, but a unique study with data from more than 30,000 individuals showed that adults whose AD started in childhood carry a far greater psychological and social burden throughout their life relative to AD starting after childhood.

These data, drawn from the ambitious Scars of Life (SOL) project, “suggest that childhood AD persisting into adulthood is its own phenotype,” reported Jonathan I. Silverberg, MD, PhD, director of clinical research, Department of Dermatology, George Washington University, Washington, DC.

Dr. Silverberg

One reasonable message from these data is that the failure to achieve adequate control of AD in children, whether by a late start of systemic agents or other reasons, results in a greater lifetime burden of disease when the burden beyond physical symptoms is measured, according to Dr. Silverberg.
 

More Than 30,000 From Five Continents Participated

In the SOL project, which was designed to analyze how the age of AD onset affects the severity of symptoms and quality of life, completed questionnaires were collected from 30,801 individuals in 27 countries on five continents. The questions, which elicited data to measure the burden of AD, were developed in association with several professional and patient associations with an interest in AD, including the National Eczema Association.

The SOL project has produced an enormous amount of data in four distinct groups, but Dr. Silverberg, speaking in a late-breaking news session at the annual congress of the European Academy of Dermatology and Venereology, focused on a comparison between the 2875 participants who had AD in childhood that has persisted into adulthood and the 7383 adults with adult-onset AD. Data from the other two subsets in SOL — AD in childhood but not in adulthood and no AD in either phase of life — are expected to fuel an extended series of publications.

In the two groups, baseline characteristics were similar with about 60% reporting moderate to severe symptoms and a median age of about 37 years. The proportion of women was 61% in both groups.

Using the PUSH-D questionnaire, which Dr. Silverberg described as a validated tool for gauging a sense of stigmatization, the greater burden of AD was remarkably consistent for those with childhood-onset AD vs adult-onset AD. With higher scores representing a greater sense of stigmatization, the differences in the overall score (23.0 vs 18.1; P < .0001) were highly significant as was every other domain evaluated.

For all five social behavior domains, such as avoiding contact in public and wariness of approaching people spontaneously, having AD onset in childhood persisting into adulthood produced significantly higher scores than having AD onset in adulthood, with no exceptions (P < .001 for all).
 

AD From Childhood Consistently Results in Worse Outcomes

Providing examples for some of the other 12 domains, Dr. Silverberg maintained that feelings of shame and psychological discomfort were always greater in adults with AD persistent since childhood vs AD starting in adulthood. The P values for these outcomes, such as experiencing bias at work or reporting a sense that others avoided them, were typically highly significant (P < .001).

Compared with those whose AD started in adulthood, “adults with atopic eczema that started during childhood have significantly more difficulties in their life, including occupational relationships, daily life, personal life, and partner or family relationships,” Dr. Silverberg reported.

He said that the data were controlled for multiple confounders, particularly greater severity of AD. He acknowledged that childhood onset might be considered a surrogate for more severe disease, but the data were controlled for this possibility.

Despite the fact that there are “thousands of studies across all age groups showing the burden of AD,” Dr. Silverberg considers these data to be unique by emphasizing the burden of chronicity rather than the impact of AD in any single moment in time.

For those with chronic AD from childhood, “the effect is not just on physical health but a deep negative influence on psychological and social aspects of life,” Dr. Silverberg said, suggesting that the independent effects of chronicity might be worth studying across other dermatologic diseases.

“Regulatory agencies focus on what you can do in that moment of time, losing the bigger picture of how patients are affected chronically,” he said, adding that this is an area of clinical research that should be further explored.

What the data further suggest “is that the earlier we intervene, the more likely patients will do better long term,” he said.
 

Data Provide Evidence of Systemic Therapy in Kids

For Gudrun Ratzinger, MD, of the Department of Dermatology and Venerology at the Medical University of Innsbruck in Austria, these are valuable data.

“When I prescribe systemic therapies to children, I often get resistance from the healthcare system and even other colleagues,” said Dr. Ratzinger, who was asked to comment on the results. “We are at a teaching hospital, but I often find that when patients return to their home physician, the systemic therapies are stopped.”

In her own practice, she believes the most effective therapies should be introduced in children and adults when complete control is not achieved on first-line drugs. “These data are very helpful for me in explaining to others the importance of effective treatment of atopic dermatitis in children,” she said.

Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies, including those that make drugs for AD. Dr. Ratzinger reported financial relationships with AbbVie, Almirall, Boehringer Ingelheim, Eli Lilly, Janssen, Leo Pharma, Novartis, Pelpharma, Pfizer, and UCB.

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

AMSTERDAM — There is a mountain of evidence that atopic dermatitis (AD) exerts a large negative impact on quality of life, but a unique study with data from more than 30,000 individuals showed that adults whose AD started in childhood carry a far greater psychological and social burden throughout their life relative to AD starting after childhood.

These data, drawn from the ambitious Scars of Life (SOL) project, “suggest that childhood AD persisting into adulthood is its own phenotype,” reported Jonathan I. Silverberg, MD, PhD, director of clinical research, Department of Dermatology, George Washington University, Washington, DC.

Dr. Silverberg

One reasonable message from these data is that the failure to achieve adequate control of AD in children, whether by a late start of systemic agents or other reasons, results in a greater lifetime burden of disease when the burden beyond physical symptoms is measured, according to Dr. Silverberg.
 

More Than 30,000 From Five Continents Participated

In the SOL project, which was designed to analyze how the age of AD onset affects the severity of symptoms and quality of life, completed questionnaires were collected from 30,801 individuals in 27 countries on five continents. The questions, which elicited data to measure the burden of AD, were developed in association with several professional and patient associations with an interest in AD, including the National Eczema Association.

The SOL project has produced an enormous amount of data in four distinct groups, but Dr. Silverberg, speaking in a late-breaking news session at the annual congress of the European Academy of Dermatology and Venereology, focused on a comparison between the 2875 participants who had AD in childhood that has persisted into adulthood and the 7383 adults with adult-onset AD. Data from the other two subsets in SOL — AD in childhood but not in adulthood and no AD in either phase of life — are expected to fuel an extended series of publications.

In the two groups, baseline characteristics were similar with about 60% reporting moderate to severe symptoms and a median age of about 37 years. The proportion of women was 61% in both groups.

Using the PUSH-D questionnaire, which Dr. Silverberg described as a validated tool for gauging a sense of stigmatization, the greater burden of AD was remarkably consistent for those with childhood-onset AD vs adult-onset AD. With higher scores representing a greater sense of stigmatization, the differences in the overall score (23.0 vs 18.1; P < .0001) were highly significant as was every other domain evaluated.

For all five social behavior domains, such as avoiding contact in public and wariness of approaching people spontaneously, having AD onset in childhood persisting into adulthood produced significantly higher scores than having AD onset in adulthood, with no exceptions (P < .001 for all).
 

AD From Childhood Consistently Results in Worse Outcomes

Providing examples for some of the other 12 domains, Dr. Silverberg maintained that feelings of shame and psychological discomfort were always greater in adults with AD persistent since childhood vs AD starting in adulthood. The P values for these outcomes, such as experiencing bias at work or reporting a sense that others avoided them, were typically highly significant (P < .001).

Compared with those whose AD started in adulthood, “adults with atopic eczema that started during childhood have significantly more difficulties in their life, including occupational relationships, daily life, personal life, and partner or family relationships,” Dr. Silverberg reported.

He said that the data were controlled for multiple confounders, particularly greater severity of AD. He acknowledged that childhood onset might be considered a surrogate for more severe disease, but the data were controlled for this possibility.

Despite the fact that there are “thousands of studies across all age groups showing the burden of AD,” Dr. Silverberg considers these data to be unique by emphasizing the burden of chronicity rather than the impact of AD in any single moment in time.

For those with chronic AD from childhood, “the effect is not just on physical health but a deep negative influence on psychological and social aspects of life,” Dr. Silverberg said, suggesting that the independent effects of chronicity might be worth studying across other dermatologic diseases.

“Regulatory agencies focus on what you can do in that moment of time, losing the bigger picture of how patients are affected chronically,” he said, adding that this is an area of clinical research that should be further explored.

What the data further suggest “is that the earlier we intervene, the more likely patients will do better long term,” he said.
 

Data Provide Evidence of Systemic Therapy in Kids

For Gudrun Ratzinger, MD, of the Department of Dermatology and Venerology at the Medical University of Innsbruck in Austria, these are valuable data.

“When I prescribe systemic therapies to children, I often get resistance from the healthcare system and even other colleagues,” said Dr. Ratzinger, who was asked to comment on the results. “We are at a teaching hospital, but I often find that when patients return to their home physician, the systemic therapies are stopped.”

In her own practice, she believes the most effective therapies should be introduced in children and adults when complete control is not achieved on first-line drugs. “These data are very helpful for me in explaining to others the importance of effective treatment of atopic dermatitis in children,” she said.

Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies, including those that make drugs for AD. Dr. Ratzinger reported financial relationships with AbbVie, Almirall, Boehringer Ingelheim, Eli Lilly, Janssen, Leo Pharma, Novartis, Pelpharma, Pfizer, and UCB.

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

AMSTERDAM — There is a mountain of evidence that atopic dermatitis (AD) exerts a large negative impact on quality of life, but a unique study with data from more than 30,000 individuals showed that adults whose AD started in childhood carry a far greater psychological and social burden throughout their life relative to AD starting after childhood.

These data, drawn from the ambitious Scars of Life (SOL) project, “suggest that childhood AD persisting into adulthood is its own phenotype,” reported Jonathan I. Silverberg, MD, PhD, director of clinical research, Department of Dermatology, George Washington University, Washington, DC.

Dr. Silverberg

One reasonable message from these data is that the failure to achieve adequate control of AD in children, whether by a late start of systemic agents or other reasons, results in a greater lifetime burden of disease when the burden beyond physical symptoms is measured, according to Dr. Silverberg.
 

More Than 30,000 From Five Continents Participated

In the SOL project, which was designed to analyze how the age of AD onset affects the severity of symptoms and quality of life, completed questionnaires were collected from 30,801 individuals in 27 countries on five continents. The questions, which elicited data to measure the burden of AD, were developed in association with several professional and patient associations with an interest in AD, including the National Eczema Association.

The SOL project has produced an enormous amount of data in four distinct groups, but Dr. Silverberg, speaking in a late-breaking news session at the annual congress of the European Academy of Dermatology and Venereology, focused on a comparison between the 2875 participants who had AD in childhood that has persisted into adulthood and the 7383 adults with adult-onset AD. Data from the other two subsets in SOL — AD in childhood but not in adulthood and no AD in either phase of life — are expected to fuel an extended series of publications.

In the two groups, baseline characteristics were similar with about 60% reporting moderate to severe symptoms and a median age of about 37 years. The proportion of women was 61% in both groups.

Using the PUSH-D questionnaire, which Dr. Silverberg described as a validated tool for gauging a sense of stigmatization, the greater burden of AD was remarkably consistent for those with childhood-onset AD vs adult-onset AD. With higher scores representing a greater sense of stigmatization, the differences in the overall score (23.0 vs 18.1; P < .0001) were highly significant as was every other domain evaluated.

For all five social behavior domains, such as avoiding contact in public and wariness of approaching people spontaneously, having AD onset in childhood persisting into adulthood produced significantly higher scores than having AD onset in adulthood, with no exceptions (P < .001 for all).
 

AD From Childhood Consistently Results in Worse Outcomes

Providing examples for some of the other 12 domains, Dr. Silverberg maintained that feelings of shame and psychological discomfort were always greater in adults with AD persistent since childhood vs AD starting in adulthood. The P values for these outcomes, such as experiencing bias at work or reporting a sense that others avoided them, were typically highly significant (P < .001).

Compared with those whose AD started in adulthood, “adults with atopic eczema that started during childhood have significantly more difficulties in their life, including occupational relationships, daily life, personal life, and partner or family relationships,” Dr. Silverberg reported.

He said that the data were controlled for multiple confounders, particularly greater severity of AD. He acknowledged that childhood onset might be considered a surrogate for more severe disease, but the data were controlled for this possibility.

Despite the fact that there are “thousands of studies across all age groups showing the burden of AD,” Dr. Silverberg considers these data to be unique by emphasizing the burden of chronicity rather than the impact of AD in any single moment in time.

For those with chronic AD from childhood, “the effect is not just on physical health but a deep negative influence on psychological and social aspects of life,” Dr. Silverberg said, suggesting that the independent effects of chronicity might be worth studying across other dermatologic diseases.

“Regulatory agencies focus on what you can do in that moment of time, losing the bigger picture of how patients are affected chronically,” he said, adding that this is an area of clinical research that should be further explored.

What the data further suggest “is that the earlier we intervene, the more likely patients will do better long term,” he said.
 

Data Provide Evidence of Systemic Therapy in Kids

For Gudrun Ratzinger, MD, of the Department of Dermatology and Venerology at the Medical University of Innsbruck in Austria, these are valuable data.

“When I prescribe systemic therapies to children, I often get resistance from the healthcare system and even other colleagues,” said Dr. Ratzinger, who was asked to comment on the results. “We are at a teaching hospital, but I often find that when patients return to their home physician, the systemic therapies are stopped.”

In her own practice, she believes the most effective therapies should be introduced in children and adults when complete control is not achieved on first-line drugs. “These data are very helpful for me in explaining to others the importance of effective treatment of atopic dermatitis in children,” she said.

Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies, including those that make drugs for AD. Dr. Ratzinger reported financial relationships with AbbVie, Almirall, Boehringer Ingelheim, Eli Lilly, Janssen, Leo Pharma, Novartis, Pelpharma, Pfizer, and UCB.

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

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

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

About 15% of ALS Has An Identifiable Genetic Cause

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

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

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

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

Numerous Disease Processes Are Potentially Targetable

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

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

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

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

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

Genetic Testing Is Key to Genetic Therapies

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

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

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

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

Early Treatment Presumed More Effective

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

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

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

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Suggested Reading

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

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

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

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

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

About 15% of ALS Has An Identifiable Genetic Cause

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

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

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

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

Numerous Disease Processes Are Potentially Targetable

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

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

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

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

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

Genetic Testing Is Key to Genetic Therapies

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

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

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

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

Early Treatment Presumed More Effective

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

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

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

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Suggested Reading

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

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

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

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

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

About 15% of ALS Has An Identifiable Genetic Cause

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

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

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

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

Numerous Disease Processes Are Potentially Targetable

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

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

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

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

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

Genetic Testing Is Key to Genetic Therapies

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

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

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

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

Early Treatment Presumed More Effective

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

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

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

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Suggested Reading

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

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

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

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

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

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

Anti-CD20 Disability Protection Already Seen in Pivotal Trial

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

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

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

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

Anti-CD20 MAB sustains Disability Protection for up to Years

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

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

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

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

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

No New Gd T1 Lesions Observed Over 12 Months

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

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

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

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

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

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

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

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

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

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

Anti-CD20 Disability Protection Already Seen in Pivotal Trial

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

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

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

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

Anti-CD20 MAB sustains Disability Protection for up to Years

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

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

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

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

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

No New Gd T1 Lesions Observed Over 12 Months

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

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

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

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

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

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

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

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

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

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

Anti-CD20 Disability Protection Already Seen in Pivotal Trial

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

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

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

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

Anti-CD20 MAB sustains Disability Protection for up to Years

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

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

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

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

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

No New Gd T1 Lesions Observed Over 12 Months

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

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

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

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

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

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

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

COPENHAGEN — There were high hopes that simvastatin, a well-tolerated lipid-lowering therapy, would reduce disability progression in patients with nonflaring secondary progressive multiple sclerosis (SPMS), but a definitive multicenter double-blind randomized trial found no benefit at all.

“There was no effect on the primary outcome of confirmed progression or on any of the secondary outcomes,” reported Jeremy Chataway, MD, PhD, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College of London, England.

For the primary outcome of progression on the Expanded Disability Status Scale (EDSS), the nonsignificant hazard ratio (HR) was, in fact, in favor of placebo (HR, 1.13; P = .26) over 45 months of follow-up and 365 progression events.
 

No Meaningful Difference Between Study Arms

“There were wide confidence intervals [95% CI, 0.91-1.39], so, really, there were no differences between the two arms,” reported Dr. Chataway, who presented the simvastatin trial, called MS-STAT2, during the late-breaker session of the 2024 ECTRIMS annual meeting.

Over a period of more than 20 years, a series of experimental and clinical studies have indicated that simvastatin and other CoA reductase inhibitors have anti-inflammatory and neuroprotective effects. These studies were the basis for the first MED-STAT study, which was a placebo-controlled randomized trial published in 2014.

Although this study did not have a clinical endpoint, it associated simvastatin with a 43% reduction (P = .003) in the annualized rate of brain atrophy, which has been widely accepted as a surrogate measure of MS progression.

In MS-STAT2, 964 patients were available for the intention-to-treat analysis. An established diagnosis of SPMS, an age of 25-65, and an EDSS score of 4.0-6.5 were among the inclusion criteria. Patients were required to be relapse-free for at least 3 months prior to study entry.

Importantly, patients were excluded if they were taking statin-lowering therapies or were candidates for these therapies due to the presence of cardiovascular disease. They were also excluded from entering the trial if taking immunosuppressants, such as methotrexate or azathioprine, or had exposure to monoclonal antibodies employed in the treatment of MS, such as natalizumab and alemtuzumab, in the prior 12 months.

Randomized to 80 mg of simvastatin (40 mg in the first month followed by rapid upward titration) or placebo in a 1:1 fashion, patients remained on their assigned therapy for 3 years in the absence of progression. At the end of this time, patients who remained progression-free could continue for up to 45 months while still blinded to treatment assignment.

Even though a large proportion of patients who were eligible to remain in the study for the full 45 months did so, the retention did not reflect clinical improvement.

Indeed, the secondary endpoints also produced no signal of benefit. On a composite secondary endpoint of EDSS, ambulation in the form of the 25-foot walk, and upper extremity function in the form of the 9-hole peg test (9-HPT), the numerical odds ratio (OR) went in the wrong direction for simvastatin although the difference was not significant (OR, 1.17; P = .26).
 

Annualized Relapse Rate Numerically Higher on Simvastatin

The annualized relapse rate, another secondary endpoint, was low in both arms of the study at 0.05 relapses/year for placebo and 0.7 relapses/year for simvastatin. Again, this result, although numerically unfavorable for simvastatin did not reach statistical significance (OR, 1.43; P = .04).

Simvastatin had a placebo-like safety profile. The single case of rhabdomyolysis in the simvastatin arm, which occurred early after randomization, resolved. Otherwise, simvastatin was well tolerated.

Conducted before and through the period of the COVID-19 pandemic, the number of progression events tripled in the year after the COVID-19 pandemic started relative to the prior year. At the end of the pandemic, progression events returned to a level similar to that before its onset. However, although Dr. Chataway noted this was an interesting example of comorbidities exacerbating MS, he emphasized that this increase was similar in the simvastatin and placebo arms.

There are more analyses to come, including patient-reported outcomes, biomarker analyses, and further comparisons of change in MRIs, but Dr. Chataway acknowledged that the study provided no support for the underlying hypothesis.

Several experts commenting after the study was presented, including Ludwig Kappos, MD, PhD, Chair of Neurology at the University Hospital, Basel, Switzerland, agreed.

“Unfortunately, these results are quite disappointing,” he said. When asked if there is any rationale for further pursuing studies of simvastatin for the treatment of SPMS, he said no.

“These data are quite convincing that there is no benefit. I do not see where you could go from here,” Dr. Kappos said in an interview.

Dr. Chataway, asked the same question, reiterated that there are a number of preplanned analyses that will be completed, but he does not foresee further studies with simvastatin for the indication studied in MS-STAT-2 trial.

However, he also emphasized strongly that simvastatin or any other lipid-lowering therapy should not be withheld from MS patients that need these drugs for a cardiovascular indication.

“We saw no benefit seen from simvastatin for patients with stable SPMS, but these drugs were well tolerated and they can be life-saving therapies for patients with increased cardiovascular risk,” Dr. Chataway said.

Dr, Chataway reported financial relationships with Biogen, Genzyme, Ionis, Lucid, Merck NerveGen, Novartis, Roche, and Sanofi. Dr. Kappos reports financial relationships with more than 20 pharmaceutical companies. The MS-STAT2 trial received no funding from industry.

COPENHAGEN — There were high hopes that simvastatin, a well-tolerated lipid-lowering therapy, would reduce disability progression in patients with nonflaring secondary progressive multiple sclerosis (SPMS), but a definitive multicenter double-blind randomized trial found no benefit at all.

“There was no effect on the primary outcome of confirmed progression or on any of the secondary outcomes,” reported Jeremy Chataway, MD, PhD, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College of London, England.

For the primary outcome of progression on the Expanded Disability Status Scale (EDSS), the nonsignificant hazard ratio (HR) was, in fact, in favor of placebo (HR, 1.13; P = .26) over 45 months of follow-up and 365 progression events.
 

No Meaningful Difference Between Study Arms

“There were wide confidence intervals [95% CI, 0.91-1.39], so, really, there were no differences between the two arms,” reported Dr. Chataway, who presented the simvastatin trial, called MS-STAT2, during the late-breaker session of the 2024 ECTRIMS annual meeting.

Over a period of more than 20 years, a series of experimental and clinical studies have indicated that simvastatin and other CoA reductase inhibitors have anti-inflammatory and neuroprotective effects. These studies were the basis for the first MED-STAT study, which was a placebo-controlled randomized trial published in 2014.

Although this study did not have a clinical endpoint, it associated simvastatin with a 43% reduction (P = .003) in the annualized rate of brain atrophy, which has been widely accepted as a surrogate measure of MS progression.

In MS-STAT2, 964 patients were available for the intention-to-treat analysis. An established diagnosis of SPMS, an age of 25-65, and an EDSS score of 4.0-6.5 were among the inclusion criteria. Patients were required to be relapse-free for at least 3 months prior to study entry.

Importantly, patients were excluded if they were taking statin-lowering therapies or were candidates for these therapies due to the presence of cardiovascular disease. They were also excluded from entering the trial if taking immunosuppressants, such as methotrexate or azathioprine, or had exposure to monoclonal antibodies employed in the treatment of MS, such as natalizumab and alemtuzumab, in the prior 12 months.

Randomized to 80 mg of simvastatin (40 mg in the first month followed by rapid upward titration) or placebo in a 1:1 fashion, patients remained on their assigned therapy for 3 years in the absence of progression. At the end of this time, patients who remained progression-free could continue for up to 45 months while still blinded to treatment assignment.

Even though a large proportion of patients who were eligible to remain in the study for the full 45 months did so, the retention did not reflect clinical improvement.

Indeed, the secondary endpoints also produced no signal of benefit. On a composite secondary endpoint of EDSS, ambulation in the form of the 25-foot walk, and upper extremity function in the form of the 9-hole peg test (9-HPT), the numerical odds ratio (OR) went in the wrong direction for simvastatin although the difference was not significant (OR, 1.17; P = .26).
 

Annualized Relapse Rate Numerically Higher on Simvastatin

The annualized relapse rate, another secondary endpoint, was low in both arms of the study at 0.05 relapses/year for placebo and 0.7 relapses/year for simvastatin. Again, this result, although numerically unfavorable for simvastatin did not reach statistical significance (OR, 1.43; P = .04).

Simvastatin had a placebo-like safety profile. The single case of rhabdomyolysis in the simvastatin arm, which occurred early after randomization, resolved. Otherwise, simvastatin was well tolerated.

Conducted before and through the period of the COVID-19 pandemic, the number of progression events tripled in the year after the COVID-19 pandemic started relative to the prior year. At the end of the pandemic, progression events returned to a level similar to that before its onset. However, although Dr. Chataway noted this was an interesting example of comorbidities exacerbating MS, he emphasized that this increase was similar in the simvastatin and placebo arms.

There are more analyses to come, including patient-reported outcomes, biomarker analyses, and further comparisons of change in MRIs, but Dr. Chataway acknowledged that the study provided no support for the underlying hypothesis.

Several experts commenting after the study was presented, including Ludwig Kappos, MD, PhD, Chair of Neurology at the University Hospital, Basel, Switzerland, agreed.

“Unfortunately, these results are quite disappointing,” he said. When asked if there is any rationale for further pursuing studies of simvastatin for the treatment of SPMS, he said no.

“These data are quite convincing that there is no benefit. I do not see where you could go from here,” Dr. Kappos said in an interview.

Dr. Chataway, asked the same question, reiterated that there are a number of preplanned analyses that will be completed, but he does not foresee further studies with simvastatin for the indication studied in MS-STAT-2 trial.

However, he also emphasized strongly that simvastatin or any other lipid-lowering therapy should not be withheld from MS patients that need these drugs for a cardiovascular indication.

“We saw no benefit seen from simvastatin for patients with stable SPMS, but these drugs were well tolerated and they can be life-saving therapies for patients with increased cardiovascular risk,” Dr. Chataway said.

Dr, Chataway reported financial relationships with Biogen, Genzyme, Ionis, Lucid, Merck NerveGen, Novartis, Roche, and Sanofi. Dr. Kappos reports financial relationships with more than 20 pharmaceutical companies. The MS-STAT2 trial received no funding from industry.

COPENHAGEN — There were high hopes that simvastatin, a well-tolerated lipid-lowering therapy, would reduce disability progression in patients with nonflaring secondary progressive multiple sclerosis (SPMS), but a definitive multicenter double-blind randomized trial found no benefit at all.

“There was no effect on the primary outcome of confirmed progression or on any of the secondary outcomes,” reported Jeremy Chataway, MD, PhD, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College of London, England.

For the primary outcome of progression on the Expanded Disability Status Scale (EDSS), the nonsignificant hazard ratio (HR) was, in fact, in favor of placebo (HR, 1.13; P = .26) over 45 months of follow-up and 365 progression events.
 

No Meaningful Difference Between Study Arms

“There were wide confidence intervals [95% CI, 0.91-1.39], so, really, there were no differences between the two arms,” reported Dr. Chataway, who presented the simvastatin trial, called MS-STAT2, during the late-breaker session of the 2024 ECTRIMS annual meeting.

Over a period of more than 20 years, a series of experimental and clinical studies have indicated that simvastatin and other CoA reductase inhibitors have anti-inflammatory and neuroprotective effects. These studies were the basis for the first MED-STAT study, which was a placebo-controlled randomized trial published in 2014.

Although this study did not have a clinical endpoint, it associated simvastatin with a 43% reduction (P = .003) in the annualized rate of brain atrophy, which has been widely accepted as a surrogate measure of MS progression.

In MS-STAT2, 964 patients were available for the intention-to-treat analysis. An established diagnosis of SPMS, an age of 25-65, and an EDSS score of 4.0-6.5 were among the inclusion criteria. Patients were required to be relapse-free for at least 3 months prior to study entry.

Importantly, patients were excluded if they were taking statin-lowering therapies or were candidates for these therapies due to the presence of cardiovascular disease. They were also excluded from entering the trial if taking immunosuppressants, such as methotrexate or azathioprine, or had exposure to monoclonal antibodies employed in the treatment of MS, such as natalizumab and alemtuzumab, in the prior 12 months.

Randomized to 80 mg of simvastatin (40 mg in the first month followed by rapid upward titration) or placebo in a 1:1 fashion, patients remained on their assigned therapy for 3 years in the absence of progression. At the end of this time, patients who remained progression-free could continue for up to 45 months while still blinded to treatment assignment.

Even though a large proportion of patients who were eligible to remain in the study for the full 45 months did so, the retention did not reflect clinical improvement.

Indeed, the secondary endpoints also produced no signal of benefit. On a composite secondary endpoint of EDSS, ambulation in the form of the 25-foot walk, and upper extremity function in the form of the 9-hole peg test (9-HPT), the numerical odds ratio (OR) went in the wrong direction for simvastatin although the difference was not significant (OR, 1.17; P = .26).
 

Annualized Relapse Rate Numerically Higher on Simvastatin

The annualized relapse rate, another secondary endpoint, was low in both arms of the study at 0.05 relapses/year for placebo and 0.7 relapses/year for simvastatin. Again, this result, although numerically unfavorable for simvastatin did not reach statistical significance (OR, 1.43; P = .04).

Simvastatin had a placebo-like safety profile. The single case of rhabdomyolysis in the simvastatin arm, which occurred early after randomization, resolved. Otherwise, simvastatin was well tolerated.

Conducted before and through the period of the COVID-19 pandemic, the number of progression events tripled in the year after the COVID-19 pandemic started relative to the prior year. At the end of the pandemic, progression events returned to a level similar to that before its onset. However, although Dr. Chataway noted this was an interesting example of comorbidities exacerbating MS, he emphasized that this increase was similar in the simvastatin and placebo arms.

There are more analyses to come, including patient-reported outcomes, biomarker analyses, and further comparisons of change in MRIs, but Dr. Chataway acknowledged that the study provided no support for the underlying hypothesis.

Several experts commenting after the study was presented, including Ludwig Kappos, MD, PhD, Chair of Neurology at the University Hospital, Basel, Switzerland, agreed.

“Unfortunately, these results are quite disappointing,” he said. When asked if there is any rationale for further pursuing studies of simvastatin for the treatment of SPMS, he said no.

“These data are quite convincing that there is no benefit. I do not see where you could go from here,” Dr. Kappos said in an interview.

Dr. Chataway, asked the same question, reiterated that there are a number of preplanned analyses that will be completed, but he does not foresee further studies with simvastatin for the indication studied in MS-STAT-2 trial.

However, he also emphasized strongly that simvastatin or any other lipid-lowering therapy should not be withheld from MS patients that need these drugs for a cardiovascular indication.

“We saw no benefit seen from simvastatin for patients with stable SPMS, but these drugs were well tolerated and they can be life-saving therapies for patients with increased cardiovascular risk,” Dr. Chataway said.

Dr, Chataway reported financial relationships with Biogen, Genzyme, Ionis, Lucid, Merck NerveGen, Novartis, Roche, and Sanofi. Dr. Kappos reports financial relationships with more than 20 pharmaceutical companies. The MS-STAT2 trial received no funding from industry.

COPENHAGEN — In two phase 3 head-to-head comparing the Bruton tyrosine kinase inhibitor (BTKi) tolebrutinib to the immunomodulatory teriflunomide for relapsing-remitting multiple sclerosis (RRMS), there was no advantage on the primary endpoint of relapse, but the greater protection against disability, a secondary endpoint, might change thinking about BTKis as a potential MS therapy.

For annualized relapse rate (ARR), which is the basis on which these two drugs were compared, “there was no difference between tolebrutinib and teriflunomide,” reported Jiwon Oh, MD, Medical Director, Barlo Multiple Sclerosis Program, St. Michael’s Hospital, University of Toronto, Canada.

In the similar GEMINI 1 and 2 trials, the ARRs were nearly identical in the first, (0.13 and 0.12), and completely identical in the second (0.11) for tolebrutinib and teriflunomide, respectively.
 

Although Negative, GEMINI Trials Offer Intriguing Data

These data rule out the study hypothesis that a BTKi offers greater protection against relapse than a commonly used immunomodulator, but Dr. Oh suggested the study is still potentially relevant to MS research. Although data on the primary endpoint were disappointing, Dr. Oh suggested that the secondary outcomes support an anti-MS mechanism for the BTKi that is different from that of teriflunomide.

“There is hope,” Dr. Oh said, when reporting the findings of the GEMINI I and II trials during the latebreaker session at the 2024 ECTRIMS annual meeting. Ultimately, a substantial part of this hope was derived from the consistency of the GEMINI data with the placebo-controlled HERCULES trial of tolebrutinib presented immediately afterwards, but the disparity between the primary and secondary outcomes of GEMINI are, by themselves, relevant, suggesting that targets of treatment change as MS progresses from an acute to a chronic inflammatory process.
 

BTKi Associated With Reduced Disability

At 3 months, the rate of confirmed disability worsening (CDW) in the pooled GEMINI trials was 18.5% and 14.7% for tolebrutinib and teriflunomide, respectively, producing at 27% reduction in hazard ratio (HR) for this outcome (HR 0.73; P = .0018). At 6 months, the protection against disability (13.2% vs. 9.9%) persisted for tolebrutinib relative to teriflunomide (HR 0.71; P = .023).*

For the outcome of a confirmed disability improvement at 6 months, the higher rate in the tolebrutinib arm did not reach statistical significance (12.8% vs. 12.0%), but it did suggest a favorable trend (HR 1.22; P = .17).

While Dr. Oh acknowledged that secondary outcomes can only be considered hypothesis generating when the primary outcome is negative, she said these outcomes provide intriguing support for the potential of this BTKi drug to inhibit “smoldering inflammation.” Even if tolebrutinib was no more effective than teriflunomide against the acute inflammation that drives relapse, the GEMINI trials data support greater inhibition of the chronic inflammation implicated in progression in the absence of flares.

On MRI, the annualized rate of new and enlarging T2 lesions, although numerically higher in the tolebrutinib group, did not differ significantly in either GEMINI 1 (5.6 vs. 5.2; P = .46) or GEMINI 2 (5.1 vs. 4.4; P = .24). The least mean square difference in brain volume at end of study relative to 6 months into the study was 0.2% less in the tolebrutinib arm than the teriflunomide arm (P = .0002) in GEMINI 1, but the 0.04 numerical advantage for tolebrutinib did not reach statistical significance in GEMINI 2 (P = .43).

Of the 974 patients randomized in GEMINI 1 and 899 randomized in GEMINI 2, about 85% completed the 3-year trial. Almost all had RRMS (99%) rather than progressing MS. The median age was approximately 36 years, the baseline EDSS score was approximately 1.2, and the median time since diagnosis was about 6.5 years. The mean number of relapses in the prior year was approximately 0.6.

In GEMINI, the secondary outcomes foreshadowed the positive findings in the phase 3 HERCULES trial that came immediately after Dr. Oh’s GEMINI trials presentation. The HERCULES trial associated tolebrutinib with a 31% reduction in the risk of confirmed disability progression (CDW) relative to placebo in patients with non-relapsing secondary progressive MS (nrSPMS).

In HERCULES, 1172 patients with nrSPMS were randomized in a 2:1 fashion to tolebrutinib or placebo. For the primary endpoint of CDW at 6 months, tolebrutinib demonstrated a major and highly significant reduction in this primary endpoint (HR 0.69; P = .00026).
 

BTKi Disability Protection Supported By Progressive MS Trial

“This is the first trial to show significant slowing of disability in people with nrSPMS,” reported the principal investigator Robert J. Fox, MD, Vice Chair of the Neurological Institute at Cleveland Clinic, Cleveland, Ohio.

For disability improvement at 6 months, tolebrutinib was associated with a nearly 2-fold improvement (HR 1.88; P = .021). According to both Dr. Oh and Dr. Fox the results of these two major phase 3 tolebrutinib studies support the principle that the BTKi, which was shown to offer inhibition of relapse comparable to teriflunomide in the GEMINI trials, offers a greater inhibition of chronic inflammation.

“These results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes,” Dr. Oh said.

Dr. Fox said that the HERCULES results will be submitted to regulatory authorities with the goal of securing an indication for tolebrutinib for nrSPMS.

Both Dr. Oh and Dr. Fox suggested these results are likely to reorient thinking about the pathophysiology of MS progression and how different processes can be targeted in the future. Other experts agreed.

“I think we are starting to look at different endpoints than ARR, particularly at those that might better reflect progression in later stages of MS and that are independent of ARR,” said Dalia Rotstein, MD, MS researcher and an assistant professor of neurology, University of Toronto, Canada.

A moderator of the ECTRIMS latebreaker session, she suggested that the differences between outcomes of the GEMINI trials and HERCULES trials might have relevance to each other even if the GEMINI trials did not meet their primary endpoint.

Dr. Oh reported financial relationships with Amgen, Biogen, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi, which provided funding for the GEMINI trials. Dr. Fox reported financial relationships with more than 15 pharmaceutical companies, including Sanofi, which also provided funding for the HERCULES trial. Dr. Rotstein reported financial relationships with Alexion, Biogen, EMD Serono, Horizon, Novartis, Roche, Sanofi, and Touch IME.

*Correction, 9/26/24: A previous version of this article contained an incorrect P value.

COPENHAGEN — In two phase 3 head-to-head comparing the Bruton tyrosine kinase inhibitor (BTKi) tolebrutinib to the immunomodulatory teriflunomide for relapsing-remitting multiple sclerosis (RRMS), there was no advantage on the primary endpoint of relapse, but the greater protection against disability, a secondary endpoint, might change thinking about BTKis as a potential MS therapy.

For annualized relapse rate (ARR), which is the basis on which these two drugs were compared, “there was no difference between tolebrutinib and teriflunomide,” reported Jiwon Oh, MD, Medical Director, Barlo Multiple Sclerosis Program, St. Michael’s Hospital, University of Toronto, Canada.

In the similar GEMINI 1 and 2 trials, the ARRs were nearly identical in the first, (0.13 and 0.12), and completely identical in the second (0.11) for tolebrutinib and teriflunomide, respectively.
 

Although Negative, GEMINI Trials Offer Intriguing Data

These data rule out the study hypothesis that a BTKi offers greater protection against relapse than a commonly used immunomodulator, but Dr. Oh suggested the study is still potentially relevant to MS research. Although data on the primary endpoint were disappointing, Dr. Oh suggested that the secondary outcomes support an anti-MS mechanism for the BTKi that is different from that of teriflunomide.

“There is hope,” Dr. Oh said, when reporting the findings of the GEMINI I and II trials during the latebreaker session at the 2024 ECTRIMS annual meeting. Ultimately, a substantial part of this hope was derived from the consistency of the GEMINI data with the placebo-controlled HERCULES trial of tolebrutinib presented immediately afterwards, but the disparity between the primary and secondary outcomes of GEMINI are, by themselves, relevant, suggesting that targets of treatment change as MS progresses from an acute to a chronic inflammatory process.
 

BTKi Associated With Reduced Disability

At 3 months, the rate of confirmed disability worsening (CDW) in the pooled GEMINI trials was 18.5% and 14.7% for tolebrutinib and teriflunomide, respectively, producing at 27% reduction in hazard ratio (HR) for this outcome (HR 0.73; P = .0018). At 6 months, the protection against disability (13.2% vs. 9.9%) persisted for tolebrutinib relative to teriflunomide (HR 0.71; P = .023).*

For the outcome of a confirmed disability improvement at 6 months, the higher rate in the tolebrutinib arm did not reach statistical significance (12.8% vs. 12.0%), but it did suggest a favorable trend (HR 1.22; P = .17).

While Dr. Oh acknowledged that secondary outcomes can only be considered hypothesis generating when the primary outcome is negative, she said these outcomes provide intriguing support for the potential of this BTKi drug to inhibit “smoldering inflammation.” Even if tolebrutinib was no more effective than teriflunomide against the acute inflammation that drives relapse, the GEMINI trials data support greater inhibition of the chronic inflammation implicated in progression in the absence of flares.

On MRI, the annualized rate of new and enlarging T2 lesions, although numerically higher in the tolebrutinib group, did not differ significantly in either GEMINI 1 (5.6 vs. 5.2; P = .46) or GEMINI 2 (5.1 vs. 4.4; P = .24). The least mean square difference in brain volume at end of study relative to 6 months into the study was 0.2% less in the tolebrutinib arm than the teriflunomide arm (P = .0002) in GEMINI 1, but the 0.04 numerical advantage for tolebrutinib did not reach statistical significance in GEMINI 2 (P = .43).

Of the 974 patients randomized in GEMINI 1 and 899 randomized in GEMINI 2, about 85% completed the 3-year trial. Almost all had RRMS (99%) rather than progressing MS. The median age was approximately 36 years, the baseline EDSS score was approximately 1.2, and the median time since diagnosis was about 6.5 years. The mean number of relapses in the prior year was approximately 0.6.

In GEMINI, the secondary outcomes foreshadowed the positive findings in the phase 3 HERCULES trial that came immediately after Dr. Oh’s GEMINI trials presentation. The HERCULES trial associated tolebrutinib with a 31% reduction in the risk of confirmed disability progression (CDW) relative to placebo in patients with non-relapsing secondary progressive MS (nrSPMS).

In HERCULES, 1172 patients with nrSPMS were randomized in a 2:1 fashion to tolebrutinib or placebo. For the primary endpoint of CDW at 6 months, tolebrutinib demonstrated a major and highly significant reduction in this primary endpoint (HR 0.69; P = .00026).
 

BTKi Disability Protection Supported By Progressive MS Trial

“This is the first trial to show significant slowing of disability in people with nrSPMS,” reported the principal investigator Robert J. Fox, MD, Vice Chair of the Neurological Institute at Cleveland Clinic, Cleveland, Ohio.

For disability improvement at 6 months, tolebrutinib was associated with a nearly 2-fold improvement (HR 1.88; P = .021). According to both Dr. Oh and Dr. Fox the results of these two major phase 3 tolebrutinib studies support the principle that the BTKi, which was shown to offer inhibition of relapse comparable to teriflunomide in the GEMINI trials, offers a greater inhibition of chronic inflammation.

“These results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes,” Dr. Oh said.

Dr. Fox said that the HERCULES results will be submitted to regulatory authorities with the goal of securing an indication for tolebrutinib for nrSPMS.

Both Dr. Oh and Dr. Fox suggested these results are likely to reorient thinking about the pathophysiology of MS progression and how different processes can be targeted in the future. Other experts agreed.

“I think we are starting to look at different endpoints than ARR, particularly at those that might better reflect progression in later stages of MS and that are independent of ARR,” said Dalia Rotstein, MD, MS researcher and an assistant professor of neurology, University of Toronto, Canada.

A moderator of the ECTRIMS latebreaker session, she suggested that the differences between outcomes of the GEMINI trials and HERCULES trials might have relevance to each other even if the GEMINI trials did not meet their primary endpoint.

Dr. Oh reported financial relationships with Amgen, Biogen, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi, which provided funding for the GEMINI trials. Dr. Fox reported financial relationships with more than 15 pharmaceutical companies, including Sanofi, which also provided funding for the HERCULES trial. Dr. Rotstein reported financial relationships with Alexion, Biogen, EMD Serono, Horizon, Novartis, Roche, Sanofi, and Touch IME.

*Correction, 9/26/24: A previous version of this article contained an incorrect P value.

COPENHAGEN — In two phase 3 head-to-head comparing the Bruton tyrosine kinase inhibitor (BTKi) tolebrutinib to the immunomodulatory teriflunomide for relapsing-remitting multiple sclerosis (RRMS), there was no advantage on the primary endpoint of relapse, but the greater protection against disability, a secondary endpoint, might change thinking about BTKis as a potential MS therapy.

For annualized relapse rate (ARR), which is the basis on which these two drugs were compared, “there was no difference between tolebrutinib and teriflunomide,” reported Jiwon Oh, MD, Medical Director, Barlo Multiple Sclerosis Program, St. Michael’s Hospital, University of Toronto, Canada.

In the similar GEMINI 1 and 2 trials, the ARRs were nearly identical in the first, (0.13 and 0.12), and completely identical in the second (0.11) for tolebrutinib and teriflunomide, respectively.
 

Although Negative, GEMINI Trials Offer Intriguing Data

These data rule out the study hypothesis that a BTKi offers greater protection against relapse than a commonly used immunomodulator, but Dr. Oh suggested the study is still potentially relevant to MS research. Although data on the primary endpoint were disappointing, Dr. Oh suggested that the secondary outcomes support an anti-MS mechanism for the BTKi that is different from that of teriflunomide.

“There is hope,” Dr. Oh said, when reporting the findings of the GEMINI I and II trials during the latebreaker session at the 2024 ECTRIMS annual meeting. Ultimately, a substantial part of this hope was derived from the consistency of the GEMINI data with the placebo-controlled HERCULES trial of tolebrutinib presented immediately afterwards, but the disparity between the primary and secondary outcomes of GEMINI are, by themselves, relevant, suggesting that targets of treatment change as MS progresses from an acute to a chronic inflammatory process.
 

BTKi Associated With Reduced Disability

At 3 months, the rate of confirmed disability worsening (CDW) in the pooled GEMINI trials was 18.5% and 14.7% for tolebrutinib and teriflunomide, respectively, producing at 27% reduction in hazard ratio (HR) for this outcome (HR 0.73; P = .0018). At 6 months, the protection against disability (13.2% vs. 9.9%) persisted for tolebrutinib relative to teriflunomide (HR 0.71; P = .023).*

For the outcome of a confirmed disability improvement at 6 months, the higher rate in the tolebrutinib arm did not reach statistical significance (12.8% vs. 12.0%), but it did suggest a favorable trend (HR 1.22; P = .17).

While Dr. Oh acknowledged that secondary outcomes can only be considered hypothesis generating when the primary outcome is negative, she said these outcomes provide intriguing support for the potential of this BTKi drug to inhibit “smoldering inflammation.” Even if tolebrutinib was no more effective than teriflunomide against the acute inflammation that drives relapse, the GEMINI trials data support greater inhibition of the chronic inflammation implicated in progression in the absence of flares.

On MRI, the annualized rate of new and enlarging T2 lesions, although numerically higher in the tolebrutinib group, did not differ significantly in either GEMINI 1 (5.6 vs. 5.2; P = .46) or GEMINI 2 (5.1 vs. 4.4; P = .24). The least mean square difference in brain volume at end of study relative to 6 months into the study was 0.2% less in the tolebrutinib arm than the teriflunomide arm (P = .0002) in GEMINI 1, but the 0.04 numerical advantage for tolebrutinib did not reach statistical significance in GEMINI 2 (P = .43).

Of the 974 patients randomized in GEMINI 1 and 899 randomized in GEMINI 2, about 85% completed the 3-year trial. Almost all had RRMS (99%) rather than progressing MS. The median age was approximately 36 years, the baseline EDSS score was approximately 1.2, and the median time since diagnosis was about 6.5 years. The mean number of relapses in the prior year was approximately 0.6.

In GEMINI, the secondary outcomes foreshadowed the positive findings in the phase 3 HERCULES trial that came immediately after Dr. Oh’s GEMINI trials presentation. The HERCULES trial associated tolebrutinib with a 31% reduction in the risk of confirmed disability progression (CDW) relative to placebo in patients with non-relapsing secondary progressive MS (nrSPMS).

In HERCULES, 1172 patients with nrSPMS were randomized in a 2:1 fashion to tolebrutinib or placebo. For the primary endpoint of CDW at 6 months, tolebrutinib demonstrated a major and highly significant reduction in this primary endpoint (HR 0.69; P = .00026).
 

BTKi Disability Protection Supported By Progressive MS Trial

“This is the first trial to show significant slowing of disability in people with nrSPMS,” reported the principal investigator Robert J. Fox, MD, Vice Chair of the Neurological Institute at Cleveland Clinic, Cleveland, Ohio.

For disability improvement at 6 months, tolebrutinib was associated with a nearly 2-fold improvement (HR 1.88; P = .021). According to both Dr. Oh and Dr. Fox the results of these two major phase 3 tolebrutinib studies support the principle that the BTKi, which was shown to offer inhibition of relapse comparable to teriflunomide in the GEMINI trials, offers a greater inhibition of chronic inflammation.

“These results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes,” Dr. Oh said.

Dr. Fox said that the HERCULES results will be submitted to regulatory authorities with the goal of securing an indication for tolebrutinib for nrSPMS.

Both Dr. Oh and Dr. Fox suggested these results are likely to reorient thinking about the pathophysiology of MS progression and how different processes can be targeted in the future. Other experts agreed.

“I think we are starting to look at different endpoints than ARR, particularly at those that might better reflect progression in later stages of MS and that are independent of ARR,” said Dalia Rotstein, MD, MS researcher and an assistant professor of neurology, University of Toronto, Canada.

A moderator of the ECTRIMS latebreaker session, she suggested that the differences between outcomes of the GEMINI trials and HERCULES trials might have relevance to each other even if the GEMINI trials did not meet their primary endpoint.

Dr. Oh reported financial relationships with Amgen, Biogen, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi, which provided funding for the GEMINI trials. Dr. Fox reported financial relationships with more than 15 pharmaceutical companies, including Sanofi, which also provided funding for the HERCULES trial. Dr. Rotstein reported financial relationships with Alexion, Biogen, EMD Serono, Horizon, Novartis, Roche, Sanofi, and Touch IME.

*Correction, 9/26/24: A previous version of this article contained an incorrect P value.

NEW YORK — Seborrheic dermatitis (SD) is a common and shared disorder across populations, but it is the third most common dermatologic complaint that Black individuals bring to the dermatologist and deserves more attention not only in this group but also overall, now that there is an approved therapy with an array of alternatives and adjunctive medications, according to Shawn Kwatra, MD.

The list of therapies effective against SD, often employed in combination, is lengthy, but topical 0.3% roflumilast foam (Zoryve), approved by the Food and Drug Administration (FDA) late last year for treating SD, has a high rate of efficacy and should now be considered a first-line treatment option, according to Dr. Kwatra, professor and chair of the Department of Dermatology, University of Maryland School of Medicine, Baltimore.
 

New Approved Therapy Draws Attention to SD

Emphasizing that topical roflumilast does not necessarily replace the use of over-the-counter shampoos and emollients or a list of prescription drugs used off-label to control this condition, he said it is also important for another reason.

Dr. Kwatra

“It shines a light on this disease,” said Dr. Kwatra, speaking at the 2024 Skin of Color Update. While his comments were focused primarily on individuals with darker skin, his major take home messages were broadly relevant across skin types.

He acknowledged that for years he “had not given seborrheic dermatitis the respect that it deserves” even though this condition comes after only acne and eczema as chief complaints among Black individuals seeing a dermatologist. The estimated global incidence is 5%, according to Dr. Kwatra, but he considers this estimate of an often “forgotten disease” too low.

One reason is that many individuals self-treat with over-the-counter solutions and never bring the complaint to a clinician. Dr. Kwatra said that he now looks for it routinely and points it out to patients who have come to him for another reason.

In patients with darker skin, the signs of SD can differ. While scalp involvement is generally easy to identify across skin types, the inflammation and erythema, sebum production, scaling and itch, and Malassezia that accompanies and drives SD might be missed in a patient with darker skin without specifically looking for these signs.
 

Skin and Gut Microbiome Involvement Suspected

The underlying causes of SD are understood as an inflammatory process involving keratinocyte disruption and proliferation that ultimately impairs skin barrier function, causes water loss, and produces scale stemming from stratum corneum, but Dr. Kwatra said that there is increasing evidence of a major role for both the skin and gut microbiome.

In regard to the skin microbiome, Malassezia has long been recognized as linked to SD and is a target of treatment, but evidence that the gut microbiome might be participating is relatively new. One clue comes from the fact that oral antifungal therapies, such as itraconazole, are known to reduce risk for SD relapse, an effect that might be a function of their ability to modulate the gut microbiome, according to Dr. Kwatra.

Topical roflumilast, a phosphodiesterase-4 inhibitor, was effective for SD in a vehicle-controlled phase 3 trial published in 2023. He characterized the adverse event profile as “pretty clean,” but he emphasized that a role for many other strategies remains. This is particularly true for challenging forms of SD. For example, topical tacrolimus provided meaningful protection against relapse over a period of more than 6 months in a 2021 trial that enrolled patients with severe facial SD.

The topical Janus kinase inhibitor ruxolitinib, 1.5%, (approved for atopic dermatitis and vitiligo) has also been reported to be effective for refractory facial SD. It is being evaluated in a phase 2 study of SD, according to Dr. Kwatra. A topical PDE4 inhibitor is also being evaluated for SD in a phase 2 study, he said.

Given the heterogeneity of the presentation of SD and the value of combining different mechanisms of action, Dr. Kwatra does not think any drug by itself will be a cure for SD. However, the chances of success with current drug combinations are high.

It is for this reason that Dr. Kwatra encourages clinicians to look for this disease routinely, including among patients who have a different presenting complaint. “Patients do not always bring it up, so bring it up,” he said.

This is good advice, according to Andrew F. Alexis, MD, MPH, professor of clinical dermatology and Vice-chair for Diversity and Inclusion of the Department of Dermatology, Weill Cornell Medicine, New York City. He agreed that the recent introduction of a therapy approved by the FDA is an impetus to look for SD and to talk with patients about treatment options.

In addition, while he also considers roflumilast foam to be a first-line drug, he agreed that combination therapies might be needed to increase the likely of rapid control of scalp and skin involvement. “SD is probably underestimated as a clinical problem, and we do have good treatments to offer for the patients who are affected,” he said at the meeting.

Dr. Kwatra reported no relevant disclosures. Dr. Alexis reported financial relationships with more than 25 pharmaceutical companies.

A version of this article appeared on Medscape.com.

NEW YORK — Seborrheic dermatitis (SD) is a common and shared disorder across populations, but it is the third most common dermatologic complaint that Black individuals bring to the dermatologist and deserves more attention not only in this group but also overall, now that there is an approved therapy with an array of alternatives and adjunctive medications, according to Shawn Kwatra, MD.

The list of therapies effective against SD, often employed in combination, is lengthy, but topical 0.3% roflumilast foam (Zoryve), approved by the Food and Drug Administration (FDA) late last year for treating SD, has a high rate of efficacy and should now be considered a first-line treatment option, according to Dr. Kwatra, professor and chair of the Department of Dermatology, University of Maryland School of Medicine, Baltimore.
 

New Approved Therapy Draws Attention to SD

Emphasizing that topical roflumilast does not necessarily replace the use of over-the-counter shampoos and emollients or a list of prescription drugs used off-label to control this condition, he said it is also important for another reason.

Dr. Kwatra

“It shines a light on this disease,” said Dr. Kwatra, speaking at the 2024 Skin of Color Update. While his comments were focused primarily on individuals with darker skin, his major take home messages were broadly relevant across skin types.

He acknowledged that for years he “had not given seborrheic dermatitis the respect that it deserves” even though this condition comes after only acne and eczema as chief complaints among Black individuals seeing a dermatologist. The estimated global incidence is 5%, according to Dr. Kwatra, but he considers this estimate of an often “forgotten disease” too low.

One reason is that many individuals self-treat with over-the-counter solutions and never bring the complaint to a clinician. Dr. Kwatra said that he now looks for it routinely and points it out to patients who have come to him for another reason.

In patients with darker skin, the signs of SD can differ. While scalp involvement is generally easy to identify across skin types, the inflammation and erythema, sebum production, scaling and itch, and Malassezia that accompanies and drives SD might be missed in a patient with darker skin without specifically looking for these signs.
 

Skin and Gut Microbiome Involvement Suspected

The underlying causes of SD are understood as an inflammatory process involving keratinocyte disruption and proliferation that ultimately impairs skin barrier function, causes water loss, and produces scale stemming from stratum corneum, but Dr. Kwatra said that there is increasing evidence of a major role for both the skin and gut microbiome.

In regard to the skin microbiome, Malassezia has long been recognized as linked to SD and is a target of treatment, but evidence that the gut microbiome might be participating is relatively new. One clue comes from the fact that oral antifungal therapies, such as itraconazole, are known to reduce risk for SD relapse, an effect that might be a function of their ability to modulate the gut microbiome, according to Dr. Kwatra.

Topical roflumilast, a phosphodiesterase-4 inhibitor, was effective for SD in a vehicle-controlled phase 3 trial published in 2023. He characterized the adverse event profile as “pretty clean,” but he emphasized that a role for many other strategies remains. This is particularly true for challenging forms of SD. For example, topical tacrolimus provided meaningful protection against relapse over a period of more than 6 months in a 2021 trial that enrolled patients with severe facial SD.

The topical Janus kinase inhibitor ruxolitinib, 1.5%, (approved for atopic dermatitis and vitiligo) has also been reported to be effective for refractory facial SD. It is being evaluated in a phase 2 study of SD, according to Dr. Kwatra. A topical PDE4 inhibitor is also being evaluated for SD in a phase 2 study, he said.

Given the heterogeneity of the presentation of SD and the value of combining different mechanisms of action, Dr. Kwatra does not think any drug by itself will be a cure for SD. However, the chances of success with current drug combinations are high.

It is for this reason that Dr. Kwatra encourages clinicians to look for this disease routinely, including among patients who have a different presenting complaint. “Patients do not always bring it up, so bring it up,” he said.

This is good advice, according to Andrew F. Alexis, MD, MPH, professor of clinical dermatology and Vice-chair for Diversity and Inclusion of the Department of Dermatology, Weill Cornell Medicine, New York City. He agreed that the recent introduction of a therapy approved by the FDA is an impetus to look for SD and to talk with patients about treatment options.

In addition, while he also considers roflumilast foam to be a first-line drug, he agreed that combination therapies might be needed to increase the likely of rapid control of scalp and skin involvement. “SD is probably underestimated as a clinical problem, and we do have good treatments to offer for the patients who are affected,” he said at the meeting.

Dr. Kwatra reported no relevant disclosures. Dr. Alexis reported financial relationships with more than 25 pharmaceutical companies.

A version of this article appeared on Medscape.com.

NEW YORK — Seborrheic dermatitis (SD) is a common and shared disorder across populations, but it is the third most common dermatologic complaint that Black individuals bring to the dermatologist and deserves more attention not only in this group but also overall, now that there is an approved therapy with an array of alternatives and adjunctive medications, according to Shawn Kwatra, MD.

The list of therapies effective against SD, often employed in combination, is lengthy, but topical 0.3% roflumilast foam (Zoryve), approved by the Food and Drug Administration (FDA) late last year for treating SD, has a high rate of efficacy and should now be considered a first-line treatment option, according to Dr. Kwatra, professor and chair of the Department of Dermatology, University of Maryland School of Medicine, Baltimore.
 

New Approved Therapy Draws Attention to SD

Emphasizing that topical roflumilast does not necessarily replace the use of over-the-counter shampoos and emollients or a list of prescription drugs used off-label to control this condition, he said it is also important for another reason.

Dr. Kwatra

“It shines a light on this disease,” said Dr. Kwatra, speaking at the 2024 Skin of Color Update. While his comments were focused primarily on individuals with darker skin, his major take home messages were broadly relevant across skin types.

He acknowledged that for years he “had not given seborrheic dermatitis the respect that it deserves” even though this condition comes after only acne and eczema as chief complaints among Black individuals seeing a dermatologist. The estimated global incidence is 5%, according to Dr. Kwatra, but he considers this estimate of an often “forgotten disease” too low.

One reason is that many individuals self-treat with over-the-counter solutions and never bring the complaint to a clinician. Dr. Kwatra said that he now looks for it routinely and points it out to patients who have come to him for another reason.

In patients with darker skin, the signs of SD can differ. While scalp involvement is generally easy to identify across skin types, the inflammation and erythema, sebum production, scaling and itch, and Malassezia that accompanies and drives SD might be missed in a patient with darker skin without specifically looking for these signs.
 

Skin and Gut Microbiome Involvement Suspected

The underlying causes of SD are understood as an inflammatory process involving keratinocyte disruption and proliferation that ultimately impairs skin barrier function, causes water loss, and produces scale stemming from stratum corneum, but Dr. Kwatra said that there is increasing evidence of a major role for both the skin and gut microbiome.

In regard to the skin microbiome, Malassezia has long been recognized as linked to SD and is a target of treatment, but evidence that the gut microbiome might be participating is relatively new. One clue comes from the fact that oral antifungal therapies, such as itraconazole, are known to reduce risk for SD relapse, an effect that might be a function of their ability to modulate the gut microbiome, according to Dr. Kwatra.

Topical roflumilast, a phosphodiesterase-4 inhibitor, was effective for SD in a vehicle-controlled phase 3 trial published in 2023. He characterized the adverse event profile as “pretty clean,” but he emphasized that a role for many other strategies remains. This is particularly true for challenging forms of SD. For example, topical tacrolimus provided meaningful protection against relapse over a period of more than 6 months in a 2021 trial that enrolled patients with severe facial SD.

The topical Janus kinase inhibitor ruxolitinib, 1.5%, (approved for atopic dermatitis and vitiligo) has also been reported to be effective for refractory facial SD. It is being evaluated in a phase 2 study of SD, according to Dr. Kwatra. A topical PDE4 inhibitor is also being evaluated for SD in a phase 2 study, he said.

Given the heterogeneity of the presentation of SD and the value of combining different mechanisms of action, Dr. Kwatra does not think any drug by itself will be a cure for SD. However, the chances of success with current drug combinations are high.

It is for this reason that Dr. Kwatra encourages clinicians to look for this disease routinely, including among patients who have a different presenting complaint. “Patients do not always bring it up, so bring it up,” he said.

This is good advice, according to Andrew F. Alexis, MD, MPH, professor of clinical dermatology and Vice-chair for Diversity and Inclusion of the Department of Dermatology, Weill Cornell Medicine, New York City. He agreed that the recent introduction of a therapy approved by the FDA is an impetus to look for SD and to talk with patients about treatment options.

In addition, while he also considers roflumilast foam to be a first-line drug, he agreed that combination therapies might be needed to increase the likely of rapid control of scalp and skin involvement. “SD is probably underestimated as a clinical problem, and we do have good treatments to offer for the patients who are affected,” he said at the meeting.

Dr. Kwatra reported no relevant disclosures. Dr. Alexis reported financial relationships with more than 25 pharmaceutical companies.

A version of this article appeared on Medscape.com.

NEW YORK — Because of their heterogeneity in appearance, drug-induced skin rashes are a common diagnostic challenge, but eruptions in skin of color, particularly those with a delayed onset, require a high index of suspicion to speed the diagnosis.

This risk for a delayed or missed diagnosis in patients with darker skin is shared across skin rashes, but drug-induced hypersensitivity syndrome (DIHS) is a telling example, according to Joanna Harp, MD, director of the Inpatient Dermatology Consult Service, NewYork–Presbyterian Hospital, New York City.

DIHS, also known as a drug reaction with eosinophilia and systemic symptoms, is a type IV hypersensitivity reaction, Dr. Harp explained. While the fact that this disorder does not always include eosinophilia prompted the DIHS acronym, the maculopapular rash often serves as a critical clue of the underlying etiology.

Signs of AGEP Can Be Subtle in Black Patients

Some of the same principles for diagnosing drug-induced rash in darker skin can also be applied to acute generalized exanthematous pustulosis (AGEP), another type IV hypersensitivity reaction. Like all drug-induced rashes, the earlier AGEP is recognized and treated, the better the outcome, but in Black patients, the signs can be subtle.

“The onset is usually fast and occurs in 1-2 days after [the causative drug] exposure,” said Dr. Harp, adding that antibiotics, such as cephalosporins or penicillin, and calcium channel blockers are among the prominent causes of AGEP.

One of the hallmark signs of early-onset AGEP are tiny erythematous pustules in flexural areas, such as the neck or the armpits. The issue of detecting erythema in darker skin is also relevant to this area, but there is an additional problem, according to Dr. Harp. The pustules often dry up quickly, leaving a neutrophilic scale that further complicates the effort to see the characteristic erythema.

“If you see a lot of scale, look for erythema underneath. Think of inflammation,” Dr. Harp said, explaining that the clinical appearance evolves quickly. “If you do not see the pustules, it does not mean they were not there; you just missed them.”

In addition to the flexural areas, “AGEP loves the ears, the face, and the geographic tongue,” she said, offering several pearls to help with the diagnosis. These include side lighting to make papules easier to see, pressing on the skin to highlight the difference between erythematous skin and blanched skin, and checking less pigmented skin, such as on the hands and feet, which makes erythema easier to see.

Steroids are often the first-line treatment for drug-induced skin rashes, but Dr. Harp moves to etanercept or cyclosporine for the most serious drug reactions, such as SJS and toxic epidermal necrolysis.

Etanercept is typically her first choice because patients with systemic hypersensitivity reactions with major organ involvement are often quite ill, making cyclosporine harder to use. In her experience, etanercept has been well tolerated.

Conversely, she cautioned against the use of intravenous immunoglobulin (IVIG). Although this has been used traditionally for severe drug hypersensitivity reactions, “the data are not there,” she said. The data are stronger for a combination of high-dose steroids and IVIG, but she thinks even these data are inconsistent and not as strong as the data supporting etanercept or cyclosporine. She encouraged centers still using IVIG to consider alternatives.

After drug sensitivity reactions are controlled, follow-up care is particularly important for Black patients who face greater risks for sequelae, such as hypopigmentation, hyperpigmentation, or keloids. She recommended aggressive use of emollients and sunscreens for an extended period after lesions resolve to lessen these risks.

Differences in the manifestations of drug-induced skin rashes by race and ethnicity are important and perhaps underappreciated, agreed Shawn Kwatra, MD, professor and chairman of the Department of Dermatology, University of Maryland, Baltimore.

Asked to comment at the meeting, Dr. Kwatra said that he appreciated Dr. Harp’s effort to translate published data and her experience into an overview that increases awareness of the risk for missed or delayed diagnoses of drug-induced rashes in skin of color. He noted that the strategies to identify erythema and pustules, such as increased suspicion in skin of color and the extra steps to rule them out, such as the use of side lighting in the case of pustules for AGEP, are simple and practical.

Dr. Harp and Dr. Kwatra had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

NEW YORK — Because of their heterogeneity in appearance, drug-induced skin rashes are a common diagnostic challenge, but eruptions in skin of color, particularly those with a delayed onset, require a high index of suspicion to speed the diagnosis.

This risk for a delayed or missed diagnosis in patients with darker skin is shared across skin rashes, but drug-induced hypersensitivity syndrome (DIHS) is a telling example, according to Joanna Harp, MD, director of the Inpatient Dermatology Consult Service, NewYork–Presbyterian Hospital, New York City.

DIHS, also known as a drug reaction with eosinophilia and systemic symptoms, is a type IV hypersensitivity reaction, Dr. Harp explained. While the fact that this disorder does not always include eosinophilia prompted the DIHS acronym, the maculopapular rash often serves as a critical clue of the underlying etiology.

Signs of AGEP Can Be Subtle in Black Patients

Some of the same principles for diagnosing drug-induced rash in darker skin can also be applied to acute generalized exanthematous pustulosis (AGEP), another type IV hypersensitivity reaction. Like all drug-induced rashes, the earlier AGEP is recognized and treated, the better the outcome, but in Black patients, the signs can be subtle.

“The onset is usually fast and occurs in 1-2 days after [the causative drug] exposure,” said Dr. Harp, adding that antibiotics, such as cephalosporins or penicillin, and calcium channel blockers are among the prominent causes of AGEP.

One of the hallmark signs of early-onset AGEP are tiny erythematous pustules in flexural areas, such as the neck or the armpits. The issue of detecting erythema in darker skin is also relevant to this area, but there is an additional problem, according to Dr. Harp. The pustules often dry up quickly, leaving a neutrophilic scale that further complicates the effort to see the characteristic erythema.

“If you see a lot of scale, look for erythema underneath. Think of inflammation,” Dr. Harp said, explaining that the clinical appearance evolves quickly. “If you do not see the pustules, it does not mean they were not there; you just missed them.”

In addition to the flexural areas, “AGEP loves the ears, the face, and the geographic tongue,” she said, offering several pearls to help with the diagnosis. These include side lighting to make papules easier to see, pressing on the skin to highlight the difference between erythematous skin and blanched skin, and checking less pigmented skin, such as on the hands and feet, which makes erythema easier to see.

Steroids are often the first-line treatment for drug-induced skin rashes, but Dr. Harp moves to etanercept or cyclosporine for the most serious drug reactions, such as SJS and toxic epidermal necrolysis.

Etanercept is typically her first choice because patients with systemic hypersensitivity reactions with major organ involvement are often quite ill, making cyclosporine harder to use. In her experience, etanercept has been well tolerated.

Conversely, she cautioned against the use of intravenous immunoglobulin (IVIG). Although this has been used traditionally for severe drug hypersensitivity reactions, “the data are not there,” she said. The data are stronger for a combination of high-dose steroids and IVIG, but she thinks even these data are inconsistent and not as strong as the data supporting etanercept or cyclosporine. She encouraged centers still using IVIG to consider alternatives.

After drug sensitivity reactions are controlled, follow-up care is particularly important for Black patients who face greater risks for sequelae, such as hypopigmentation, hyperpigmentation, or keloids. She recommended aggressive use of emollients and sunscreens for an extended period after lesions resolve to lessen these risks.

Differences in the manifestations of drug-induced skin rashes by race and ethnicity are important and perhaps underappreciated, agreed Shawn Kwatra, MD, professor and chairman of the Department of Dermatology, University of Maryland, Baltimore.

Asked to comment at the meeting, Dr. Kwatra said that he appreciated Dr. Harp’s effort to translate published data and her experience into an overview that increases awareness of the risk for missed or delayed diagnoses of drug-induced rashes in skin of color. He noted that the strategies to identify erythema and pustules, such as increased suspicion in skin of color and the extra steps to rule them out, such as the use of side lighting in the case of pustules for AGEP, are simple and practical.

Dr. Harp and Dr. Kwatra had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

NEW YORK — Because of their heterogeneity in appearance, drug-induced skin rashes are a common diagnostic challenge, but eruptions in skin of color, particularly those with a delayed onset, require a high index of suspicion to speed the diagnosis.

This risk for a delayed or missed diagnosis in patients with darker skin is shared across skin rashes, but drug-induced hypersensitivity syndrome (DIHS) is a telling example, according to Joanna Harp, MD, director of the Inpatient Dermatology Consult Service, NewYork–Presbyterian Hospital, New York City.

DIHS, also known as a drug reaction with eosinophilia and systemic symptoms, is a type IV hypersensitivity reaction, Dr. Harp explained. While the fact that this disorder does not always include eosinophilia prompted the DIHS acronym, the maculopapular rash often serves as a critical clue of the underlying etiology.

Signs of AGEP Can Be Subtle in Black Patients

Some of the same principles for diagnosing drug-induced rash in darker skin can also be applied to acute generalized exanthematous pustulosis (AGEP), another type IV hypersensitivity reaction. Like all drug-induced rashes, the earlier AGEP is recognized and treated, the better the outcome, but in Black patients, the signs can be subtle.

“The onset is usually fast and occurs in 1-2 days after [the causative drug] exposure,” said Dr. Harp, adding that antibiotics, such as cephalosporins or penicillin, and calcium channel blockers are among the prominent causes of AGEP.

One of the hallmark signs of early-onset AGEP are tiny erythematous pustules in flexural areas, such as the neck or the armpits. The issue of detecting erythema in darker skin is also relevant to this area, but there is an additional problem, according to Dr. Harp. The pustules often dry up quickly, leaving a neutrophilic scale that further complicates the effort to see the characteristic erythema.

“If you see a lot of scale, look for erythema underneath. Think of inflammation,” Dr. Harp said, explaining that the clinical appearance evolves quickly. “If you do not see the pustules, it does not mean they were not there; you just missed them.”

In addition to the flexural areas, “AGEP loves the ears, the face, and the geographic tongue,” she said, offering several pearls to help with the diagnosis. These include side lighting to make papules easier to see, pressing on the skin to highlight the difference between erythematous skin and blanched skin, and checking less pigmented skin, such as on the hands and feet, which makes erythema easier to see.

Steroids are often the first-line treatment for drug-induced skin rashes, but Dr. Harp moves to etanercept or cyclosporine for the most serious drug reactions, such as SJS and toxic epidermal necrolysis.

Etanercept is typically her first choice because patients with systemic hypersensitivity reactions with major organ involvement are often quite ill, making cyclosporine harder to use. In her experience, etanercept has been well tolerated.

Conversely, she cautioned against the use of intravenous immunoglobulin (IVIG). Although this has been used traditionally for severe drug hypersensitivity reactions, “the data are not there,” she said. The data are stronger for a combination of high-dose steroids and IVIG, but she thinks even these data are inconsistent and not as strong as the data supporting etanercept or cyclosporine. She encouraged centers still using IVIG to consider alternatives.

After drug sensitivity reactions are controlled, follow-up care is particularly important for Black patients who face greater risks for sequelae, such as hypopigmentation, hyperpigmentation, or keloids. She recommended aggressive use of emollients and sunscreens for an extended period after lesions resolve to lessen these risks.

Differences in the manifestations of drug-induced skin rashes by race and ethnicity are important and perhaps underappreciated, agreed Shawn Kwatra, MD, professor and chairman of the Department of Dermatology, University of Maryland, Baltimore.

Asked to comment at the meeting, Dr. Kwatra said that he appreciated Dr. Harp’s effort to translate published data and her experience into an overview that increases awareness of the risk for missed or delayed diagnoses of drug-induced rashes in skin of color. He noted that the strategies to identify erythema and pustules, such as increased suspicion in skin of color and the extra steps to rule them out, such as the use of side lighting in the case of pustules for AGEP, are simple and practical.

Dr. Harp and Dr. Kwatra had no relevant disclosures.
 

A version of this article appeared on Medscape.com.