Ted Bosworth

DENVER — Upon entry into the open-label extension (OLE) of the pivotal trial that led to approval of lecanemab for Alzheimer’s disease, placebo patients failed to show any appreciable catch up to the benefit achieved in the experimental arm, according to a first report of 6-month OLE data.

Due to the steady disease progression observed after the switch of placebo to active therapy, the message of these data is that “early initiation of lecanemab is important,” according to Michael Irizarry, MD, the senior vice president of clinical research at Eisai Ltd, which markets lecanemab.

The 6-month OLE data along with data from a tau PET substudy were presented by Dr. Irizarry at the 2024 annual meeting of the American Academy of Neurology.

From the start of the OLE through the 6-month follow-up, the downward trajectory of cognitive function, as measured with the Clinical Dementia Rating – Sum of Boxes (CDR-SB), has been parallel for the lecanemab-start and switch arms. As a result, the degree of separation between active and placebo groups over the course of the OLE has remained unchanged from the end of the randomized trial.

This does not rule out any benefit in the switch arm, according to Dr. Irizarry. Although there was no discernible change in the trajectory of decline among placebo patients after they were switched to lecanemab, Dr. Irizarry postulated that this might overlook the greater likely decline over time with no treatment.

“There was no placebo group in the OLE to compare with those on active treatment,” he pointed out. He then juxtaposed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Over the same 6-month timeframe, these data show a hypothetical separation of the curves if no treatment had been received.

The 6-month OLE data provide a preliminary look at outcomes in a planned 4-year follow-up. At the end of the randomized CLARITY trial, the mean decline from the baseline CDR-SB score of 3.2, was 1.21 in the lecanemab group, translating into a 38% decline, and 1.66 in the placebo group, translating into about a 50% decline. Over the 6 months of OLE, there has been a further mean CDR-SB reduction of approximately 0.6 in both arms, suggesting a further 18% decline from baseline.
 

Additional Data

In the pivotal CLARITY trial, which was published a few months prior to regulatory approval early last year, 1785 patients were randomized to 10 mg/kg lecanemab or placebo infused every 2 weeks. At the end of 18 months, the superiority of lecanemab for the primary endpoint of adverse change in CDR-SB was highly significant (P < .001) as were the differences in key secondary endpoints, such as Alzheimer’s Disease Composite Score (P < .001).

Of those who participated in CLARITY, 1385 patients entered the OLE. Placebo patients were switched to lecanemab which is being maintained in all patients on the trial schedule of 10 mg/kg administered by intravenous infusion every 2 weeks.

In addition to the overall OLE 6-month data, which has not raised any new safety signals, Dr. Irizarry provided a new look at the PET TAU substudy with a focus on patients who entered the study with a low relative tau burden. Of the three classifications, which also included medium and high tau, as measured with positron-emission tomography (PET), the low tau group represented 41.2% of the 342 tau PET substudy participants. With only 2.9% entering the study with a high tau burden, almost all the others fell in the medium stratification.

Due to the potential for a lower therapeutic response, “patients with low Tau are often excluded from trials,” Dr. Irizarry said. But the sizable proportion of low tau patients has permitted an assessment of relative response with lecanemab, which turned out to be substantial.

“Consistent rates of clinical stability or improvements were observed regardless of baseline tau levels with the highest rates of improvements observed for the low tau group after 24 months of follow-up,” Dr. Irizarry reported.

In previously reported results from the tau PET substudy, lecanemab was shown to slow tau spread at least numerically in every section of the brain evaluated, including the frontal, cingulate, parietal, and whole cortical gray matter areas. The reductions reached significance for the medial temporal (P = .0024), meta temporal (P = .012), and temporal (P = .16) portions.

When most recently evaluated in the OLE, the CDR-SB score declined 38% less among those treated with lecanemab than those treated with placebo in the subgroup enrolled in the tau PET substudy.

Relative to those with intermediate or high tau, patients in the low tau had an even greater reduction in cognitive decline than those with higher tau burdens. Although Dr. Irizarry cautioned that greater baseline CDR-SB scores exaggerated the treatment effect in the low tau group, the message is that “a lecanemab treatment effect is seen even when baseline tau levels are low.”

Now, with the recent market withdrawal of aducanumab, another anti-amyloid monoclonal antibody that was previously approved for Alzheimer’s disease, lecanemab is the only therapy currently available for the goal of changing disease progression, not just modifying symptoms.
 

Looking Long Term

Both sets of data provide important messages for clinicians, according to Marcelo Matiello, MD, a physician investigator at Mass General Hospital and associate professor of neurology at Harvard Medical School, Boston.

“Clinicians are really looking for more data because this remains a relatively new drug,” he said. Both sets of findings presented by Dr. Irizarry “look good but the follow-up is still short, so I think everyone is still looking closely at long-term safety and efficacy.”

The need for continuous indefinite therapy is one concern that Dr. Matiello expressed. As moderator of the session in which these data were presented, Dr. Matiello specifically asked Dr. Irizarry if there are plans to explore whether periods without treatment might be a means to reduce the cost and burden of frequent infusions while preserving cognitive gains.

In response, Dr. Irizarry said that earlier studies showed rapid progression when lecanemab was stopped. On this basis, he thinks therapy must be maintained, but he did say that there are plans to look at less frequent dosing, such as once per month. He also said that a subcutaneous formulation in development might also reduce the burden of prolonged treatment.

Dr. Irizarry is an employee of Eisai Ltd., which manufacturers lecanemab. Dr. Matiello reports no potential conflicts of interest.

DENVER — Upon entry into the open-label extension (OLE) of the pivotal trial that led to approval of lecanemab for Alzheimer’s disease, placebo patients failed to show any appreciable catch up to the benefit achieved in the experimental arm, according to a first report of 6-month OLE data.

Due to the steady disease progression observed after the switch of placebo to active therapy, the message of these data is that “early initiation of lecanemab is important,” according to Michael Irizarry, MD, the senior vice president of clinical research at Eisai Ltd, which markets lecanemab.

The 6-month OLE data along with data from a tau PET substudy were presented by Dr. Irizarry at the 2024 annual meeting of the American Academy of Neurology.

From the start of the OLE through the 6-month follow-up, the downward trajectory of cognitive function, as measured with the Clinical Dementia Rating – Sum of Boxes (CDR-SB), has been parallel for the lecanemab-start and switch arms. As a result, the degree of separation between active and placebo groups over the course of the OLE has remained unchanged from the end of the randomized trial.

This does not rule out any benefit in the switch arm, according to Dr. Irizarry. Although there was no discernible change in the trajectory of decline among placebo patients after they were switched to lecanemab, Dr. Irizarry postulated that this might overlook the greater likely decline over time with no treatment.

“There was no placebo group in the OLE to compare with those on active treatment,” he pointed out. He then juxtaposed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Over the same 6-month timeframe, these data show a hypothetical separation of the curves if no treatment had been received.

The 6-month OLE data provide a preliminary look at outcomes in a planned 4-year follow-up. At the end of the randomized CLARITY trial, the mean decline from the baseline CDR-SB score of 3.2, was 1.21 in the lecanemab group, translating into a 38% decline, and 1.66 in the placebo group, translating into about a 50% decline. Over the 6 months of OLE, there has been a further mean CDR-SB reduction of approximately 0.6 in both arms, suggesting a further 18% decline from baseline.
 

Additional Data

In the pivotal CLARITY trial, which was published a few months prior to regulatory approval early last year, 1785 patients were randomized to 10 mg/kg lecanemab or placebo infused every 2 weeks. At the end of 18 months, the superiority of lecanemab for the primary endpoint of adverse change in CDR-SB was highly significant (P < .001) as were the differences in key secondary endpoints, such as Alzheimer’s Disease Composite Score (P < .001).

Of those who participated in CLARITY, 1385 patients entered the OLE. Placebo patients were switched to lecanemab which is being maintained in all patients on the trial schedule of 10 mg/kg administered by intravenous infusion every 2 weeks.

In addition to the overall OLE 6-month data, which has not raised any new safety signals, Dr. Irizarry provided a new look at the PET TAU substudy with a focus on patients who entered the study with a low relative tau burden. Of the three classifications, which also included medium and high tau, as measured with positron-emission tomography (PET), the low tau group represented 41.2% of the 342 tau PET substudy participants. With only 2.9% entering the study with a high tau burden, almost all the others fell in the medium stratification.

Due to the potential for a lower therapeutic response, “patients with low Tau are often excluded from trials,” Dr. Irizarry said. But the sizable proportion of low tau patients has permitted an assessment of relative response with lecanemab, which turned out to be substantial.

“Consistent rates of clinical stability or improvements were observed regardless of baseline tau levels with the highest rates of improvements observed for the low tau group after 24 months of follow-up,” Dr. Irizarry reported.

In previously reported results from the tau PET substudy, lecanemab was shown to slow tau spread at least numerically in every section of the brain evaluated, including the frontal, cingulate, parietal, and whole cortical gray matter areas. The reductions reached significance for the medial temporal (P = .0024), meta temporal (P = .012), and temporal (P = .16) portions.

When most recently evaluated in the OLE, the CDR-SB score declined 38% less among those treated with lecanemab than those treated with placebo in the subgroup enrolled in the tau PET substudy.

Relative to those with intermediate or high tau, patients in the low tau had an even greater reduction in cognitive decline than those with higher tau burdens. Although Dr. Irizarry cautioned that greater baseline CDR-SB scores exaggerated the treatment effect in the low tau group, the message is that “a lecanemab treatment effect is seen even when baseline tau levels are low.”

Now, with the recent market withdrawal of aducanumab, another anti-amyloid monoclonal antibody that was previously approved for Alzheimer’s disease, lecanemab is the only therapy currently available for the goal of changing disease progression, not just modifying symptoms.
 

Looking Long Term

Both sets of data provide important messages for clinicians, according to Marcelo Matiello, MD, a physician investigator at Mass General Hospital and associate professor of neurology at Harvard Medical School, Boston.

“Clinicians are really looking for more data because this remains a relatively new drug,” he said. Both sets of findings presented by Dr. Irizarry “look good but the follow-up is still short, so I think everyone is still looking closely at long-term safety and efficacy.”

The need for continuous indefinite therapy is one concern that Dr. Matiello expressed. As moderator of the session in which these data were presented, Dr. Matiello specifically asked Dr. Irizarry if there are plans to explore whether periods without treatment might be a means to reduce the cost and burden of frequent infusions while preserving cognitive gains.

In response, Dr. Irizarry said that earlier studies showed rapid progression when lecanemab was stopped. On this basis, he thinks therapy must be maintained, but he did say that there are plans to look at less frequent dosing, such as once per month. He also said that a subcutaneous formulation in development might also reduce the burden of prolonged treatment.

Dr. Irizarry is an employee of Eisai Ltd., which manufacturers lecanemab. Dr. Matiello reports no potential conflicts of interest.

DENVER — Upon entry into the open-label extension (OLE) of the pivotal trial that led to approval of lecanemab for Alzheimer’s disease, placebo patients failed to show any appreciable catch up to the benefit achieved in the experimental arm, according to a first report of 6-month OLE data.

Due to the steady disease progression observed after the switch of placebo to active therapy, the message of these data is that “early initiation of lecanemab is important,” according to Michael Irizarry, MD, the senior vice president of clinical research at Eisai Ltd, which markets lecanemab.

The 6-month OLE data along with data from a tau PET substudy were presented by Dr. Irizarry at the 2024 annual meeting of the American Academy of Neurology.

From the start of the OLE through the 6-month follow-up, the downward trajectory of cognitive function, as measured with the Clinical Dementia Rating – Sum of Boxes (CDR-SB), has been parallel for the lecanemab-start and switch arms. As a result, the degree of separation between active and placebo groups over the course of the OLE has remained unchanged from the end of the randomized trial.

This does not rule out any benefit in the switch arm, according to Dr. Irizarry. Although there was no discernible change in the trajectory of decline among placebo patients after they were switched to lecanemab, Dr. Irizarry postulated that this might overlook the greater likely decline over time with no treatment.

“There was no placebo group in the OLE to compare with those on active treatment,” he pointed out. He then juxtaposed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Over the same 6-month timeframe, these data show a hypothetical separation of the curves if no treatment had been received.

The 6-month OLE data provide a preliminary look at outcomes in a planned 4-year follow-up. At the end of the randomized CLARITY trial, the mean decline from the baseline CDR-SB score of 3.2, was 1.21 in the lecanemab group, translating into a 38% decline, and 1.66 in the placebo group, translating into about a 50% decline. Over the 6 months of OLE, there has been a further mean CDR-SB reduction of approximately 0.6 in both arms, suggesting a further 18% decline from baseline.
 

Additional Data

In the pivotal CLARITY trial, which was published a few months prior to regulatory approval early last year, 1785 patients were randomized to 10 mg/kg lecanemab or placebo infused every 2 weeks. At the end of 18 months, the superiority of lecanemab for the primary endpoint of adverse change in CDR-SB was highly significant (P < .001) as were the differences in key secondary endpoints, such as Alzheimer’s Disease Composite Score (P < .001).

Of those who participated in CLARITY, 1385 patients entered the OLE. Placebo patients were switched to lecanemab which is being maintained in all patients on the trial schedule of 10 mg/kg administered by intravenous infusion every 2 weeks.

In addition to the overall OLE 6-month data, which has not raised any new safety signals, Dr. Irizarry provided a new look at the PET TAU substudy with a focus on patients who entered the study with a low relative tau burden. Of the three classifications, which also included medium and high tau, as measured with positron-emission tomography (PET), the low tau group represented 41.2% of the 342 tau PET substudy participants. With only 2.9% entering the study with a high tau burden, almost all the others fell in the medium stratification.

Due to the potential for a lower therapeutic response, “patients with low Tau are often excluded from trials,” Dr. Irizarry said. But the sizable proportion of low tau patients has permitted an assessment of relative response with lecanemab, which turned out to be substantial.

“Consistent rates of clinical stability or improvements were observed regardless of baseline tau levels with the highest rates of improvements observed for the low tau group after 24 months of follow-up,” Dr. Irizarry reported.

In previously reported results from the tau PET substudy, lecanemab was shown to slow tau spread at least numerically in every section of the brain evaluated, including the frontal, cingulate, parietal, and whole cortical gray matter areas. The reductions reached significance for the medial temporal (P = .0024), meta temporal (P = .012), and temporal (P = .16) portions.

When most recently evaluated in the OLE, the CDR-SB score declined 38% less among those treated with lecanemab than those treated with placebo in the subgroup enrolled in the tau PET substudy.

Relative to those with intermediate or high tau, patients in the low tau had an even greater reduction in cognitive decline than those with higher tau burdens. Although Dr. Irizarry cautioned that greater baseline CDR-SB scores exaggerated the treatment effect in the low tau group, the message is that “a lecanemab treatment effect is seen even when baseline tau levels are low.”

Now, with the recent market withdrawal of aducanumab, another anti-amyloid monoclonal antibody that was previously approved for Alzheimer’s disease, lecanemab is the only therapy currently available for the goal of changing disease progression, not just modifying symptoms.
 

Looking Long Term

Both sets of data provide important messages for clinicians, according to Marcelo Matiello, MD, a physician investigator at Mass General Hospital and associate professor of neurology at Harvard Medical School, Boston.

“Clinicians are really looking for more data because this remains a relatively new drug,” he said. Both sets of findings presented by Dr. Irizarry “look good but the follow-up is still short, so I think everyone is still looking closely at long-term safety and efficacy.”

The need for continuous indefinite therapy is one concern that Dr. Matiello expressed. As moderator of the session in which these data were presented, Dr. Matiello specifically asked Dr. Irizarry if there are plans to explore whether periods without treatment might be a means to reduce the cost and burden of frequent infusions while preserving cognitive gains.

In response, Dr. Irizarry said that earlier studies showed rapid progression when lecanemab was stopped. On this basis, he thinks therapy must be maintained, but he did say that there are plans to look at less frequent dosing, such as once per month. He also said that a subcutaneous formulation in development might also reduce the burden of prolonged treatment.

Dr. Irizarry is an employee of Eisai Ltd., which manufacturers lecanemab. Dr. Matiello reports no potential conflicts of interest.

DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.

According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.

“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.

In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.

“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,

This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
 

The New Focus on Prevention

The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.

There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.

A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.

Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.

Dr. Feldman reported no potential conflicts of interest.

DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.

According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.

“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.

In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.

“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,

This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
 

The New Focus on Prevention

The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.

There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.

A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.

Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.

Dr. Feldman reported no potential conflicts of interest.

DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.

According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.

“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.

In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.

“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,

This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
 

The New Focus on Prevention

The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.

There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.

A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.

Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.

Dr. Feldman reported no potential conflicts of interest.

DENVER — Unlike traditional antidiabetic therapies, which have never been associated with a significant reduction in stroke in a major trial, some of the newer drugs are showing that benefit, but the protection is not linked to tighter glycemic control.

In patients with type 2 diabetes mellitus (T2DM), the evidence is strong that “they are not working through glycemic control per se,” according to Larry B. Goldstein, MD, chair of neurology, University of Kentucky School of Medicine, Louisville. “But it is not yet clear what the mechanism of benefit is.”

Ted Bosworth/MDedge News

Stroke Prevention With Antidiabetic Drugs

“What has changed is that we have new ways of glycemic control, and some of these do show protection against stroke,” Dr. Goldstein said. Yet, the newer drugs do not do a better job at sustained reductions of HbA1c or other measures of reaching lower blood glucose reductions when adherence is similar.

“The level of glucose control with the newer agents is really about the same,” Dr. Goldstein said at the annual meeting of the American Academy of Neurology, where he led a symposium called Controversies in Stroke Treatment and Prevention.

The newer agents, such as sodium glucose co-transport-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), have been associated with significant and clinically meaningful reductions in cardiovascular events. However, it is not clear that even these two medications perform similarly for stroke prevention specifically.

Of these two drug classes, Dr. Goldstein said the evidence most strongly supports GLP-1 receptor agonists. He cited one meta-analysis of eight randomized studies that calculated a risk reduction of about 15% whether calculated for fatal or nonfatal strokes. For each the protection was highly statistically significant (P = .0002 and P < .001, respectively).

In contrast, the effect of SGLT-2 inhibitors is weaker. In a study that distilled data from large cardiovascular trials with GLP-1RA, SGLT2i, dipeptidyl peptidase-4 inhibitors (DPP4i), and pioglitazone, a thiazolidinedione, only GLP-1RA drugs were associated with a highly significant (P < .001) reduction in risk of stroke. The risk reduction for pioglitazone reached significance (P = .025), but there was no signal of risk reduction for SGLT2i (P = .88) or for DPP4i (P = .5).
 

Weight Loss Is Potential Mechanism

Looking to explain the protection from stroke associated with some of the newer antidiabetic therapies, Gordon Kelley, MD, who leads the stroke program for AdventHealth Medical Group, Shawnee Mission, Kansas, suggested that weight loss is probably important.

“In our group, we work as a team to manage stroke risk in patients with diabetes, so I am not much involved in the choice of antidiabetic therapies, but it does seem that SGLT2 inhibitors and the GLP-1 receptor agonists share weight loss as an effect beyond glucose control,” he said.

Dr. Goldstein agreed that weight loss is a potential contributor to the cardiovascular benefits of GLP-1RA and SGLT2i, but he indicated that it might not help explain the reduction in stroke, an effect demonstrated repeatedly with GLP-1RA but inconsistently with SGLT2i.

The argument against weight loss as the critical mechanism of stroke prevention from newer antidiabetic drugs is strengthened by studies that suggest weight loss with SGLT2i appears to be even better than on GLP-1RA. In a study published in a pharmacy journal, weight loss was about twice as great among T2DM patients after 6 months of treatment managed with SGLT2i relative to those on a GLP-1RA (-2.8 vs 1.15 kg; P = .014).
 

Newer Antidiabetic Agents Guideline Recommended

In the 2019 American College of Cardiology/American Heart Association guidelines on the Primary Prevention of Cardiovascular Disease, stroke reduction is not discussed as an isolated risk, but these guidelines do recommend GLP-1RA or SGLT2i after metformin for glycemic control in T2DM patients with atherosclerotic cardiovascular disease (ASCVD) risk factors. This is based on evidence that drugs of both classes reduce risk for ASCVD events. The risk reduction has been particularly strong for heart failure.

For the risk of stroke specifically in patients with T2DM, Dr. Goldstein recommended calculating the ASCVD risk with the simple but well validated ACC risk calculator that is available online and is quickly completed when values for patient risk factors are readily available. For those with greater than 10% risk of an event in the next 10 years, he thinks GLP-1RA are a reasonable choice for prevention of stroke and other ASCVD events.

“GLP-1RA is mentioned in the guidelines, so this is supported,” said Dr. Goldstein, although adding that his choice of this class over SGLT2i is a personal if informed recommendation. He believes that the data favor GLP-1RA even if the exact mechanism of this protection is yet to be identified.

Dr. Goldstein and Dr. Kelley report no potential conflicts of interest.

DENVER — Unlike traditional antidiabetic therapies, which have never been associated with a significant reduction in stroke in a major trial, some of the newer drugs are showing that benefit, but the protection is not linked to tighter glycemic control.

In patients with type 2 diabetes mellitus (T2DM), the evidence is strong that “they are not working through glycemic control per se,” according to Larry B. Goldstein, MD, chair of neurology, University of Kentucky School of Medicine, Louisville. “But it is not yet clear what the mechanism of benefit is.”

Ted Bosworth/MDedge News

Stroke Prevention With Antidiabetic Drugs

“What has changed is that we have new ways of glycemic control, and some of these do show protection against stroke,” Dr. Goldstein said. Yet, the newer drugs do not do a better job at sustained reductions of HbA1c or other measures of reaching lower blood glucose reductions when adherence is similar.

“The level of glucose control with the newer agents is really about the same,” Dr. Goldstein said at the annual meeting of the American Academy of Neurology, where he led a symposium called Controversies in Stroke Treatment and Prevention.

The newer agents, such as sodium glucose co-transport-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), have been associated with significant and clinically meaningful reductions in cardiovascular events. However, it is not clear that even these two medications perform similarly for stroke prevention specifically.

Of these two drug classes, Dr. Goldstein said the evidence most strongly supports GLP-1 receptor agonists. He cited one meta-analysis of eight randomized studies that calculated a risk reduction of about 15% whether calculated for fatal or nonfatal strokes. For each the protection was highly statistically significant (P = .0002 and P < .001, respectively).

In contrast, the effect of SGLT-2 inhibitors is weaker. In a study that distilled data from large cardiovascular trials with GLP-1RA, SGLT2i, dipeptidyl peptidase-4 inhibitors (DPP4i), and pioglitazone, a thiazolidinedione, only GLP-1RA drugs were associated with a highly significant (P < .001) reduction in risk of stroke. The risk reduction for pioglitazone reached significance (P = .025), but there was no signal of risk reduction for SGLT2i (P = .88) or for DPP4i (P = .5).
 

Weight Loss Is Potential Mechanism

Looking to explain the protection from stroke associated with some of the newer antidiabetic therapies, Gordon Kelley, MD, who leads the stroke program for AdventHealth Medical Group, Shawnee Mission, Kansas, suggested that weight loss is probably important.

“In our group, we work as a team to manage stroke risk in patients with diabetes, so I am not much involved in the choice of antidiabetic therapies, but it does seem that SGLT2 inhibitors and the GLP-1 receptor agonists share weight loss as an effect beyond glucose control,” he said.

Dr. Goldstein agreed that weight loss is a potential contributor to the cardiovascular benefits of GLP-1RA and SGLT2i, but he indicated that it might not help explain the reduction in stroke, an effect demonstrated repeatedly with GLP-1RA but inconsistently with SGLT2i.

The argument against weight loss as the critical mechanism of stroke prevention from newer antidiabetic drugs is strengthened by studies that suggest weight loss with SGLT2i appears to be even better than on GLP-1RA. In a study published in a pharmacy journal, weight loss was about twice as great among T2DM patients after 6 months of treatment managed with SGLT2i relative to those on a GLP-1RA (-2.8 vs 1.15 kg; P = .014).
 

Newer Antidiabetic Agents Guideline Recommended

In the 2019 American College of Cardiology/American Heart Association guidelines on the Primary Prevention of Cardiovascular Disease, stroke reduction is not discussed as an isolated risk, but these guidelines do recommend GLP-1RA or SGLT2i after metformin for glycemic control in T2DM patients with atherosclerotic cardiovascular disease (ASCVD) risk factors. This is based on evidence that drugs of both classes reduce risk for ASCVD events. The risk reduction has been particularly strong for heart failure.

For the risk of stroke specifically in patients with T2DM, Dr. Goldstein recommended calculating the ASCVD risk with the simple but well validated ACC risk calculator that is available online and is quickly completed when values for patient risk factors are readily available. For those with greater than 10% risk of an event in the next 10 years, he thinks GLP-1RA are a reasonable choice for prevention of stroke and other ASCVD events.

“GLP-1RA is mentioned in the guidelines, so this is supported,” said Dr. Goldstein, although adding that his choice of this class over SGLT2i is a personal if informed recommendation. He believes that the data favor GLP-1RA even if the exact mechanism of this protection is yet to be identified.

Dr. Goldstein and Dr. Kelley report no potential conflicts of interest.

DENVER — Unlike traditional antidiabetic therapies, which have never been associated with a significant reduction in stroke in a major trial, some of the newer drugs are showing that benefit, but the protection is not linked to tighter glycemic control.

In patients with type 2 diabetes mellitus (T2DM), the evidence is strong that “they are not working through glycemic control per se,” according to Larry B. Goldstein, MD, chair of neurology, University of Kentucky School of Medicine, Louisville. “But it is not yet clear what the mechanism of benefit is.”

Ted Bosworth/MDedge News

Stroke Prevention With Antidiabetic Drugs

“What has changed is that we have new ways of glycemic control, and some of these do show protection against stroke,” Dr. Goldstein said. Yet, the newer drugs do not do a better job at sustained reductions of HbA1c or other measures of reaching lower blood glucose reductions when adherence is similar.

“The level of glucose control with the newer agents is really about the same,” Dr. Goldstein said at the annual meeting of the American Academy of Neurology, where he led a symposium called Controversies in Stroke Treatment and Prevention.

The newer agents, such as sodium glucose co-transport-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), have been associated with significant and clinically meaningful reductions in cardiovascular events. However, it is not clear that even these two medications perform similarly for stroke prevention specifically.

Of these two drug classes, Dr. Goldstein said the evidence most strongly supports GLP-1 receptor agonists. He cited one meta-analysis of eight randomized studies that calculated a risk reduction of about 15% whether calculated for fatal or nonfatal strokes. For each the protection was highly statistically significant (P = .0002 and P < .001, respectively).

In contrast, the effect of SGLT-2 inhibitors is weaker. In a study that distilled data from large cardiovascular trials with GLP-1RA, SGLT2i, dipeptidyl peptidase-4 inhibitors (DPP4i), and pioglitazone, a thiazolidinedione, only GLP-1RA drugs were associated with a highly significant (P < .001) reduction in risk of stroke. The risk reduction for pioglitazone reached significance (P = .025), but there was no signal of risk reduction for SGLT2i (P = .88) or for DPP4i (P = .5).
 

Weight Loss Is Potential Mechanism

Looking to explain the protection from stroke associated with some of the newer antidiabetic therapies, Gordon Kelley, MD, who leads the stroke program for AdventHealth Medical Group, Shawnee Mission, Kansas, suggested that weight loss is probably important.

“In our group, we work as a team to manage stroke risk in patients with diabetes, so I am not much involved in the choice of antidiabetic therapies, but it does seem that SGLT2 inhibitors and the GLP-1 receptor agonists share weight loss as an effect beyond glucose control,” he said.

Dr. Goldstein agreed that weight loss is a potential contributor to the cardiovascular benefits of GLP-1RA and SGLT2i, but he indicated that it might not help explain the reduction in stroke, an effect demonstrated repeatedly with GLP-1RA but inconsistently with SGLT2i.

The argument against weight loss as the critical mechanism of stroke prevention from newer antidiabetic drugs is strengthened by studies that suggest weight loss with SGLT2i appears to be even better than on GLP-1RA. In a study published in a pharmacy journal, weight loss was about twice as great among T2DM patients after 6 months of treatment managed with SGLT2i relative to those on a GLP-1RA (-2.8 vs 1.15 kg; P = .014).
 

Newer Antidiabetic Agents Guideline Recommended

In the 2019 American College of Cardiology/American Heart Association guidelines on the Primary Prevention of Cardiovascular Disease, stroke reduction is not discussed as an isolated risk, but these guidelines do recommend GLP-1RA or SGLT2i after metformin for glycemic control in T2DM patients with atherosclerotic cardiovascular disease (ASCVD) risk factors. This is based on evidence that drugs of both classes reduce risk for ASCVD events. The risk reduction has been particularly strong for heart failure.

For the risk of stroke specifically in patients with T2DM, Dr. Goldstein recommended calculating the ASCVD risk with the simple but well validated ACC risk calculator that is available online and is quickly completed when values for patient risk factors are readily available. For those with greater than 10% risk of an event in the next 10 years, he thinks GLP-1RA are a reasonable choice for prevention of stroke and other ASCVD events.

“GLP-1RA is mentioned in the guidelines, so this is supported,” said Dr. Goldstein, although adding that his choice of this class over SGLT2i is a personal if informed recommendation. He believes that the data favor GLP-1RA even if the exact mechanism of this protection is yet to be identified.

Dr. Goldstein and Dr. Kelley report no potential conflicts of interest.

SAN DIEGO — In patients with alopecia areata (AA), the decision of when to give up on JAK inhibitors because of an inadequate response is being complicated by long-term follow-up showing that some patients accrue hair very slowly, according to late breaker data presented at the annual meeting of the American Academy of Dermatology.

Although the majority respond within months, response curves have so far climbed for as long as patients are followed, allowing many with disappointing early results to catch up, according to Rodney D. Sinclair, MD, professor of dermatology at the University of Melbourne, Australia.

His remarks were derived specifically from new long-term follow-up with baricitinib, the first JAK inhibitor approved for AA, but the pattern appears to be similar with ritlecitinib, the only other JAK inhibitor approved for AA, and for several if not all JAK inhibitors in phase 3 AA trials.

“We have had patients on baricitinib where not much was happening at 18 months, but now, at 4 years, they have a SALT score of zero,” Dr. Sinclair reported

A Severity of Alopecia Tool (SALT) score of 0 signifies complete hair regrowth. On a scale with a maximum score of 100 (complete hair loss), a SALT score of 20 or less, signaling clinical success, has been a primary endpoint in many JAK inhibitor trials, including those conducted with baricitinib.

Providing the most recent analysis in patients with severe AA participating in the phase 3 BRAVE-AA1 and BRAVE-AA2 trials of baricitinib, which were published together in 2022, Dr. Sinclair broke the data down into responders, mixed responders, and nonresponders at 52 weeks. The proportion of patients who responded with even longer follow-up were then tallied.

In the as-observed responses over time, the trajectory of response continued to climb through 76 weeks of follow-up in all three groups.

Relative to the 44.5% rate of overall response (SALT ≤ 20 ) at 52 weeks, there was some further growth in every group maintained on JAK inhibitor therapy over longer follow-up. In Dr. Sinclair’s late breaking analysis, this did not include nonresponders, who stopped therapy by week 52, but 78.4% of the combined responders and mixed responders who remained on treatment had reached treatment success at 76 weeks.
 

Response Curves Climb More Slowly With Severe Alopecia

While improvement in SALT scores was even seen in nonresponders over time as long as they remained on therapy, Dr. Sinclair reported that response curves tended to climb more slowly in those with more severe alopecia at baseline. Yet, they still climbed. For example, 28.1% of those with a baseline SALT score of 95 to 100 had reached treatment success at week 52, but the proportion had climbed to 35.4% by week 76.

The response curves climbed more quickly among those with a SALT score between 50 and 95 at baseline than among those with more severe alopecia, but the differences in SALT scores at 52 weeks and 76 weeks among patients in this range of baseline SALT scores were small.

Basically, “those with a SALT score of 94 did just as well as those with a SALT score of 51 when followed long-term,” he said, noting that this was among several findings that confounded expectations.

Duration of AA was found to be an important prognostic factor, with 4 years emerging as a general threshold separating those with a diminished likelihood of benefit relative to those with a shorter AA duration.

“When the duration of AA is more than 4 years, the response to any JAK inhibitor seems to fall off a cliff,” Dr. Sinclair said.

To clarify this observation, Dr. Sinclair made an analogy between acute and chronic urticaria. Chronicity appears to change the pathophysiology of both urticaria and AA, making durable remissions more difficult to achieve if the inflammatory response was persistently upregulated, he said.

The delayed responses in some patients “suggests that it is not enough to control inflammation for the hair to regrow. You actually have to activate the hair to grow as well as treat the inflammation,” Dr. Sinclair said.

This heterogeneity that has been observed in the speed of AA response to JAK inhibitors might be explained at least in part by the individual differences in hair growth activation. For ritlecitinib, the only other JAK inhibitor approved for AA to date, 62% were categorized as responders in the registration ALLEGRO trials, but only 44% were early responders, meaning SALT scores of ≤ 20 by week 24, according to a summary published last year. Of the remaining 16%, 11% were middle responders, meaning a SALT score of ≤ 20 reached at week 48, and 6% were late responders, meaning a SALT score of ≤ 20 reached at week 96.

In the context of late breaking 68-week data with deuruxolitinib, an oral JAK inhibitor currently under FDA review for treating moderate to severe AA, presented in the same AAD session as Dr. Sinclair’s baricitinib data, Brett King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Connecticut, described similar long-term response curves. At 24 weeks, the SALT ≤ 20 response was achieved in 34.9% of patients, but climbed to 62.8% with continuous therapy over 68 weeks.

Time Factor Is Important for Response

“What we are learning is that patients keep getting better over time,” Dr. Sinclair said. Asked specifically how long he would treat a patient before giving up, he acknowledged that he used to consider 6 months adequate, but that he has now changed his mind.

“It might be that even 2 years is too short,” he said, although he conceded that a trial of therapy for this long “might be an issue for third-part payers.”

Asked to comment, Melissa Piliang, MD, chair of the department of dermatology at the Cleveland Clinic, agreed with the principle that early responses are not necessarily predictive of complete response.

Dr. Piliang

SAN DIEGO — In patients with alopecia areata (AA), the decision of when to give up on JAK inhibitors because of an inadequate response is being complicated by long-term follow-up showing that some patients accrue hair very slowly, according to late breaker data presented at the annual meeting of the American Academy of Dermatology.

Although the majority respond within months, response curves have so far climbed for as long as patients are followed, allowing many with disappointing early results to catch up, according to Rodney D. Sinclair, MD, professor of dermatology at the University of Melbourne, Australia.

His remarks were derived specifically from new long-term follow-up with baricitinib, the first JAK inhibitor approved for AA, but the pattern appears to be similar with ritlecitinib, the only other JAK inhibitor approved for AA, and for several if not all JAK inhibitors in phase 3 AA trials.

“We have had patients on baricitinib where not much was happening at 18 months, but now, at 4 years, they have a SALT score of zero,” Dr. Sinclair reported

A Severity of Alopecia Tool (SALT) score of 0 signifies complete hair regrowth. On a scale with a maximum score of 100 (complete hair loss), a SALT score of 20 or less, signaling clinical success, has been a primary endpoint in many JAK inhibitor trials, including those conducted with baricitinib.

Providing the most recent analysis in patients with severe AA participating in the phase 3 BRAVE-AA1 and BRAVE-AA2 trials of baricitinib, which were published together in 2022, Dr. Sinclair broke the data down into responders, mixed responders, and nonresponders at 52 weeks. The proportion of patients who responded with even longer follow-up were then tallied.

In the as-observed responses over time, the trajectory of response continued to climb through 76 weeks of follow-up in all three groups.

Relative to the 44.5% rate of overall response (SALT ≤ 20 ) at 52 weeks, there was some further growth in every group maintained on JAK inhibitor therapy over longer follow-up. In Dr. Sinclair’s late breaking analysis, this did not include nonresponders, who stopped therapy by week 52, but 78.4% of the combined responders and mixed responders who remained on treatment had reached treatment success at 76 weeks.
 

Response Curves Climb More Slowly With Severe Alopecia

While improvement in SALT scores was even seen in nonresponders over time as long as they remained on therapy, Dr. Sinclair reported that response curves tended to climb more slowly in those with more severe alopecia at baseline. Yet, they still climbed. For example, 28.1% of those with a baseline SALT score of 95 to 100 had reached treatment success at week 52, but the proportion had climbed to 35.4% by week 76.

The response curves climbed more quickly among those with a SALT score between 50 and 95 at baseline than among those with more severe alopecia, but the differences in SALT scores at 52 weeks and 76 weeks among patients in this range of baseline SALT scores were small.

Basically, “those with a SALT score of 94 did just as well as those with a SALT score of 51 when followed long-term,” he said, noting that this was among several findings that confounded expectations.

Duration of AA was found to be an important prognostic factor, with 4 years emerging as a general threshold separating those with a diminished likelihood of benefit relative to those with a shorter AA duration.

“When the duration of AA is more than 4 years, the response to any JAK inhibitor seems to fall off a cliff,” Dr. Sinclair said.

To clarify this observation, Dr. Sinclair made an analogy between acute and chronic urticaria. Chronicity appears to change the pathophysiology of both urticaria and AA, making durable remissions more difficult to achieve if the inflammatory response was persistently upregulated, he said.

The delayed responses in some patients “suggests that it is not enough to control inflammation for the hair to regrow. You actually have to activate the hair to grow as well as treat the inflammation,” Dr. Sinclair said.

This heterogeneity that has been observed in the speed of AA response to JAK inhibitors might be explained at least in part by the individual differences in hair growth activation. For ritlecitinib, the only other JAK inhibitor approved for AA to date, 62% were categorized as responders in the registration ALLEGRO trials, but only 44% were early responders, meaning SALT scores of ≤ 20 by week 24, according to a summary published last year. Of the remaining 16%, 11% were middle responders, meaning a SALT score of ≤ 20 reached at week 48, and 6% were late responders, meaning a SALT score of ≤ 20 reached at week 96.

In the context of late breaking 68-week data with deuruxolitinib, an oral JAK inhibitor currently under FDA review for treating moderate to severe AA, presented in the same AAD session as Dr. Sinclair’s baricitinib data, Brett King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Connecticut, described similar long-term response curves. At 24 weeks, the SALT ≤ 20 response was achieved in 34.9% of patients, but climbed to 62.8% with continuous therapy over 68 weeks.

Time Factor Is Important for Response

“What we are learning is that patients keep getting better over time,” Dr. Sinclair said. Asked specifically how long he would treat a patient before giving up, he acknowledged that he used to consider 6 months adequate, but that he has now changed his mind.

“It might be that even 2 years is too short,” he said, although he conceded that a trial of therapy for this long “might be an issue for third-part payers.”

Asked to comment, Melissa Piliang, MD, chair of the department of dermatology at the Cleveland Clinic, agreed with the principle that early responses are not necessarily predictive of complete response.

Dr. Piliang

SAN DIEGO — In patients with alopecia areata (AA), the decision of when to give up on JAK inhibitors because of an inadequate response is being complicated by long-term follow-up showing that some patients accrue hair very slowly, according to late breaker data presented at the annual meeting of the American Academy of Dermatology.

Although the majority respond within months, response curves have so far climbed for as long as patients are followed, allowing many with disappointing early results to catch up, according to Rodney D. Sinclair, MD, professor of dermatology at the University of Melbourne, Australia.

His remarks were derived specifically from new long-term follow-up with baricitinib, the first JAK inhibitor approved for AA, but the pattern appears to be similar with ritlecitinib, the only other JAK inhibitor approved for AA, and for several if not all JAK inhibitors in phase 3 AA trials.

“We have had patients on baricitinib where not much was happening at 18 months, but now, at 4 years, they have a SALT score of zero,” Dr. Sinclair reported

A Severity of Alopecia Tool (SALT) score of 0 signifies complete hair regrowth. On a scale with a maximum score of 100 (complete hair loss), a SALT score of 20 or less, signaling clinical success, has been a primary endpoint in many JAK inhibitor trials, including those conducted with baricitinib.

Providing the most recent analysis in patients with severe AA participating in the phase 3 BRAVE-AA1 and BRAVE-AA2 trials of baricitinib, which were published together in 2022, Dr. Sinclair broke the data down into responders, mixed responders, and nonresponders at 52 weeks. The proportion of patients who responded with even longer follow-up were then tallied.

In the as-observed responses over time, the trajectory of response continued to climb through 76 weeks of follow-up in all three groups.

Relative to the 44.5% rate of overall response (SALT ≤ 20 ) at 52 weeks, there was some further growth in every group maintained on JAK inhibitor therapy over longer follow-up. In Dr. Sinclair’s late breaking analysis, this did not include nonresponders, who stopped therapy by week 52, but 78.4% of the combined responders and mixed responders who remained on treatment had reached treatment success at 76 weeks.
 

Response Curves Climb More Slowly With Severe Alopecia

While improvement in SALT scores was even seen in nonresponders over time as long as they remained on therapy, Dr. Sinclair reported that response curves tended to climb more slowly in those with more severe alopecia at baseline. Yet, they still climbed. For example, 28.1% of those with a baseline SALT score of 95 to 100 had reached treatment success at week 52, but the proportion had climbed to 35.4% by week 76.

The response curves climbed more quickly among those with a SALT score between 50 and 95 at baseline than among those with more severe alopecia, but the differences in SALT scores at 52 weeks and 76 weeks among patients in this range of baseline SALT scores were small.

Basically, “those with a SALT score of 94 did just as well as those with a SALT score of 51 when followed long-term,” he said, noting that this was among several findings that confounded expectations.

Duration of AA was found to be an important prognostic factor, with 4 years emerging as a general threshold separating those with a diminished likelihood of benefit relative to those with a shorter AA duration.

“When the duration of AA is more than 4 years, the response to any JAK inhibitor seems to fall off a cliff,” Dr. Sinclair said.

To clarify this observation, Dr. Sinclair made an analogy between acute and chronic urticaria. Chronicity appears to change the pathophysiology of both urticaria and AA, making durable remissions more difficult to achieve if the inflammatory response was persistently upregulated, he said.

The delayed responses in some patients “suggests that it is not enough to control inflammation for the hair to regrow. You actually have to activate the hair to grow as well as treat the inflammation,” Dr. Sinclair said.

This heterogeneity that has been observed in the speed of AA response to JAK inhibitors might be explained at least in part by the individual differences in hair growth activation. For ritlecitinib, the only other JAK inhibitor approved for AA to date, 62% were categorized as responders in the registration ALLEGRO trials, but only 44% were early responders, meaning SALT scores of ≤ 20 by week 24, according to a summary published last year. Of the remaining 16%, 11% were middle responders, meaning a SALT score of ≤ 20 reached at week 48, and 6% were late responders, meaning a SALT score of ≤ 20 reached at week 96.

In the context of late breaking 68-week data with deuruxolitinib, an oral JAK inhibitor currently under FDA review for treating moderate to severe AA, presented in the same AAD session as Dr. Sinclair’s baricitinib data, Brett King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Connecticut, described similar long-term response curves. At 24 weeks, the SALT ≤ 20 response was achieved in 34.9% of patients, but climbed to 62.8% with continuous therapy over 68 weeks.

Time Factor Is Important for Response

“What we are learning is that patients keep getting better over time,” Dr. Sinclair said. Asked specifically how long he would treat a patient before giving up, he acknowledged that he used to consider 6 months adequate, but that he has now changed his mind.

“It might be that even 2 years is too short,” he said, although he conceded that a trial of therapy for this long “might be an issue for third-part payers.”

Asked to comment, Melissa Piliang, MD, chair of the department of dermatology at the Cleveland Clinic, agreed with the principle that early responses are not necessarily predictive of complete response.

Dr. Piliang

ATLANTA — A novel antisense therapy called olezarsen reduced triglycerides (TGs) by approximately 50% with either of the two study doses relative to placebo and did so with a low relative risk for adverse events, new data from a phase 2b trial showed.

“The reduction in triglycerides was greater than that currently possible with any available therapy,” reported Brian A. Bergmark, MD, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The drug also produced meaningful improvements in multiple other lipid subfractions associated with increased cardiovascular (CV) risk, including ApoC-III, very low–density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol. High-density lipoprotein (HDL) cholesterol levels were significantly raised.

The results were presented on April 7 as a late breaker at the American College of Cardiology (ACC) Scientific Session 2024 and published online simultaneously in The New England Journal of Medicine.
 

No Major Subgroup Failed to Respond

The effect was seen across all the key subgroups evaluated, including women and patients with diabetes, obesity, and severe as well as moderate elevations in TGs at baseline, Dr. Bergmark reported.

Olezarsen is a N-acetylgalactosamine–conjugated antisense oligonucleotide targeting APOC3 RNA. The results of this randomized trial, called BRIDGE-TIMI 73a, are consistent with other evidence that inhibiting expression of ApoC-III lowers the levels of TGs and other lipid subfractions to a degree that would predict clinical benefit.

In this study, 154 patients at 24 sites in North America were randomized in a 1:1 ratio to 50 or 80 mg olezarsen. Those in each of these cohorts were then randomized in a 3:1 ratio to active therapy or placebo. All therapies were administered by subcutaneous injection once per month.

Patients were eligible for the trial if they had moderate hypertriglyceridemia, defined as a level of 150-499 mg/dL, and elevated CV risk or if they had severe hypertriglyceridemia (≥ 500 mg/dL) with or without other evidence of elevated CV risk. The primary endpoint was a change in TGs at 6 months. Complete follow-up was available in about 97% of patients regardless of treatment assignment.

With a slight numerical advantage for the higher dose, the TG reductions were 49.1% for the 50-mg dose and 53.1% for the 80-mg dose relative to no significant change in the placebo group (P < .001 for both olezarsen doses). The reductions in ApoC-III, an upstream driver of TG production and a CV risk factor, were 64.2% and 73.2% relative to placebo (both P < .001), respectively, Dr. Bergmark reported.

In those with moderate hypertriglyceridemia, normal TG levels, defined as < 150 mg/dL, were reached at 6 months in 85.7% and 93.3% in the 40-mg and 80-mg dose groups, respectively. Relative to these reductions, normalization was seen in only 11.8% of placebo patients (P < .001).
 

TG Lowering Might Not Be Best Endpoint

The primary endpoint in this trial was a change in TGs, but this target was questioned by an invited ACC discussant, Daniel Soffer, MD, who is both an adjunct professor assistant professor of medicine at Penn Medicine, Philadelphia, and current president of the National Lipid Association.

Dr. Soffer noted that highly elevated TGs are a major risk factor for acute pancreatitis, so this predicts a clinical benefit for this purpose, but he thought the other lipid subfractions are far more important for the goal of reducing atherosclerotic cardiovascular disease (ASCVD).

Indeed, he said categorically that it is not TGs that drive ASCVD risk and therefore not what is the real importance of these data. Rather, “it is the non-HDL cholesterol and ApoB lowering” that will drive the likely benefits from this therapy in CV disease.

In addition to the TG reductions, olezarsen did, in fact, produce significant reductions in many of the lipid subfractions associated with increased CV risk. While slightly more favorable in most cases with the higher dose of olezarsen, even the lower dose reduced Apo C-III from baseline by 64.2% (P < .001), VLDL by 46.2% (P < .001), remnant cholesterol by 46.6% (P < .001), ApoB by 18.2% (P < .001), and non-HDL cholesterol by 25.4% (P < .001). HDL cholesterol was increased by 39.6% (P < .001).

These favorable effects on TG and other lipid subfractions were achieved with a safety profile that was reassuring, Dr. Bergmark said. Serious adverse events leading to discontinuation occurred in 0%, 1.7%, and 1.8% of the placebo, lower-dose, and higher-dose arms, respectively. These rates did not differ significantly.
 

Increased Liver Enzymes Is Common

Liver enzymes were significantly elevated (P < .001) for both doses of olezarsen vs placebo, but liver enzymes > 3× the upper limit of normal did not reach significance on either dose of olezarsen relative to placebo. Low platelet counts and reductions in kidney function were observed in a minority of patients but were generally manageable, according to Dr. Bergmark. There was no impact on hemoglobin A1c levels.

Further evaluation of change in hepatic function is planned in the ongoing extension studies.

Characterizing these results as “exciting,” Neha J. Pagidipati, MD, a member of the Duke Clinical Research Institute and an assistant professor at the Duke School of Medicine, Durham, North Carolina, said that identifying a drug effective for hypertriglyceridemia is likely to be a major advance. While elevated TGs are “one of the toughest” lipid abnormalities to manage, “there is not much out there to offer for treatment.”

She, like Dr. Soffer, was encouraged by the favorable effects on multiple lipid abnormalities associated with increased CV risk, but she said the ultimate clinical utility of this or other agents that lower TGs for ASCVD requires a study showing a change in CV events.

Dr. Bergmark reported financial relationships with 15 pharmaceutical companies, including Ionis, which provided funding for the BRIDGE-TIMI 73a trial. Soffer had financial relationships with Akcea, Amgen, Amryt, AstraZeneca, Ionis, Novartis, Regeneron, and Verve. Dr. Pagidipati had financial relationships with more than 10 pharmaceutical companies but was not involved in the design of management of the BRIDGE-TIMI 73a trial.

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

ATLANTA — A novel antisense therapy called olezarsen reduced triglycerides (TGs) by approximately 50% with either of the two study doses relative to placebo and did so with a low relative risk for adverse events, new data from a phase 2b trial showed.

“The reduction in triglycerides was greater than that currently possible with any available therapy,” reported Brian A. Bergmark, MD, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The drug also produced meaningful improvements in multiple other lipid subfractions associated with increased cardiovascular (CV) risk, including ApoC-III, very low–density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol. High-density lipoprotein (HDL) cholesterol levels were significantly raised.

The results were presented on April 7 as a late breaker at the American College of Cardiology (ACC) Scientific Session 2024 and published online simultaneously in The New England Journal of Medicine.
 

No Major Subgroup Failed to Respond

The effect was seen across all the key subgroups evaluated, including women and patients with diabetes, obesity, and severe as well as moderate elevations in TGs at baseline, Dr. Bergmark reported.

Olezarsen is a N-acetylgalactosamine–conjugated antisense oligonucleotide targeting APOC3 RNA. The results of this randomized trial, called BRIDGE-TIMI 73a, are consistent with other evidence that inhibiting expression of ApoC-III lowers the levels of TGs and other lipid subfractions to a degree that would predict clinical benefit.

In this study, 154 patients at 24 sites in North America were randomized in a 1:1 ratio to 50 or 80 mg olezarsen. Those in each of these cohorts were then randomized in a 3:1 ratio to active therapy or placebo. All therapies were administered by subcutaneous injection once per month.

Patients were eligible for the trial if they had moderate hypertriglyceridemia, defined as a level of 150-499 mg/dL, and elevated CV risk or if they had severe hypertriglyceridemia (≥ 500 mg/dL) with or without other evidence of elevated CV risk. The primary endpoint was a change in TGs at 6 months. Complete follow-up was available in about 97% of patients regardless of treatment assignment.

With a slight numerical advantage for the higher dose, the TG reductions were 49.1% for the 50-mg dose and 53.1% for the 80-mg dose relative to no significant change in the placebo group (P < .001 for both olezarsen doses). The reductions in ApoC-III, an upstream driver of TG production and a CV risk factor, were 64.2% and 73.2% relative to placebo (both P < .001), respectively, Dr. Bergmark reported.

In those with moderate hypertriglyceridemia, normal TG levels, defined as < 150 mg/dL, were reached at 6 months in 85.7% and 93.3% in the 40-mg and 80-mg dose groups, respectively. Relative to these reductions, normalization was seen in only 11.8% of placebo patients (P < .001).
 

TG Lowering Might Not Be Best Endpoint

The primary endpoint in this trial was a change in TGs, but this target was questioned by an invited ACC discussant, Daniel Soffer, MD, who is both an adjunct professor assistant professor of medicine at Penn Medicine, Philadelphia, and current president of the National Lipid Association.

Dr. Soffer noted that highly elevated TGs are a major risk factor for acute pancreatitis, so this predicts a clinical benefit for this purpose, but he thought the other lipid subfractions are far more important for the goal of reducing atherosclerotic cardiovascular disease (ASCVD).

Indeed, he said categorically that it is not TGs that drive ASCVD risk and therefore not what is the real importance of these data. Rather, “it is the non-HDL cholesterol and ApoB lowering” that will drive the likely benefits from this therapy in CV disease.

In addition to the TG reductions, olezarsen did, in fact, produce significant reductions in many of the lipid subfractions associated with increased CV risk. While slightly more favorable in most cases with the higher dose of olezarsen, even the lower dose reduced Apo C-III from baseline by 64.2% (P < .001), VLDL by 46.2% (P < .001), remnant cholesterol by 46.6% (P < .001), ApoB by 18.2% (P < .001), and non-HDL cholesterol by 25.4% (P < .001). HDL cholesterol was increased by 39.6% (P < .001).

These favorable effects on TG and other lipid subfractions were achieved with a safety profile that was reassuring, Dr. Bergmark said. Serious adverse events leading to discontinuation occurred in 0%, 1.7%, and 1.8% of the placebo, lower-dose, and higher-dose arms, respectively. These rates did not differ significantly.
 

Increased Liver Enzymes Is Common

Liver enzymes were significantly elevated (P < .001) for both doses of olezarsen vs placebo, but liver enzymes > 3× the upper limit of normal did not reach significance on either dose of olezarsen relative to placebo. Low platelet counts and reductions in kidney function were observed in a minority of patients but were generally manageable, according to Dr. Bergmark. There was no impact on hemoglobin A1c levels.

Further evaluation of change in hepatic function is planned in the ongoing extension studies.

Characterizing these results as “exciting,” Neha J. Pagidipati, MD, a member of the Duke Clinical Research Institute and an assistant professor at the Duke School of Medicine, Durham, North Carolina, said that identifying a drug effective for hypertriglyceridemia is likely to be a major advance. While elevated TGs are “one of the toughest” lipid abnormalities to manage, “there is not much out there to offer for treatment.”

She, like Dr. Soffer, was encouraged by the favorable effects on multiple lipid abnormalities associated with increased CV risk, but she said the ultimate clinical utility of this or other agents that lower TGs for ASCVD requires a study showing a change in CV events.

Dr. Bergmark reported financial relationships with 15 pharmaceutical companies, including Ionis, which provided funding for the BRIDGE-TIMI 73a trial. Soffer had financial relationships with Akcea, Amgen, Amryt, AstraZeneca, Ionis, Novartis, Regeneron, and Verve. Dr. Pagidipati had financial relationships with more than 10 pharmaceutical companies but was not involved in the design of management of the BRIDGE-TIMI 73a trial.

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

ATLANTA — A novel antisense therapy called olezarsen reduced triglycerides (TGs) by approximately 50% with either of the two study doses relative to placebo and did so with a low relative risk for adverse events, new data from a phase 2b trial showed.

“The reduction in triglycerides was greater than that currently possible with any available therapy,” reported Brian A. Bergmark, MD, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The drug also produced meaningful improvements in multiple other lipid subfractions associated with increased cardiovascular (CV) risk, including ApoC-III, very low–density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol. High-density lipoprotein (HDL) cholesterol levels were significantly raised.

The results were presented on April 7 as a late breaker at the American College of Cardiology (ACC) Scientific Session 2024 and published online simultaneously in The New England Journal of Medicine.
 

No Major Subgroup Failed to Respond

The effect was seen across all the key subgroups evaluated, including women and patients with diabetes, obesity, and severe as well as moderate elevations in TGs at baseline, Dr. Bergmark reported.

Olezarsen is a N-acetylgalactosamine–conjugated antisense oligonucleotide targeting APOC3 RNA. The results of this randomized trial, called BRIDGE-TIMI 73a, are consistent with other evidence that inhibiting expression of ApoC-III lowers the levels of TGs and other lipid subfractions to a degree that would predict clinical benefit.

In this study, 154 patients at 24 sites in North America were randomized in a 1:1 ratio to 50 or 80 mg olezarsen. Those in each of these cohorts were then randomized in a 3:1 ratio to active therapy or placebo. All therapies were administered by subcutaneous injection once per month.

Patients were eligible for the trial if they had moderate hypertriglyceridemia, defined as a level of 150-499 mg/dL, and elevated CV risk or if they had severe hypertriglyceridemia (≥ 500 mg/dL) with or without other evidence of elevated CV risk. The primary endpoint was a change in TGs at 6 months. Complete follow-up was available in about 97% of patients regardless of treatment assignment.

With a slight numerical advantage for the higher dose, the TG reductions were 49.1% for the 50-mg dose and 53.1% for the 80-mg dose relative to no significant change in the placebo group (P < .001 for both olezarsen doses). The reductions in ApoC-III, an upstream driver of TG production and a CV risk factor, were 64.2% and 73.2% relative to placebo (both P < .001), respectively, Dr. Bergmark reported.

In those with moderate hypertriglyceridemia, normal TG levels, defined as < 150 mg/dL, were reached at 6 months in 85.7% and 93.3% in the 40-mg and 80-mg dose groups, respectively. Relative to these reductions, normalization was seen in only 11.8% of placebo patients (P < .001).
 

TG Lowering Might Not Be Best Endpoint

The primary endpoint in this trial was a change in TGs, but this target was questioned by an invited ACC discussant, Daniel Soffer, MD, who is both an adjunct professor assistant professor of medicine at Penn Medicine, Philadelphia, and current president of the National Lipid Association.

Dr. Soffer noted that highly elevated TGs are a major risk factor for acute pancreatitis, so this predicts a clinical benefit for this purpose, but he thought the other lipid subfractions are far more important for the goal of reducing atherosclerotic cardiovascular disease (ASCVD).

Indeed, he said categorically that it is not TGs that drive ASCVD risk and therefore not what is the real importance of these data. Rather, “it is the non-HDL cholesterol and ApoB lowering” that will drive the likely benefits from this therapy in CV disease.

In addition to the TG reductions, olezarsen did, in fact, produce significant reductions in many of the lipid subfractions associated with increased CV risk. While slightly more favorable in most cases with the higher dose of olezarsen, even the lower dose reduced Apo C-III from baseline by 64.2% (P < .001), VLDL by 46.2% (P < .001), remnant cholesterol by 46.6% (P < .001), ApoB by 18.2% (P < .001), and non-HDL cholesterol by 25.4% (P < .001). HDL cholesterol was increased by 39.6% (P < .001).

These favorable effects on TG and other lipid subfractions were achieved with a safety profile that was reassuring, Dr. Bergmark said. Serious adverse events leading to discontinuation occurred in 0%, 1.7%, and 1.8% of the placebo, lower-dose, and higher-dose arms, respectively. These rates did not differ significantly.
 

Increased Liver Enzymes Is Common

Liver enzymes were significantly elevated (P < .001) for both doses of olezarsen vs placebo, but liver enzymes > 3× the upper limit of normal did not reach significance on either dose of olezarsen relative to placebo. Low platelet counts and reductions in kidney function were observed in a minority of patients but were generally manageable, according to Dr. Bergmark. There was no impact on hemoglobin A1c levels.

Further evaluation of change in hepatic function is planned in the ongoing extension studies.

Characterizing these results as “exciting,” Neha J. Pagidipati, MD, a member of the Duke Clinical Research Institute and an assistant professor at the Duke School of Medicine, Durham, North Carolina, said that identifying a drug effective for hypertriglyceridemia is likely to be a major advance. While elevated TGs are “one of the toughest” lipid abnormalities to manage, “there is not much out there to offer for treatment.”

She, like Dr. Soffer, was encouraged by the favorable effects on multiple lipid abnormalities associated with increased CV risk, but she said the ultimate clinical utility of this or other agents that lower TGs for ASCVD requires a study showing a change in CV events.

Dr. Bergmark reported financial relationships with 15 pharmaceutical companies, including Ionis, which provided funding for the BRIDGE-TIMI 73a trial. Soffer had financial relationships with Akcea, Amgen, Amryt, AstraZeneca, Ionis, Novartis, Regeneron, and Verve. Dr. Pagidipati had financial relationships with more than 10 pharmaceutical companies but was not involved in the design of management of the BRIDGE-TIMI 73a trial.

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

SAN DIEGO — In two different phase 2b trial extensions, oral treatment with Janus kinase (JAK) inhibitors showed improved skin clearance in patients with vitiligo, according to presentations at a late-breaking session at the annual meeting of the American Academy of Dermatology (AAD).

In one, the addition of narrow-band ultraviolet-B (NB-UVB) light therapy to ritlecitinib appears more effective than ritlecitinib alone. In the other study, the effectiveness of upadacitinib appears to improve over time.

Based on the ritlecitinib data, “if you have phototherapy in your office, it might be good to couple it with ritlecitinib for vitiligo patients,” said Emma Guttman-Yassky, MD, PhD, chair of the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York City, who presented the findings.

However, because of the relatively small numbers in the extension study, Dr. Guttman-Yassky characterized the evidence as preliminary and in need of further investigation.

For vitiligo, the only approved JAK inhibitor is ruxolitinib, 1.5%, in a cream formulation. In June, ritlecitinib (Litfulo) was approved by the Food and Drug Administration (FDA) for alopecia areata. Phototherapy, which has been used for decades in the treatment of vitiligo, has an established efficacy and safety profile as a stand-alone vitiligo treatment. Upadacitinib has numerous indications for inflammatory diseases, such as rheumatoid arthritis, and was granted FDA approval for atopic dermatitis in 2022.
 

NB-UVB Arm Added in Ritlecitinib Extension

The ritlecitinib study population was drawn from patients with non-segmental vitiligo who initially participated in a 24-week dose-ranging period of a phase 2b trial published last year. In that study, 364 patients were randomized to doses of once-daily ritlecitinib ranging from 10 to 50 mg with or without a 4-week loading regimen. Higher doses were generally associated with greater efficacy on the primary endpoint of facial vitiligo area scoring index (F-VASI) but not with a greater risk for adverse events.

In the 24-week extension study, 187 patients received a 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib for the remaining 20 weeks. Another 43 patients were randomized to one of two arms: The same 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib or to 50-mg daily ritlecitinib without a loading dose but combined with NB-UVB delivered twice per week.

Important to interpretation of results, there was an additional twist. Patients in the randomized arm who had < 10% improvement in the total vitiligo area severity index (T-VASI) at week 12 of the extension were discontinued from the study.

The endpoints considered when comparing ritlecitinib with or without NB-UVB at the end of the extension study were F-VASI, T-VASI, patient global impression of change, and adverse events. Responses were assessed on the basis of both observed and last observation carried forward (LOCF).

Of the 43 people, who were randomized in the extension study, nine (21%) had < 10% improvement in T-VASI and were therefore discontinued from the study.

At the end of 24 weeks, both groups had a substantial response to their assigned therapy, but the addition of NB-UVB increased rates of response, although not always at a level of statistical significance, according to Dr. Guttman-Yassky.

For the percent improvement in F-VASI, specifically, the increase did not reach significance on the basis of LOCF (57.9% vs 51.5%; P = .158) but was highly significant on the basis of observed responses (69.6% vs 55.1%; P = .009). For T-VASI, differences for adjunctive NB-UVB over monotherapy did not reach significance for either observed or LOCF responses, but it was significant for observed responses in a patient global impression of change.
 

Small Numbers Limit Strength of Ritlecitinib, NB-UVB Evidence

However, Dr. Guttman-Yassky said it is important “to pay attention to the sample sizes” when noting the lack of significance.

The combination appeared safe, and there were no side effects associated with the addition of twice-weekly NB-UVB to ritlecitinib.

She acknowledged that the design of this analysis was “complicated” and that the number of randomized patients was small. She suggested the findings support the potential for benefit from the combination of a JAK inhibitor and NB-UVB, both of which have shown efficacy as monotherapy in previous studies. She indicated that a trial of this combination is reasonable while awaiting a more definitive study.

One of the questions that might be posed in a larger study is the timing of NB-UVB, such as whether it is best reserved for those with inadequate early response to a JAK inhibitor or if optimal results are achieved when a JAK inhibitor and NB-UVB are initiated simultaneously.

Upadacitinib Monotherapy Results

One rationale for initiating therapy with the combination of a JAK inhibitor and NB-UVB is the potential for a more rapid response, but extended results from a second phase 2b study with a different oral JAK inhibitor, upadacitinib, suggested responses on JAK inhibitor monotherapy improve steadily over time.

“The overall efficacy continued to improve without reaching a plateau at 1 year,” reported Thierry Passeron, MD, PhD, professor and chair, Department of Dermatology, Université Côte d’Azur, Nice, France. He spoke at the same AAD late-breaking session as Dr. Guttman-Yassky.

The 24-week dose-ranging data from the upadacitinib trial were previously reported at the 2023 annual meeting of the European Association of Dermatology and Venereology. In the placebo-controlled portion, which randomized 185 patients with extensive non-segmental vitiligo to 6 mg, 11 mg, or 22 mg, the two higher doses were significantly more effective than placebo.

In the extension, patients in the placebo group were randomized to 11 mg or 22 mg, while those in the higher dose groups remained on their assigned therapies.
 

F-VASI Almost Doubled in Extension Trial

From week 24 to week 52, there was nearly a doubling of the percent F-VASI reduction, climbing from 32% to 60.8% in the 11-mg group and from 38.7% to 64.9% in the 22-mg group, Dr. Passeron said. Placebo groups who were switched to active therapy at 24 weeks rapidly approached the rates of F-VASI response of those initiated on upadacitinib.

The percent reductions in T-VASI, although lower, followed the same pattern. For the 11-mg group, the reduction climbed from 16% at 24 weeks to 44.7% at 52 weeks. For the 22-mg group, the reduction climbed from 22.9% to 44.4%. Patients who were switched from placebo to 11 mg or to 22 mg also experienced improvements in T-VASI up to 52 weeks, although the level of improvement was lower than that in patients initially randomized to the higher doses of upadacitinib.

There were “no new safety signals” for upadacitinib, which is FDA-approved for multiple indications, according to Dr. Passeron. He said acne-like lesions were the most bothersome adverse event, and cases of herpes zoster were “rare.”

A version of these data was published in a British Journal of Dermatology supplement just prior to the AAD meeting.

Phase 3 vitiligo trials are planned for both ritlecitinib and upadacitinib.

Dr. Guttman-Yassky reported financial relationships with approximately 45 pharmaceutical companies, including Pfizer, which makes ritlecitinib and provided funding for the study she discussed. Dr. Passeron reported financial relationships with approximately 40 pharmaceutical companies, including AbbVie, which makes upadacitinib and provided funding for the study he discussed.

A version of this article appeared on Medscape.com.

SAN DIEGO — In two different phase 2b trial extensions, oral treatment with Janus kinase (JAK) inhibitors showed improved skin clearance in patients with vitiligo, according to presentations at a late-breaking session at the annual meeting of the American Academy of Dermatology (AAD).

In one, the addition of narrow-band ultraviolet-B (NB-UVB) light therapy to ritlecitinib appears more effective than ritlecitinib alone. In the other study, the effectiveness of upadacitinib appears to improve over time.

Based on the ritlecitinib data, “if you have phototherapy in your office, it might be good to couple it with ritlecitinib for vitiligo patients,” said Emma Guttman-Yassky, MD, PhD, chair of the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York City, who presented the findings.

However, because of the relatively small numbers in the extension study, Dr. Guttman-Yassky characterized the evidence as preliminary and in need of further investigation.

For vitiligo, the only approved JAK inhibitor is ruxolitinib, 1.5%, in a cream formulation. In June, ritlecitinib (Litfulo) was approved by the Food and Drug Administration (FDA) for alopecia areata. Phototherapy, which has been used for decades in the treatment of vitiligo, has an established efficacy and safety profile as a stand-alone vitiligo treatment. Upadacitinib has numerous indications for inflammatory diseases, such as rheumatoid arthritis, and was granted FDA approval for atopic dermatitis in 2022.
 

NB-UVB Arm Added in Ritlecitinib Extension

The ritlecitinib study population was drawn from patients with non-segmental vitiligo who initially participated in a 24-week dose-ranging period of a phase 2b trial published last year. In that study, 364 patients were randomized to doses of once-daily ritlecitinib ranging from 10 to 50 mg with or without a 4-week loading regimen. Higher doses were generally associated with greater efficacy on the primary endpoint of facial vitiligo area scoring index (F-VASI) but not with a greater risk for adverse events.

In the 24-week extension study, 187 patients received a 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib for the remaining 20 weeks. Another 43 patients were randomized to one of two arms: The same 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib or to 50-mg daily ritlecitinib without a loading dose but combined with NB-UVB delivered twice per week.

Important to interpretation of results, there was an additional twist. Patients in the randomized arm who had < 10% improvement in the total vitiligo area severity index (T-VASI) at week 12 of the extension were discontinued from the study.

The endpoints considered when comparing ritlecitinib with or without NB-UVB at the end of the extension study were F-VASI, T-VASI, patient global impression of change, and adverse events. Responses were assessed on the basis of both observed and last observation carried forward (LOCF).

Of the 43 people, who were randomized in the extension study, nine (21%) had < 10% improvement in T-VASI and were therefore discontinued from the study.

At the end of 24 weeks, both groups had a substantial response to their assigned therapy, but the addition of NB-UVB increased rates of response, although not always at a level of statistical significance, according to Dr. Guttman-Yassky.

For the percent improvement in F-VASI, specifically, the increase did not reach significance on the basis of LOCF (57.9% vs 51.5%; P = .158) but was highly significant on the basis of observed responses (69.6% vs 55.1%; P = .009). For T-VASI, differences for adjunctive NB-UVB over monotherapy did not reach significance for either observed or LOCF responses, but it was significant for observed responses in a patient global impression of change.
 

Small Numbers Limit Strength of Ritlecitinib, NB-UVB Evidence

However, Dr. Guttman-Yassky said it is important “to pay attention to the sample sizes” when noting the lack of significance.

The combination appeared safe, and there were no side effects associated with the addition of twice-weekly NB-UVB to ritlecitinib.

She acknowledged that the design of this analysis was “complicated” and that the number of randomized patients was small. She suggested the findings support the potential for benefit from the combination of a JAK inhibitor and NB-UVB, both of which have shown efficacy as monotherapy in previous studies. She indicated that a trial of this combination is reasonable while awaiting a more definitive study.

One of the questions that might be posed in a larger study is the timing of NB-UVB, such as whether it is best reserved for those with inadequate early response to a JAK inhibitor or if optimal results are achieved when a JAK inhibitor and NB-UVB are initiated simultaneously.

Upadacitinib Monotherapy Results

One rationale for initiating therapy with the combination of a JAK inhibitor and NB-UVB is the potential for a more rapid response, but extended results from a second phase 2b study with a different oral JAK inhibitor, upadacitinib, suggested responses on JAK inhibitor monotherapy improve steadily over time.

“The overall efficacy continued to improve without reaching a plateau at 1 year,” reported Thierry Passeron, MD, PhD, professor and chair, Department of Dermatology, Université Côte d’Azur, Nice, France. He spoke at the same AAD late-breaking session as Dr. Guttman-Yassky.

The 24-week dose-ranging data from the upadacitinib trial were previously reported at the 2023 annual meeting of the European Association of Dermatology and Venereology. In the placebo-controlled portion, which randomized 185 patients with extensive non-segmental vitiligo to 6 mg, 11 mg, or 22 mg, the two higher doses were significantly more effective than placebo.

In the extension, patients in the placebo group were randomized to 11 mg or 22 mg, while those in the higher dose groups remained on their assigned therapies.
 

F-VASI Almost Doubled in Extension Trial

From week 24 to week 52, there was nearly a doubling of the percent F-VASI reduction, climbing from 32% to 60.8% in the 11-mg group and from 38.7% to 64.9% in the 22-mg group, Dr. Passeron said. Placebo groups who were switched to active therapy at 24 weeks rapidly approached the rates of F-VASI response of those initiated on upadacitinib.

The percent reductions in T-VASI, although lower, followed the same pattern. For the 11-mg group, the reduction climbed from 16% at 24 weeks to 44.7% at 52 weeks. For the 22-mg group, the reduction climbed from 22.9% to 44.4%. Patients who were switched from placebo to 11 mg or to 22 mg also experienced improvements in T-VASI up to 52 weeks, although the level of improvement was lower than that in patients initially randomized to the higher doses of upadacitinib.

There were “no new safety signals” for upadacitinib, which is FDA-approved for multiple indications, according to Dr. Passeron. He said acne-like lesions were the most bothersome adverse event, and cases of herpes zoster were “rare.”

A version of these data was published in a British Journal of Dermatology supplement just prior to the AAD meeting.

Phase 3 vitiligo trials are planned for both ritlecitinib and upadacitinib.

Dr. Guttman-Yassky reported financial relationships with approximately 45 pharmaceutical companies, including Pfizer, which makes ritlecitinib and provided funding for the study she discussed. Dr. Passeron reported financial relationships with approximately 40 pharmaceutical companies, including AbbVie, which makes upadacitinib and provided funding for the study he discussed.

A version of this article appeared on Medscape.com.

SAN DIEGO — In two different phase 2b trial extensions, oral treatment with Janus kinase (JAK) inhibitors showed improved skin clearance in patients with vitiligo, according to presentations at a late-breaking session at the annual meeting of the American Academy of Dermatology (AAD).

In one, the addition of narrow-band ultraviolet-B (NB-UVB) light therapy to ritlecitinib appears more effective than ritlecitinib alone. In the other study, the effectiveness of upadacitinib appears to improve over time.

Based on the ritlecitinib data, “if you have phototherapy in your office, it might be good to couple it with ritlecitinib for vitiligo patients,” said Emma Guttman-Yassky, MD, PhD, chair of the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York City, who presented the findings.

However, because of the relatively small numbers in the extension study, Dr. Guttman-Yassky characterized the evidence as preliminary and in need of further investigation.

For vitiligo, the only approved JAK inhibitor is ruxolitinib, 1.5%, in a cream formulation. In June, ritlecitinib (Litfulo) was approved by the Food and Drug Administration (FDA) for alopecia areata. Phototherapy, which has been used for decades in the treatment of vitiligo, has an established efficacy and safety profile as a stand-alone vitiligo treatment. Upadacitinib has numerous indications for inflammatory diseases, such as rheumatoid arthritis, and was granted FDA approval for atopic dermatitis in 2022.
 

NB-UVB Arm Added in Ritlecitinib Extension

The ritlecitinib study population was drawn from patients with non-segmental vitiligo who initially participated in a 24-week dose-ranging period of a phase 2b trial published last year. In that study, 364 patients were randomized to doses of once-daily ritlecitinib ranging from 10 to 50 mg with or without a 4-week loading regimen. Higher doses were generally associated with greater efficacy on the primary endpoint of facial vitiligo area scoring index (F-VASI) but not with a greater risk for adverse events.

In the 24-week extension study, 187 patients received a 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib for the remaining 20 weeks. Another 43 patients were randomized to one of two arms: The same 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib or to 50-mg daily ritlecitinib without a loading dose but combined with NB-UVB delivered twice per week.

Important to interpretation of results, there was an additional twist. Patients in the randomized arm who had < 10% improvement in the total vitiligo area severity index (T-VASI) at week 12 of the extension were discontinued from the study.

The endpoints considered when comparing ritlecitinib with or without NB-UVB at the end of the extension study were F-VASI, T-VASI, patient global impression of change, and adverse events. Responses were assessed on the basis of both observed and last observation carried forward (LOCF).

Of the 43 people, who were randomized in the extension study, nine (21%) had < 10% improvement in T-VASI and were therefore discontinued from the study.

At the end of 24 weeks, both groups had a substantial response to their assigned therapy, but the addition of NB-UVB increased rates of response, although not always at a level of statistical significance, according to Dr. Guttman-Yassky.

For the percent improvement in F-VASI, specifically, the increase did not reach significance on the basis of LOCF (57.9% vs 51.5%; P = .158) but was highly significant on the basis of observed responses (69.6% vs 55.1%; P = .009). For T-VASI, differences for adjunctive NB-UVB over monotherapy did not reach significance for either observed or LOCF responses, but it was significant for observed responses in a patient global impression of change.
 

Small Numbers Limit Strength of Ritlecitinib, NB-UVB Evidence

However, Dr. Guttman-Yassky said it is important “to pay attention to the sample sizes” when noting the lack of significance.

The combination appeared safe, and there were no side effects associated with the addition of twice-weekly NB-UVB to ritlecitinib.

She acknowledged that the design of this analysis was “complicated” and that the number of randomized patients was small. She suggested the findings support the potential for benefit from the combination of a JAK inhibitor and NB-UVB, both of which have shown efficacy as monotherapy in previous studies. She indicated that a trial of this combination is reasonable while awaiting a more definitive study.

One of the questions that might be posed in a larger study is the timing of NB-UVB, such as whether it is best reserved for those with inadequate early response to a JAK inhibitor or if optimal results are achieved when a JAK inhibitor and NB-UVB are initiated simultaneously.

Upadacitinib Monotherapy Results

One rationale for initiating therapy with the combination of a JAK inhibitor and NB-UVB is the potential for a more rapid response, but extended results from a second phase 2b study with a different oral JAK inhibitor, upadacitinib, suggested responses on JAK inhibitor monotherapy improve steadily over time.

“The overall efficacy continued to improve without reaching a plateau at 1 year,” reported Thierry Passeron, MD, PhD, professor and chair, Department of Dermatology, Université Côte d’Azur, Nice, France. He spoke at the same AAD late-breaking session as Dr. Guttman-Yassky.

The 24-week dose-ranging data from the upadacitinib trial were previously reported at the 2023 annual meeting of the European Association of Dermatology and Venereology. In the placebo-controlled portion, which randomized 185 patients with extensive non-segmental vitiligo to 6 mg, 11 mg, or 22 mg, the two higher doses were significantly more effective than placebo.

In the extension, patients in the placebo group were randomized to 11 mg or 22 mg, while those in the higher dose groups remained on their assigned therapies.
 

F-VASI Almost Doubled in Extension Trial

From week 24 to week 52, there was nearly a doubling of the percent F-VASI reduction, climbing from 32% to 60.8% in the 11-mg group and from 38.7% to 64.9% in the 22-mg group, Dr. Passeron said. Placebo groups who were switched to active therapy at 24 weeks rapidly approached the rates of F-VASI response of those initiated on upadacitinib.

The percent reductions in T-VASI, although lower, followed the same pattern. For the 11-mg group, the reduction climbed from 16% at 24 weeks to 44.7% at 52 weeks. For the 22-mg group, the reduction climbed from 22.9% to 44.4%. Patients who were switched from placebo to 11 mg or to 22 mg also experienced improvements in T-VASI up to 52 weeks, although the level of improvement was lower than that in patients initially randomized to the higher doses of upadacitinib.

There were “no new safety signals” for upadacitinib, which is FDA-approved for multiple indications, according to Dr. Passeron. He said acne-like lesions were the most bothersome adverse event, and cases of herpes zoster were “rare.”

A version of these data was published in a British Journal of Dermatology supplement just prior to the AAD meeting.

Phase 3 vitiligo trials are planned for both ritlecitinib and upadacitinib.

Dr. Guttman-Yassky reported financial relationships with approximately 45 pharmaceutical companies, including Pfizer, which makes ritlecitinib and provided funding for the study she discussed. Dr. Passeron reported financial relationships with approximately 40 pharmaceutical companies, including AbbVie, which makes upadacitinib and provided funding for the study he discussed.

A version of this article appeared on Medscape.com.

SAN DIEGO — Just a day before the annual meeting of the American Academy of Dermatology (AAD) began, a study was published online in JAMA Dermatology, cautioning that most downloadable mobile apps driven by artificial intelligence (AI) for use in monitoring dermatologic conditions lack validation.

Not least of the problems among the 41 apps evaluated, the majority offered no supporting evidence, no information about whether the app performance had been validated, and no information about how user privacy would be managed, reported Shannon Wongvibulsin, MD, PhD, a resident in the dermatology program at the University of California, Los Angeles, and her coauthors.

The findings from this report were also summarized in a poster at the AAD meeting, and the major themes were reiterated in several AAD symposia devoted to AI at the meeting. Veronica Rotemberg, MD, PhD, a dermatologist at Memorial Sloan Kettering Cancer Center, New York City, was one of those who weighed in on the future of AI. Although she was the senior author of the report, she did not address the report or poster directly, but her presentation on the practical aspects of incorporating AI into dermatology practice revisited several of its themes. 

Of the different themes, perhaps the most important were the concept that the source of AI data matters and the point that practicing clinicians should be familiar with the data source.

To date, “there is not much transparency in what data AI models are using,” Dr. Rotemberg said at the meeting. Based on the expectation that dermatologists will be purchasing rather than developing their own AI-based systems, she reiterated more than once that “transparency of data is critical,” even if vendors are often reluctant to reveal how their proprietary systems have been developed.

Few Dermatology Apps Are Vetted for Accuracy

In the poster and in the more detailed JAMA Dermatology paper, Dr. Wongvibulsin and her coinvestigators evaluated direct-to-consumer downloadable apps that claim to help with the assessment and management of skin conditions. Very few provided any supporting evidence of accuracy or even information about how they functioned.

The 41 apps were drawn from more than 300 apps; the others were excluded for failing to meet such criteria as failing to employ AI, not being available in English, or not addressing clinical management of dermatologic diseases. Dr. Wongvibulsin pointed out that none of the apps had been granted regulatory approval even though only two provided a disclaimer to that effect.

In all, just 5 of the 41 provided supporting evidence from a peer-reviewed journal, and less than 40% were created with any input from a dermatologist, Dr. Wongvibulsin reported. The result is that the utility and accuracy of these apps were, for the most part, difficult to judge.

“At a minimum, app developers should provide details on what AI algorithms are used, what data sets were used for training, testing, and validation, whether there was any clinician input, whether there are any supporting publications, how user-submitted images are used, and if there are any measures used to ensure data privacy,” Dr. Wongvibulsin wrote in the poster.

For AI-based apps or systems designed for use by dermatologists, Dr. Rotemberg made similar assertions in her overview of what clinicians should be considering for proprietary AI systems, whether to help with diagnosis or improve office efficiency.
 

Only One Dermatology App Cleared By the FDA

Currently, the only FDA-cleared app for dermatologic use is the DermaSensor, an AI-driven device. It was cleared for use in January 2024 for the evaluation of skin lesions “suggestive” of melanoma, basal cell carcinoma, and/or squamous cell carcinoma in patients aged ≥ 40 years “to assist health care providers in determining whether to refer a patient to a dermatologist,” according to an FDA announcement.

Using elastic scattering spectroscopy to analyze light reflecting off the skin to detect malignancy, the manufacturer’s promotional material claims a 96% sensitivity and a 97% specificity. 

While Dr. Rotemberg did not comment on these claims, she cautioned that AI models differ with regards to how they were trained and the relative heterogeneity of the training dataset defined by types of patients, types of skin, and types of AI learning processes. All of these variables are relevant in whether the AI will perform in a given clinical setting at the level it performed during development.

“The most accurate models employ narrow datasets, but these do not necessarily mimic what we see in practice,” she said.

In addition, even when an AI-based system is working for a given task, it must be monitored over time. Dr. Rotemberg warned about the potential for “data drift,” which describes the slow evolution in how diseases present, their prevalence by age, or other factors that might affect AI performance. She explained that repeated validation is needed to ensure that the AI-based models remain as accurate over time as they were when first used.

Many of these concepts were explored in a consensus statement from the International Skin Imaging Collaboration AI Working Group, published in JAMA Dermatology in December 2021. The statement, of which Dr. Rotemberg was a coauthor, provided recommendations for the principles of AI algorithm development specific to dermatologic considerations.

At the AAD symposium, Dr. Rotemberg asked the audience for suggestions about the needs they hoped AI might address for in office care or efficiency. Their responses included generating prior authorizations for prescriptions, triaging email for importance, and helping to improve efficiency for common front desk tasks. She liked all of these suggestions, but she warned that as powerful as it can be, AI is not likely to provide technology that will fit seamlessly into workflows without adjustment.

“Our current systems do not allow human integration of AI models,” Dr. Rotemberg said. Rather than counting on AI to adapt to current practices, she cautioned that “we may have to redesign our entire structure to actually be able to accommodate AI-based” systems. The risk for users is tasks that become more challenging before they become easier. 

AI Should Not Be a Black Box

AI is promising, but it is not magic, according to other investigators, including Tofunmi A. Omiye, PhD, a postdoctoral scholar in dermatology at Stanford University, California. First author of a recent review of AI in dermatology published in Frontiers in Medicine, Dr. Omiye agreed that clinicians who want to employ AI should be able to understand basic principles if they want the technology to perform as expected.

“I totally agree that physicians should at least have a basic understanding of the data sources for training AI models as we have found that to be important to the performance of these models in the clinical setting,” he told this news organization.

“Beyond understanding the data sources, I believe physicians can also try to have a comprehensive understanding of what AI means, its training process, and evaluation as this will help them to evaluate its utility in their practice,” he added. He also reinforced the relevance of data drift.

“Concepts like distribution shift — where models perform less well over time due to changes in the patient population — are also important to keep in mind,” Dr. Omiye said.

Dr. Wongvibulsin, Dr. Rotemberg, and Dr. Omiye reported no potential financial conflicts of interest relevant to this topic. 

A version of this article appeared on Medscape.com .

SAN DIEGO — Just a day before the annual meeting of the American Academy of Dermatology (AAD) began, a study was published online in JAMA Dermatology, cautioning that most downloadable mobile apps driven by artificial intelligence (AI) for use in monitoring dermatologic conditions lack validation.

Not least of the problems among the 41 apps evaluated, the majority offered no supporting evidence, no information about whether the app performance had been validated, and no information about how user privacy would be managed, reported Shannon Wongvibulsin, MD, PhD, a resident in the dermatology program at the University of California, Los Angeles, and her coauthors.

The findings from this report were also summarized in a poster at the AAD meeting, and the major themes were reiterated in several AAD symposia devoted to AI at the meeting. Veronica Rotemberg, MD, PhD, a dermatologist at Memorial Sloan Kettering Cancer Center, New York City, was one of those who weighed in on the future of AI. Although she was the senior author of the report, she did not address the report or poster directly, but her presentation on the practical aspects of incorporating AI into dermatology practice revisited several of its themes. 

Of the different themes, perhaps the most important were the concept that the source of AI data matters and the point that practicing clinicians should be familiar with the data source.

To date, “there is not much transparency in what data AI models are using,” Dr. Rotemberg said at the meeting. Based on the expectation that dermatologists will be purchasing rather than developing their own AI-based systems, she reiterated more than once that “transparency of data is critical,” even if vendors are often reluctant to reveal how their proprietary systems have been developed.

Few Dermatology Apps Are Vetted for Accuracy

In the poster and in the more detailed JAMA Dermatology paper, Dr. Wongvibulsin and her coinvestigators evaluated direct-to-consumer downloadable apps that claim to help with the assessment and management of skin conditions. Very few provided any supporting evidence of accuracy or even information about how they functioned.

The 41 apps were drawn from more than 300 apps; the others were excluded for failing to meet such criteria as failing to employ AI, not being available in English, or not addressing clinical management of dermatologic diseases. Dr. Wongvibulsin pointed out that none of the apps had been granted regulatory approval even though only two provided a disclaimer to that effect.

In all, just 5 of the 41 provided supporting evidence from a peer-reviewed journal, and less than 40% were created with any input from a dermatologist, Dr. Wongvibulsin reported. The result is that the utility and accuracy of these apps were, for the most part, difficult to judge.

“At a minimum, app developers should provide details on what AI algorithms are used, what data sets were used for training, testing, and validation, whether there was any clinician input, whether there are any supporting publications, how user-submitted images are used, and if there are any measures used to ensure data privacy,” Dr. Wongvibulsin wrote in the poster.

For AI-based apps or systems designed for use by dermatologists, Dr. Rotemberg made similar assertions in her overview of what clinicians should be considering for proprietary AI systems, whether to help with diagnosis or improve office efficiency.
 

Only One Dermatology App Cleared By the FDA

Currently, the only FDA-cleared app for dermatologic use is the DermaSensor, an AI-driven device. It was cleared for use in January 2024 for the evaluation of skin lesions “suggestive” of melanoma, basal cell carcinoma, and/or squamous cell carcinoma in patients aged ≥ 40 years “to assist health care providers in determining whether to refer a patient to a dermatologist,” according to an FDA announcement.

Using elastic scattering spectroscopy to analyze light reflecting off the skin to detect malignancy, the manufacturer’s promotional material claims a 96% sensitivity and a 97% specificity. 

While Dr. Rotemberg did not comment on these claims, she cautioned that AI models differ with regards to how they were trained and the relative heterogeneity of the training dataset defined by types of patients, types of skin, and types of AI learning processes. All of these variables are relevant in whether the AI will perform in a given clinical setting at the level it performed during development.

“The most accurate models employ narrow datasets, but these do not necessarily mimic what we see in practice,” she said.

In addition, even when an AI-based system is working for a given task, it must be monitored over time. Dr. Rotemberg warned about the potential for “data drift,” which describes the slow evolution in how diseases present, their prevalence by age, or other factors that might affect AI performance. She explained that repeated validation is needed to ensure that the AI-based models remain as accurate over time as they were when first used.

Many of these concepts were explored in a consensus statement from the International Skin Imaging Collaboration AI Working Group, published in JAMA Dermatology in December 2021. The statement, of which Dr. Rotemberg was a coauthor, provided recommendations for the principles of AI algorithm development specific to dermatologic considerations.

At the AAD symposium, Dr. Rotemberg asked the audience for suggestions about the needs they hoped AI might address for in office care or efficiency. Their responses included generating prior authorizations for prescriptions, triaging email for importance, and helping to improve efficiency for common front desk tasks. She liked all of these suggestions, but she warned that as powerful as it can be, AI is not likely to provide technology that will fit seamlessly into workflows without adjustment.

“Our current systems do not allow human integration of AI models,” Dr. Rotemberg said. Rather than counting on AI to adapt to current practices, she cautioned that “we may have to redesign our entire structure to actually be able to accommodate AI-based” systems. The risk for users is tasks that become more challenging before they become easier. 

AI Should Not Be a Black Box

AI is promising, but it is not magic, according to other investigators, including Tofunmi A. Omiye, PhD, a postdoctoral scholar in dermatology at Stanford University, California. First author of a recent review of AI in dermatology published in Frontiers in Medicine, Dr. Omiye agreed that clinicians who want to employ AI should be able to understand basic principles if they want the technology to perform as expected.

“I totally agree that physicians should at least have a basic understanding of the data sources for training AI models as we have found that to be important to the performance of these models in the clinical setting,” he told this news organization.

“Beyond understanding the data sources, I believe physicians can also try to have a comprehensive understanding of what AI means, its training process, and evaluation as this will help them to evaluate its utility in their practice,” he added. He also reinforced the relevance of data drift.

“Concepts like distribution shift — where models perform less well over time due to changes in the patient population — are also important to keep in mind,” Dr. Omiye said.

Dr. Wongvibulsin, Dr. Rotemberg, and Dr. Omiye reported no potential financial conflicts of interest relevant to this topic. 

A version of this article appeared on Medscape.com .

SAN DIEGO — Just a day before the annual meeting of the American Academy of Dermatology (AAD) began, a study was published online in JAMA Dermatology, cautioning that most downloadable mobile apps driven by artificial intelligence (AI) for use in monitoring dermatologic conditions lack validation.

Not least of the problems among the 41 apps evaluated, the majority offered no supporting evidence, no information about whether the app performance had been validated, and no information about how user privacy would be managed, reported Shannon Wongvibulsin, MD, PhD, a resident in the dermatology program at the University of California, Los Angeles, and her coauthors.

The findings from this report were also summarized in a poster at the AAD meeting, and the major themes were reiterated in several AAD symposia devoted to AI at the meeting. Veronica Rotemberg, MD, PhD, a dermatologist at Memorial Sloan Kettering Cancer Center, New York City, was one of those who weighed in on the future of AI. Although she was the senior author of the report, she did not address the report or poster directly, but her presentation on the practical aspects of incorporating AI into dermatology practice revisited several of its themes. 

Of the different themes, perhaps the most important were the concept that the source of AI data matters and the point that practicing clinicians should be familiar with the data source.

To date, “there is not much transparency in what data AI models are using,” Dr. Rotemberg said at the meeting. Based on the expectation that dermatologists will be purchasing rather than developing their own AI-based systems, she reiterated more than once that “transparency of data is critical,” even if vendors are often reluctant to reveal how their proprietary systems have been developed.

Few Dermatology Apps Are Vetted for Accuracy

In the poster and in the more detailed JAMA Dermatology paper, Dr. Wongvibulsin and her coinvestigators evaluated direct-to-consumer downloadable apps that claim to help with the assessment and management of skin conditions. Very few provided any supporting evidence of accuracy or even information about how they functioned.

The 41 apps were drawn from more than 300 apps; the others were excluded for failing to meet such criteria as failing to employ AI, not being available in English, or not addressing clinical management of dermatologic diseases. Dr. Wongvibulsin pointed out that none of the apps had been granted regulatory approval even though only two provided a disclaimer to that effect.

In all, just 5 of the 41 provided supporting evidence from a peer-reviewed journal, and less than 40% were created with any input from a dermatologist, Dr. Wongvibulsin reported. The result is that the utility and accuracy of these apps were, for the most part, difficult to judge.

“At a minimum, app developers should provide details on what AI algorithms are used, what data sets were used for training, testing, and validation, whether there was any clinician input, whether there are any supporting publications, how user-submitted images are used, and if there are any measures used to ensure data privacy,” Dr. Wongvibulsin wrote in the poster.

For AI-based apps or systems designed for use by dermatologists, Dr. Rotemberg made similar assertions in her overview of what clinicians should be considering for proprietary AI systems, whether to help with diagnosis or improve office efficiency.
 

Only One Dermatology App Cleared By the FDA

Currently, the only FDA-cleared app for dermatologic use is the DermaSensor, an AI-driven device. It was cleared for use in January 2024 for the evaluation of skin lesions “suggestive” of melanoma, basal cell carcinoma, and/or squamous cell carcinoma in patients aged ≥ 40 years “to assist health care providers in determining whether to refer a patient to a dermatologist,” according to an FDA announcement.

Using elastic scattering spectroscopy to analyze light reflecting off the skin to detect malignancy, the manufacturer’s promotional material claims a 96% sensitivity and a 97% specificity. 

While Dr. Rotemberg did not comment on these claims, she cautioned that AI models differ with regards to how they were trained and the relative heterogeneity of the training dataset defined by types of patients, types of skin, and types of AI learning processes. All of these variables are relevant in whether the AI will perform in a given clinical setting at the level it performed during development.

“The most accurate models employ narrow datasets, but these do not necessarily mimic what we see in practice,” she said.

In addition, even when an AI-based system is working for a given task, it must be monitored over time. Dr. Rotemberg warned about the potential for “data drift,” which describes the slow evolution in how diseases present, their prevalence by age, or other factors that might affect AI performance. She explained that repeated validation is needed to ensure that the AI-based models remain as accurate over time as they were when first used.

Many of these concepts were explored in a consensus statement from the International Skin Imaging Collaboration AI Working Group, published in JAMA Dermatology in December 2021. The statement, of which Dr. Rotemberg was a coauthor, provided recommendations for the principles of AI algorithm development specific to dermatologic considerations.

At the AAD symposium, Dr. Rotemberg asked the audience for suggestions about the needs they hoped AI might address for in office care or efficiency. Their responses included generating prior authorizations for prescriptions, triaging email for importance, and helping to improve efficiency for common front desk tasks. She liked all of these suggestions, but she warned that as powerful as it can be, AI is not likely to provide technology that will fit seamlessly into workflows without adjustment.

“Our current systems do not allow human integration of AI models,” Dr. Rotemberg said. Rather than counting on AI to adapt to current practices, she cautioned that “we may have to redesign our entire structure to actually be able to accommodate AI-based” systems. The risk for users is tasks that become more challenging before they become easier. 

AI Should Not Be a Black Box

AI is promising, but it is not magic, according to other investigators, including Tofunmi A. Omiye, PhD, a postdoctoral scholar in dermatology at Stanford University, California. First author of a recent review of AI in dermatology published in Frontiers in Medicine, Dr. Omiye agreed that clinicians who want to employ AI should be able to understand basic principles if they want the technology to perform as expected.

“I totally agree that physicians should at least have a basic understanding of the data sources for training AI models as we have found that to be important to the performance of these models in the clinical setting,” he told this news organization.

“Beyond understanding the data sources, I believe physicians can also try to have a comprehensive understanding of what AI means, its training process, and evaluation as this will help them to evaluate its utility in their practice,” he added. He also reinforced the relevance of data drift.

“Concepts like distribution shift — where models perform less well over time due to changes in the patient population — are also important to keep in mind,” Dr. Omiye said.

Dr. Wongvibulsin, Dr. Rotemberg, and Dr. Omiye reported no potential financial conflicts of interest relevant to this topic. 

A version of this article appeared on Medscape.com .

SAN DIEGO — Nemolizumab, the first-in-class inhibitor of interleukin-31 (IL-31), a neuroimmune cytokine linked to the promotion of pruritus and inflammation, continues to show good efficacy and safety for prurigo nodularis in an open-label follow-up pivotal trial following patients out to 52 weeks.

The OLYMPIA 2 trial, published just a few months ago, was positive for the primary endpoint of itch, and the 52-week data show “on-going improvement” not just in this key symptom but in the resolution of skin lesions, according to Shawn Kwatra, MD, director of the itch center and associate professor of dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.

The drug, which was found well tolerated in the double-blind OLYMPIA 2 study at 16 weeks, has not been associated with any new adverse events (AEs) in follow-up so far, according to Dr. Kwatra, who presented these findings in a late-breaker session at the annual meeting of the American Academy of Dermatology (AAD).

The promise of an anti-IL-31 drug for sustained control of itch and inflammation was further supported by a separate late breaker on long-term maintenance data on nemolizumab for moderate to severe atopic dermatitis (AD).
 

New Prurigo Nodularis Therapies Needed

For prurigo nodularis, excitement about a new therapy is particularly warranted, according to Dr. Kwatra. Current treatment options, such as steroids and antihistamines, are neither well-tolerated nor particularly effective in most patients. He indicated that the very positive interim 52-week data from the ongoing open-label extension suggests that nemolizumab might be an important step forward for patients with this disease.

The interim 52-week analysis included 307 patients on continuous nemolizumab and 174 patients randomized previously to placebo and were nemolizumab-naive when they entered the open-label extension. Participants were drawn from the phase 3 trial as well as an earlier phase 2 study. Nemolizumab in all patients was delivered at a subcutaneous dose of 45 mg every 4 weeks.

Pointing out that the 2024 AAD annual meeting, with more than 19,000 attendees, “was the largest dermatology conference in the history of the world,” he added that his late-breaker results represent “the largest prurigo nodularis clinical study in the history of the world.”

At 52 weeks, 89.9% and 83.3% of those on continuous nemolizumab and those switched to nemolizumab, respectively, had achieved at least a 4-point reduction from baseline on the Peak Pruritus Numerical Rating Scale (NRS), which has a range from 0 to 10.

Approximately two thirds of patients (67.8% and 64.4%, respectively) had a weekly average peak NRS of ≤ 2, meaning they were free or almost free of itch. The improvement in a sleep index and in quality of life as measured with the Dermatology Life Quality Index closely followed the relief of itch with the large gains achieved within weeks of initiating treatment continuing on an upward slope at 52 weeks.

Over this time, lesions were also resolving. By week 52, healing of more than 75% of lesions had been achieved by 79.1% in both those on continuous nemolizumab and those who had been switched to nemolizumab. The rate of response was again about two thirds for those with lesion resolution considered clear or almost clear by the Investigator’s Global Assessment (IGA) response.
 

No Serious AEs Over Extended Follow-Up

With a mean duration of 388 days follow-up, there were no serious AEs that were clearly treatment related, but Dr. Kwatra did report that some patients developed mild eczematous lesions that typically responded to topical therapy. He also reported that asthma, particularly worsening asthma in patients already diagnosed with this disease, was seen in a small proportion of patients. Both were considered manageable, and no patients discontinued therapy because of these events, Dr. Kwatra said.

While further follow-up is planned, “we have never seen data in a prurigo nodularis [treatment trial] past 6 months,” he pointed out. For a challenging disease with a major adverse effect on quality of life, nemolizumab, if approved, will offer an important option for a difficult disease, he added.

Itch Improves in Patients with AD

Further support for the long-term safety of nemolizumab and its efficacy against itch was provided by another phase 3 extension study conducted in the treatment of AD. These long-term extension results were also presented in a late breaker session at the AAD meeting.

Evaluating maintenance data from responders, defined as a 75% reduction lesions on the Eczema Area and Severity Index (EASI-75) or as clear or almost clear skin on IGA at the end of the randomized ARCADIA 1 and 2 trials, there were 169 patients on every 4-week nemolizumab, 169 patients on every 8-week nemolizumab, and 169 patients on every 4-week placebo.

For pruritus, a ≥ 4 point NRS reduction was achieved at week 48 in 76.2% of those on the every 4-week dose, 59.7% of those on the every 8-week dose, and 41% on those on placebo, reported Jonathan Silverberg, MD, PhD, director of clinical research, Department of Dermatology, George Washington School of Medicine, Washington.

These not only represented sustained responses over the course of 48 weeks, but there was a gradual rise in this rate of success from baseline in the higher dose group. For a NRS score of ≤ 2, meaning no itch or almost no itch, the proportions were 64.9%, 52.9%, and 31.3%, respectively. These were accompanied by sustained responses in IGA and EASI-75 scores.

Overall, there was a “nice durability of response” over the maintenance period, with no new or dose-related safety signals, according to Dr. Silverberg. He pointed out that the every 8-week dose response was lower than every 4-week dose response, but “it looks very good” in regard to response and duration of response, “suggesting that this might be an option for a large subset of patients.”

Andrew Blauvelt, MD, an investigator with Oregon Medical Research Center, Portland, Oregon, cautioned that despite the promise, dermatologists “might need help” in understanding this new agent and using it appropriately. He pointed out that it employs a new mechanism of action, and it has “a couple of new twists that we have not seen with other drugs,” including its association with worsening asthma.

Noting that asthma exacerbation has been reported in a proportion of treated patients approaching 4%, he expressed concern “that this is not rare.” He also expressed concern about reports of peripheral edema and asked Dr. Kwatra specifically how this should be handled in the routine clinical setting.

Pointing out that the 1% of new cases of asthma in the nemolizumab arm was, in fact, lower than the rate of new cases in the placebo arm, Dr. Kwatra said that there have been cases of increased asthma symptoms in patients with existing disease. However, he added that this and the reports of peripheral edema, some of which appear to be simply associated with prurigo nodularis, typically resolve with routine interventions. He said, however, that these side effects represent legitimate concerns that clinicians should consider, but he indicated that they do not appear to be a threat to the benefit-to-risk ratio of this agent.

In February 2024, the Food and Drug Administration and the European Medicines Agency accepted submissions for nemolizumab for the treatment of prurigo nodularis and AD, according to Galderma, the company developing nemolizumab.

Dr. Kwatra reported a financial relationship with more than 15 pharmaceutical companies, including Galderma, which sponsored the nemolizumab trials. Dr. Silverberg reported financial relationships with more than 35 pharmaceutical companies, including Galderma. Dr. Blauvelt reported financial relationships with more than 20 pharmaceutical companies, including Galderma.

A version of this article appeared on Medscape.com.

SAN DIEGO — Nemolizumab, the first-in-class inhibitor of interleukin-31 (IL-31), a neuroimmune cytokine linked to the promotion of pruritus and inflammation, continues to show good efficacy and safety for prurigo nodularis in an open-label follow-up pivotal trial following patients out to 52 weeks.

The OLYMPIA 2 trial, published just a few months ago, was positive for the primary endpoint of itch, and the 52-week data show “on-going improvement” not just in this key symptom but in the resolution of skin lesions, according to Shawn Kwatra, MD, director of the itch center and associate professor of dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.

The drug, which was found well tolerated in the double-blind OLYMPIA 2 study at 16 weeks, has not been associated with any new adverse events (AEs) in follow-up so far, according to Dr. Kwatra, who presented these findings in a late-breaker session at the annual meeting of the American Academy of Dermatology (AAD).

The promise of an anti-IL-31 drug for sustained control of itch and inflammation was further supported by a separate late breaker on long-term maintenance data on nemolizumab for moderate to severe atopic dermatitis (AD).
 

New Prurigo Nodularis Therapies Needed

For prurigo nodularis, excitement about a new therapy is particularly warranted, according to Dr. Kwatra. Current treatment options, such as steroids and antihistamines, are neither well-tolerated nor particularly effective in most patients. He indicated that the very positive interim 52-week data from the ongoing open-label extension suggests that nemolizumab might be an important step forward for patients with this disease.

The interim 52-week analysis included 307 patients on continuous nemolizumab and 174 patients randomized previously to placebo and were nemolizumab-naive when they entered the open-label extension. Participants were drawn from the phase 3 trial as well as an earlier phase 2 study. Nemolizumab in all patients was delivered at a subcutaneous dose of 45 mg every 4 weeks.

Pointing out that the 2024 AAD annual meeting, with more than 19,000 attendees, “was the largest dermatology conference in the history of the world,” he added that his late-breaker results represent “the largest prurigo nodularis clinical study in the history of the world.”

At 52 weeks, 89.9% and 83.3% of those on continuous nemolizumab and those switched to nemolizumab, respectively, had achieved at least a 4-point reduction from baseline on the Peak Pruritus Numerical Rating Scale (NRS), which has a range from 0 to 10.

Approximately two thirds of patients (67.8% and 64.4%, respectively) had a weekly average peak NRS of ≤ 2, meaning they were free or almost free of itch. The improvement in a sleep index and in quality of life as measured with the Dermatology Life Quality Index closely followed the relief of itch with the large gains achieved within weeks of initiating treatment continuing on an upward slope at 52 weeks.

Over this time, lesions were also resolving. By week 52, healing of more than 75% of lesions had been achieved by 79.1% in both those on continuous nemolizumab and those who had been switched to nemolizumab. The rate of response was again about two thirds for those with lesion resolution considered clear or almost clear by the Investigator’s Global Assessment (IGA) response.
 

No Serious AEs Over Extended Follow-Up

With a mean duration of 388 days follow-up, there were no serious AEs that were clearly treatment related, but Dr. Kwatra did report that some patients developed mild eczematous lesions that typically responded to topical therapy. He also reported that asthma, particularly worsening asthma in patients already diagnosed with this disease, was seen in a small proportion of patients. Both were considered manageable, and no patients discontinued therapy because of these events, Dr. Kwatra said.

While further follow-up is planned, “we have never seen data in a prurigo nodularis [treatment trial] past 6 months,” he pointed out. For a challenging disease with a major adverse effect on quality of life, nemolizumab, if approved, will offer an important option for a difficult disease, he added.

Itch Improves in Patients with AD

Further support for the long-term safety of nemolizumab and its efficacy against itch was provided by another phase 3 extension study conducted in the treatment of AD. These long-term extension results were also presented in a late breaker session at the AAD meeting.

Evaluating maintenance data from responders, defined as a 75% reduction lesions on the Eczema Area and Severity Index (EASI-75) or as clear or almost clear skin on IGA at the end of the randomized ARCADIA 1 and 2 trials, there were 169 patients on every 4-week nemolizumab, 169 patients on every 8-week nemolizumab, and 169 patients on every 4-week placebo.

For pruritus, a ≥ 4 point NRS reduction was achieved at week 48 in 76.2% of those on the every 4-week dose, 59.7% of those on the every 8-week dose, and 41% on those on placebo, reported Jonathan Silverberg, MD, PhD, director of clinical research, Department of Dermatology, George Washington School of Medicine, Washington.

These not only represented sustained responses over the course of 48 weeks, but there was a gradual rise in this rate of success from baseline in the higher dose group. For a NRS score of ≤ 2, meaning no itch or almost no itch, the proportions were 64.9%, 52.9%, and 31.3%, respectively. These were accompanied by sustained responses in IGA and EASI-75 scores.

Overall, there was a “nice durability of response” over the maintenance period, with no new or dose-related safety signals, according to Dr. Silverberg. He pointed out that the every 8-week dose response was lower than every 4-week dose response, but “it looks very good” in regard to response and duration of response, “suggesting that this might be an option for a large subset of patients.”

Andrew Blauvelt, MD, an investigator with Oregon Medical Research Center, Portland, Oregon, cautioned that despite the promise, dermatologists “might need help” in understanding this new agent and using it appropriately. He pointed out that it employs a new mechanism of action, and it has “a couple of new twists that we have not seen with other drugs,” including its association with worsening asthma.

Noting that asthma exacerbation has been reported in a proportion of treated patients approaching 4%, he expressed concern “that this is not rare.” He also expressed concern about reports of peripheral edema and asked Dr. Kwatra specifically how this should be handled in the routine clinical setting.

Pointing out that the 1% of new cases of asthma in the nemolizumab arm was, in fact, lower than the rate of new cases in the placebo arm, Dr. Kwatra said that there have been cases of increased asthma symptoms in patients with existing disease. However, he added that this and the reports of peripheral edema, some of which appear to be simply associated with prurigo nodularis, typically resolve with routine interventions. He said, however, that these side effects represent legitimate concerns that clinicians should consider, but he indicated that they do not appear to be a threat to the benefit-to-risk ratio of this agent.

In February 2024, the Food and Drug Administration and the European Medicines Agency accepted submissions for nemolizumab for the treatment of prurigo nodularis and AD, according to Galderma, the company developing nemolizumab.

Dr. Kwatra reported a financial relationship with more than 15 pharmaceutical companies, including Galderma, which sponsored the nemolizumab trials. Dr. Silverberg reported financial relationships with more than 35 pharmaceutical companies, including Galderma. Dr. Blauvelt reported financial relationships with more than 20 pharmaceutical companies, including Galderma.

A version of this article appeared on Medscape.com.

SAN DIEGO — Nemolizumab, the first-in-class inhibitor of interleukin-31 (IL-31), a neuroimmune cytokine linked to the promotion of pruritus and inflammation, continues to show good efficacy and safety for prurigo nodularis in an open-label follow-up pivotal trial following patients out to 52 weeks.

The OLYMPIA 2 trial, published just a few months ago, was positive for the primary endpoint of itch, and the 52-week data show “on-going improvement” not just in this key symptom but in the resolution of skin lesions, according to Shawn Kwatra, MD, director of the itch center and associate professor of dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.

The drug, which was found well tolerated in the double-blind OLYMPIA 2 study at 16 weeks, has not been associated with any new adverse events (AEs) in follow-up so far, according to Dr. Kwatra, who presented these findings in a late-breaker session at the annual meeting of the American Academy of Dermatology (AAD).

The promise of an anti-IL-31 drug for sustained control of itch and inflammation was further supported by a separate late breaker on long-term maintenance data on nemolizumab for moderate to severe atopic dermatitis (AD).
 

New Prurigo Nodularis Therapies Needed

For prurigo nodularis, excitement about a new therapy is particularly warranted, according to Dr. Kwatra. Current treatment options, such as steroids and antihistamines, are neither well-tolerated nor particularly effective in most patients. He indicated that the very positive interim 52-week data from the ongoing open-label extension suggests that nemolizumab might be an important step forward for patients with this disease.

The interim 52-week analysis included 307 patients on continuous nemolizumab and 174 patients randomized previously to placebo and were nemolizumab-naive when they entered the open-label extension. Participants were drawn from the phase 3 trial as well as an earlier phase 2 study. Nemolizumab in all patients was delivered at a subcutaneous dose of 45 mg every 4 weeks.

Pointing out that the 2024 AAD annual meeting, with more than 19,000 attendees, “was the largest dermatology conference in the history of the world,” he added that his late-breaker results represent “the largest prurigo nodularis clinical study in the history of the world.”

At 52 weeks, 89.9% and 83.3% of those on continuous nemolizumab and those switched to nemolizumab, respectively, had achieved at least a 4-point reduction from baseline on the Peak Pruritus Numerical Rating Scale (NRS), which has a range from 0 to 10.

Approximately two thirds of patients (67.8% and 64.4%, respectively) had a weekly average peak NRS of ≤ 2, meaning they were free or almost free of itch. The improvement in a sleep index and in quality of life as measured with the Dermatology Life Quality Index closely followed the relief of itch with the large gains achieved within weeks of initiating treatment continuing on an upward slope at 52 weeks.

Over this time, lesions were also resolving. By week 52, healing of more than 75% of lesions had been achieved by 79.1% in both those on continuous nemolizumab and those who had been switched to nemolizumab. The rate of response was again about two thirds for those with lesion resolution considered clear or almost clear by the Investigator’s Global Assessment (IGA) response.
 

No Serious AEs Over Extended Follow-Up

With a mean duration of 388 days follow-up, there were no serious AEs that were clearly treatment related, but Dr. Kwatra did report that some patients developed mild eczematous lesions that typically responded to topical therapy. He also reported that asthma, particularly worsening asthma in patients already diagnosed with this disease, was seen in a small proportion of patients. Both were considered manageable, and no patients discontinued therapy because of these events, Dr. Kwatra said.

While further follow-up is planned, “we have never seen data in a prurigo nodularis [treatment trial] past 6 months,” he pointed out. For a challenging disease with a major adverse effect on quality of life, nemolizumab, if approved, will offer an important option for a difficult disease, he added.

Itch Improves in Patients with AD

Further support for the long-term safety of nemolizumab and its efficacy against itch was provided by another phase 3 extension study conducted in the treatment of AD. These long-term extension results were also presented in a late breaker session at the AAD meeting.

Evaluating maintenance data from responders, defined as a 75% reduction lesions on the Eczema Area and Severity Index (EASI-75) or as clear or almost clear skin on IGA at the end of the randomized ARCADIA 1 and 2 trials, there were 169 patients on every 4-week nemolizumab, 169 patients on every 8-week nemolizumab, and 169 patients on every 4-week placebo.

For pruritus, a ≥ 4 point NRS reduction was achieved at week 48 in 76.2% of those on the every 4-week dose, 59.7% of those on the every 8-week dose, and 41% on those on placebo, reported Jonathan Silverberg, MD, PhD, director of clinical research, Department of Dermatology, George Washington School of Medicine, Washington.

These not only represented sustained responses over the course of 48 weeks, but there was a gradual rise in this rate of success from baseline in the higher dose group. For a NRS score of ≤ 2, meaning no itch or almost no itch, the proportions were 64.9%, 52.9%, and 31.3%, respectively. These were accompanied by sustained responses in IGA and EASI-75 scores.

Overall, there was a “nice durability of response” over the maintenance period, with no new or dose-related safety signals, according to Dr. Silverberg. He pointed out that the every 8-week dose response was lower than every 4-week dose response, but “it looks very good” in regard to response and duration of response, “suggesting that this might be an option for a large subset of patients.”

Andrew Blauvelt, MD, an investigator with Oregon Medical Research Center, Portland, Oregon, cautioned that despite the promise, dermatologists “might need help” in understanding this new agent and using it appropriately. He pointed out that it employs a new mechanism of action, and it has “a couple of new twists that we have not seen with other drugs,” including its association with worsening asthma.

Noting that asthma exacerbation has been reported in a proportion of treated patients approaching 4%, he expressed concern “that this is not rare.” He also expressed concern about reports of peripheral edema and asked Dr. Kwatra specifically how this should be handled in the routine clinical setting.

Pointing out that the 1% of new cases of asthma in the nemolizumab arm was, in fact, lower than the rate of new cases in the placebo arm, Dr. Kwatra said that there have been cases of increased asthma symptoms in patients with existing disease. However, he added that this and the reports of peripheral edema, some of which appear to be simply associated with prurigo nodularis, typically resolve with routine interventions. He said, however, that these side effects represent legitimate concerns that clinicians should consider, but he indicated that they do not appear to be a threat to the benefit-to-risk ratio of this agent.

In February 2024, the Food and Drug Administration and the European Medicines Agency accepted submissions for nemolizumab for the treatment of prurigo nodularis and AD, according to Galderma, the company developing nemolizumab.

Dr. Kwatra reported a financial relationship with more than 15 pharmaceutical companies, including Galderma, which sponsored the nemolizumab trials. Dr. Silverberg reported financial relationships with more than 35 pharmaceutical companies, including Galderma. Dr. Blauvelt reported financial relationships with more than 20 pharmaceutical companies, including Galderma.

A version of this article appeared on Medscape.com.

SAN DIEGO — In published trials, both an interleukin (IL)–17 inhibitor and an IL-23 inhibitor achieved impressive rates of clear or almost clear responses in patients with moderate to severe plaque psoriasis, but late-breaker data presented at the annual meeting of the American Academy of Dermatology show that these types of responses are sustained for as long as patients have remained on therapy.

Of the two, the longer follow up is with the IL-17 inhibitor bimekizumab (Bimzelx). In a 4-year open-label extension study, the Psoriasis Area and Severity Index (PASI) 90 rate was approximately 85% in treated patients, according to Mark Lebwohl, MD, professor and chairman emeritus of the Department of Dermatology, Icahn School of Medicine at Mount Sinai in New York City

A PASI 90 score signifies that 90% of skin surface area is cleared. The proportion of patients who achieved a PASI 100 score, signifying total clearance, approached 70% at 4 years in the group with the greatest response. PASI 90 and PASI 100 rates at this point were only modestly lower than those reported at the end of the double-blind phase 3 trial when evaluated 3 years earlier. 

Follow-up with a novel oral anti-IL-23 inhibitor JNJ-2113 (JNJ-77242113) was only 52 weeks, far shorter. But again, the response for the most effective dose at the end of this period was essentially unchanged from that at 16 weeks. Among those on the highest and most effective test dose of once-daily 100 mg, the PASI 90 at 1 year was 64.3%, a rate that was essentially unchanged from week 16.

No Apparent Loss of Benefit Over Time

“We can really look at those dose-response curves and see that there is, overall, a maintenance of response,” reported Laura K. Ferris, MD, PhD, professor and director of clinical trials, Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. In her presentation of the data, she showed similar sustained control for the most effective doses of JNJ-2113 for multiple clinical outcomes, including an investigator’s global assessment (IGA) score of 0 or 1, also signifying clear or near clear skin.

Bimekizumab, a monoclonal antibody that inhibits both IL-17A and IL-17F, is already approved for the treatment of plaque psoriasis. The 52-week BE SURE trial, which provided the 478 patients who entered into the BE BRIGHT open label extension study, was published in The New England Journal of Medicine in July 2021. 

In the 4-year data reported by Dr. Lebwohl, three groups were compared: Those initially randomized to an every-4-week dosing schedule of bimekizumab over the course of the 52-week BE SURE trial; those randomized to an every-4-week bimekizumab schedule who were then subsequently switched to an every-8-week schedule; and those initiated on the TNF-inhibitor adalimumab (Humira) and were then switched at week 24 to every-4-week bimekizumab.

The PASI 90 responses at 52 weeks in these three groups, respectively, were 91.2%, 89.3%, and 95.2%. At 4 years, this almost clear response was observed in 82.4%, 83.2%, and 87.6%, respectively. At 52 weeks, the PASI 100 responses in these three groups, respectively, were 75.3%, 74.2%, and 72.9%. At 4 years, 61.9%, 58.5%, and 69.5% still had complete skin clearance.

Bimekizumab was well tolerated during the randomized trial, reported Dr. Lebwohl. The rates of nasopharyngitis and oral candidiasis, which were observed in approximately 12% and 8%, respectively, of treated patients during the randomized phase remained at about the same level in the long-term follow up. There were no new safety signals, he said.
 

JNJ-2113 Is First Potential Oral IL-23 Inhibitor

JNJ-2113 is a first-in-class oral peptide that binds to the IL-23 receptor, blocking the IL-23 signaling pathway. If approved, it would be the first oral therapy targeting IL-23. The 16-week outcomes of the dose-finding FRONTIER 1 phase 2b trial were published in The New England Journal of Medicine earlier this year. The primary endpoint was PASI 75, achieved by 79% of those on the 100 mg twice daily dose at week 16, vs 9% on placebo, and at 52 weeks, was 76%. 

“The proportion of patients achieving the FRONTIER 1 primary endpoint was maintained from week 16 to the end of week 52 in the extension study,” Dr. Ferris said, but further pointed out that rates of near or complete clearance achieved at week 16 were also essentially unchanged at week 52. This was true of PASI scores and IGA. 

Clearance of psoriatic lesions on the scalp was particularly impressive. By scalp-specific IGA, rates of clear or near clear (0/1) were not just maintained but improved over the course of follow-up, reaching 75.1% at 52 weeks in the highest dose group, she said.

JNJ-2113 was well tolerated in FRONTIER 1 and remained so during long-term follow-up, in the FRONTIER 2 extension study, according to Dr. Ferris. The most common complaints with JNJ-2113, such as nasopharyngitis (18.1% vs 25.7% in placebo), did not appear to differ significantly from placebo and the treatment remained well tolerated over the course of the extended follow-up.

There are limited direct comparisons of different biologics active in the treatment of plaque psoriasis for efficacy and safety, but these data appear to show a depth and durability of benefit for psoriasis that is exceptional, Dr. Lebwohl told this news organization. “The PASI 100 scores achieved by bimekizumab exceed anything we have seen to date,” he said. “And the durability of those exceedingly high scores is remarkable.”

Dr. Lebwohl reports financial relationships with approximately 40 pharmaceutical companies, including UCB Pharma, which developed bimekizumab. Dr. Ferris reports financial relationships with more than 20 pharmaceutical companies, including Janssen, which is developing JNJ-2113. 

A version of this article appeared on Medscape.com.

SAN DIEGO — In published trials, both an interleukin (IL)–17 inhibitor and an IL-23 inhibitor achieved impressive rates of clear or almost clear responses in patients with moderate to severe plaque psoriasis, but late-breaker data presented at the annual meeting of the American Academy of Dermatology show that these types of responses are sustained for as long as patients have remained on therapy.

Of the two, the longer follow up is with the IL-17 inhibitor bimekizumab (Bimzelx). In a 4-year open-label extension study, the Psoriasis Area and Severity Index (PASI) 90 rate was approximately 85% in treated patients, according to Mark Lebwohl, MD, professor and chairman emeritus of the Department of Dermatology, Icahn School of Medicine at Mount Sinai in New York City

A PASI 90 score signifies that 90% of skin surface area is cleared. The proportion of patients who achieved a PASI 100 score, signifying total clearance, approached 70% at 4 years in the group with the greatest response. PASI 90 and PASI 100 rates at this point were only modestly lower than those reported at the end of the double-blind phase 3 trial when evaluated 3 years earlier. 

Follow-up with a novel oral anti-IL-23 inhibitor JNJ-2113 (JNJ-77242113) was only 52 weeks, far shorter. But again, the response for the most effective dose at the end of this period was essentially unchanged from that at 16 weeks. Among those on the highest and most effective test dose of once-daily 100 mg, the PASI 90 at 1 year was 64.3%, a rate that was essentially unchanged from week 16.

No Apparent Loss of Benefit Over Time

“We can really look at those dose-response curves and see that there is, overall, a maintenance of response,” reported Laura K. Ferris, MD, PhD, professor and director of clinical trials, Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. In her presentation of the data, she showed similar sustained control for the most effective doses of JNJ-2113 for multiple clinical outcomes, including an investigator’s global assessment (IGA) score of 0 or 1, also signifying clear or near clear skin.

Bimekizumab, a monoclonal antibody that inhibits both IL-17A and IL-17F, is already approved for the treatment of plaque psoriasis. The 52-week BE SURE trial, which provided the 478 patients who entered into the BE BRIGHT open label extension study, was published in The New England Journal of Medicine in July 2021. 

In the 4-year data reported by Dr. Lebwohl, three groups were compared: Those initially randomized to an every-4-week dosing schedule of bimekizumab over the course of the 52-week BE SURE trial; those randomized to an every-4-week bimekizumab schedule who were then subsequently switched to an every-8-week schedule; and those initiated on the TNF-inhibitor adalimumab (Humira) and were then switched at week 24 to every-4-week bimekizumab.

The PASI 90 responses at 52 weeks in these three groups, respectively, were 91.2%, 89.3%, and 95.2%. At 4 years, this almost clear response was observed in 82.4%, 83.2%, and 87.6%, respectively. At 52 weeks, the PASI 100 responses in these three groups, respectively, were 75.3%, 74.2%, and 72.9%. At 4 years, 61.9%, 58.5%, and 69.5% still had complete skin clearance.

Bimekizumab was well tolerated during the randomized trial, reported Dr. Lebwohl. The rates of nasopharyngitis and oral candidiasis, which were observed in approximately 12% and 8%, respectively, of treated patients during the randomized phase remained at about the same level in the long-term follow up. There were no new safety signals, he said.
 

JNJ-2113 Is First Potential Oral IL-23 Inhibitor

JNJ-2113 is a first-in-class oral peptide that binds to the IL-23 receptor, blocking the IL-23 signaling pathway. If approved, it would be the first oral therapy targeting IL-23. The 16-week outcomes of the dose-finding FRONTIER 1 phase 2b trial were published in The New England Journal of Medicine earlier this year. The primary endpoint was PASI 75, achieved by 79% of those on the 100 mg twice daily dose at week 16, vs 9% on placebo, and at 52 weeks, was 76%. 

“The proportion of patients achieving the FRONTIER 1 primary endpoint was maintained from week 16 to the end of week 52 in the extension study,” Dr. Ferris said, but further pointed out that rates of near or complete clearance achieved at week 16 were also essentially unchanged at week 52. This was true of PASI scores and IGA. 

Clearance of psoriatic lesions on the scalp was particularly impressive. By scalp-specific IGA, rates of clear or near clear (0/1) were not just maintained but improved over the course of follow-up, reaching 75.1% at 52 weeks in the highest dose group, she said.

JNJ-2113 was well tolerated in FRONTIER 1 and remained so during long-term follow-up, in the FRONTIER 2 extension study, according to Dr. Ferris. The most common complaints with JNJ-2113, such as nasopharyngitis (18.1% vs 25.7% in placebo), did not appear to differ significantly from placebo and the treatment remained well tolerated over the course of the extended follow-up.

There are limited direct comparisons of different biologics active in the treatment of plaque psoriasis for efficacy and safety, but these data appear to show a depth and durability of benefit for psoriasis that is exceptional, Dr. Lebwohl told this news organization. “The PASI 100 scores achieved by bimekizumab exceed anything we have seen to date,” he said. “And the durability of those exceedingly high scores is remarkable.”

Dr. Lebwohl reports financial relationships with approximately 40 pharmaceutical companies, including UCB Pharma, which developed bimekizumab. Dr. Ferris reports financial relationships with more than 20 pharmaceutical companies, including Janssen, which is developing JNJ-2113. 

A version of this article appeared on Medscape.com.

SAN DIEGO — In published trials, both an interleukin (IL)–17 inhibitor and an IL-23 inhibitor achieved impressive rates of clear or almost clear responses in patients with moderate to severe plaque psoriasis, but late-breaker data presented at the annual meeting of the American Academy of Dermatology show that these types of responses are sustained for as long as patients have remained on therapy.

Of the two, the longer follow up is with the IL-17 inhibitor bimekizumab (Bimzelx). In a 4-year open-label extension study, the Psoriasis Area and Severity Index (PASI) 90 rate was approximately 85% in treated patients, according to Mark Lebwohl, MD, professor and chairman emeritus of the Department of Dermatology, Icahn School of Medicine at Mount Sinai in New York City

A PASI 90 score signifies that 90% of skin surface area is cleared. The proportion of patients who achieved a PASI 100 score, signifying total clearance, approached 70% at 4 years in the group with the greatest response. PASI 90 and PASI 100 rates at this point were only modestly lower than those reported at the end of the double-blind phase 3 trial when evaluated 3 years earlier. 

Follow-up with a novel oral anti-IL-23 inhibitor JNJ-2113 (JNJ-77242113) was only 52 weeks, far shorter. But again, the response for the most effective dose at the end of this period was essentially unchanged from that at 16 weeks. Among those on the highest and most effective test dose of once-daily 100 mg, the PASI 90 at 1 year was 64.3%, a rate that was essentially unchanged from week 16.

No Apparent Loss of Benefit Over Time

“We can really look at those dose-response curves and see that there is, overall, a maintenance of response,” reported Laura K. Ferris, MD, PhD, professor and director of clinical trials, Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. In her presentation of the data, she showed similar sustained control for the most effective doses of JNJ-2113 for multiple clinical outcomes, including an investigator’s global assessment (IGA) score of 0 or 1, also signifying clear or near clear skin.

Bimekizumab, a monoclonal antibody that inhibits both IL-17A and IL-17F, is already approved for the treatment of plaque psoriasis. The 52-week BE SURE trial, which provided the 478 patients who entered into the BE BRIGHT open label extension study, was published in The New England Journal of Medicine in July 2021. 

In the 4-year data reported by Dr. Lebwohl, three groups were compared: Those initially randomized to an every-4-week dosing schedule of bimekizumab over the course of the 52-week BE SURE trial; those randomized to an every-4-week bimekizumab schedule who were then subsequently switched to an every-8-week schedule; and those initiated on the TNF-inhibitor adalimumab (Humira) and were then switched at week 24 to every-4-week bimekizumab.

The PASI 90 responses at 52 weeks in these three groups, respectively, were 91.2%, 89.3%, and 95.2%. At 4 years, this almost clear response was observed in 82.4%, 83.2%, and 87.6%, respectively. At 52 weeks, the PASI 100 responses in these three groups, respectively, were 75.3%, 74.2%, and 72.9%. At 4 years, 61.9%, 58.5%, and 69.5% still had complete skin clearance.

Bimekizumab was well tolerated during the randomized trial, reported Dr. Lebwohl. The rates of nasopharyngitis and oral candidiasis, which were observed in approximately 12% and 8%, respectively, of treated patients during the randomized phase remained at about the same level in the long-term follow up. There were no new safety signals, he said.
 

JNJ-2113 Is First Potential Oral IL-23 Inhibitor

JNJ-2113 is a first-in-class oral peptide that binds to the IL-23 receptor, blocking the IL-23 signaling pathway. If approved, it would be the first oral therapy targeting IL-23. The 16-week outcomes of the dose-finding FRONTIER 1 phase 2b trial were published in The New England Journal of Medicine earlier this year. The primary endpoint was PASI 75, achieved by 79% of those on the 100 mg twice daily dose at week 16, vs 9% on placebo, and at 52 weeks, was 76%. 

“The proportion of patients achieving the FRONTIER 1 primary endpoint was maintained from week 16 to the end of week 52 in the extension study,” Dr. Ferris said, but further pointed out that rates of near or complete clearance achieved at week 16 were also essentially unchanged at week 52. This was true of PASI scores and IGA. 

Clearance of psoriatic lesions on the scalp was particularly impressive. By scalp-specific IGA, rates of clear or near clear (0/1) were not just maintained but improved over the course of follow-up, reaching 75.1% at 52 weeks in the highest dose group, she said.

JNJ-2113 was well tolerated in FRONTIER 1 and remained so during long-term follow-up, in the FRONTIER 2 extension study, according to Dr. Ferris. The most common complaints with JNJ-2113, such as nasopharyngitis (18.1% vs 25.7% in placebo), did not appear to differ significantly from placebo and the treatment remained well tolerated over the course of the extended follow-up.

There are limited direct comparisons of different biologics active in the treatment of plaque psoriasis for efficacy and safety, but these data appear to show a depth and durability of benefit for psoriasis that is exceptional, Dr. Lebwohl told this news organization. “The PASI 100 scores achieved by bimekizumab exceed anything we have seen to date,” he said. “And the durability of those exceedingly high scores is remarkable.”

Dr. Lebwohl reports financial relationships with approximately 40 pharmaceutical companies, including UCB Pharma, which developed bimekizumab. Dr. Ferris reports financial relationships with more than 20 pharmaceutical companies, including Janssen, which is developing JNJ-2113. 

A version of this article appeared on Medscape.com.

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

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

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

Ted Bosworth/MDedge News

No Outcome Supported an Evobrutinib Advantage

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

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

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

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

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

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

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

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

No Resolution of CNS Lesions

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

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

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

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

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

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

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

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

Ted Bosworth/MDedge News

No Outcome Supported an Evobrutinib Advantage

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

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

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

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

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

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

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

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

No Resolution of CNS Lesions

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

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

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

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

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

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

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

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

Ted Bosworth/MDedge News

No Outcome Supported an Evobrutinib Advantage

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

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

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

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

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

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

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

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

No Resolution of CNS Lesions

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

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

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

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

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