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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.
When released at the end of 2023, the primary endpoints of the annualized relapse rate (ARR) were identical or nearly identical for evobrutinib relative to teriflunomide in RMS1 (0.15 vs 0.14) and RMS2 (0.11 vs 0.11).
Yet, many researchers were still hoping to see some greater advantage for the BTK inhibitor, which modulates B cell activity and inhibits activation of inflammatory cells in the central nervous system, on one or more secondary endpoints.
“The primary ARR endpoint was mandated by the regulatory agencies,” explained Mark S. Freedman, MD, director of the MS Research Unit, University of Ottawa, Canada. Although he was not greatly surprised that evobrutinib failed to show superiority over the already low ARR rates typically achieved on teriflunomide, he had held out hope that a benefit on one or more secondary outcomes would support BTK inhibition as an MS target.
However, the time to confirmed disability progression and time to confirmed disability improvement among the two treatment groups traced the same course over 24 weeks. Graphically, the lines were nearly superimposed.
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.
When released at the end of 2023, the primary endpoints of the annualized relapse rate (ARR) were identical or nearly identical for evobrutinib relative to teriflunomide in RMS1 (0.15 vs 0.14) and RMS2 (0.11 vs 0.11).
Yet, many researchers were still hoping to see some greater advantage for the BTK inhibitor, which modulates B cell activity and inhibits activation of inflammatory cells in the central nervous system, on one or more secondary endpoints.
“The primary ARR endpoint was mandated by the regulatory agencies,” explained Mark S. Freedman, MD, director of the MS Research Unit, University of Ottawa, Canada. Although he was not greatly surprised that evobrutinib failed to show superiority over the already low ARR rates typically achieved on teriflunomide, he had held out hope that a benefit on one or more secondary outcomes would support BTK inhibition as an MS target.
However, the time to confirmed disability progression and time to confirmed disability improvement among the two treatment groups traced the same course over 24 weeks. Graphically, the lines were nearly superimposed.
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.
When released at the end of 2023, the primary endpoints of the annualized relapse rate (ARR) were identical or nearly identical for evobrutinib relative to teriflunomide in RMS1 (0.15 vs 0.14) and RMS2 (0.11 vs 0.11).
Yet, many researchers were still hoping to see some greater advantage for the BTK inhibitor, which modulates B cell activity and inhibits activation of inflammatory cells in the central nervous system, on one or more secondary endpoints.
“The primary ARR endpoint was mandated by the regulatory agencies,” explained Mark S. Freedman, MD, director of the MS Research Unit, University of Ottawa, Canada. Although he was not greatly surprised that evobrutinib failed to show superiority over the already low ARR rates typically achieved on teriflunomide, he had held out hope that a benefit on one or more secondary outcomes would support BTK inhibition as an MS target.
However, the time to confirmed disability progression and time to confirmed disability improvement among the two treatment groups traced the same course over 24 weeks. Graphically, the lines were nearly superimposed.
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.
FROM ACTRIMS FORUM 2024