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Novel Agent First to Slow Disability in Nonrelapsing Secondary MS
COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).
In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.
However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.
The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting.
“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said.
Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said.
He estimated that up to 30% of patients with MS at his clinic may fall into this category.
A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained.
“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.
Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.
He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting.
He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses.
Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
Trial Results
The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months.
They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required.
About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.
The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years.
“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.
Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88).
Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.
In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).
A ‘Head-scratcher’ Finding
Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy.
“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Dr. Fox reported.
He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.”
In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group vs 1.6% in the placebo group.
A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. Fox.
However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment.
Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension.
Weekly Liver Enzyme Testing
Dr. Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”
The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later in 2024.
Commenting on the trial, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.”
“The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added.
Dr. Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
GEMINI Trials Also Show Slowed Disability
Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug with teriflunomide, a standard of care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates, compared with teriflunomide.
However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial.
“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Dr. Fox said.
The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.
A version of this article first appeared on Medscape.com.
COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).
In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.
However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.
The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting.
“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said.
Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said.
He estimated that up to 30% of patients with MS at his clinic may fall into this category.
A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained.
“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.
Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.
He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting.
He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses.
Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
Trial Results
The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months.
They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required.
About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.
The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years.
“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.
Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88).
Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.
In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).
A ‘Head-scratcher’ Finding
Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy.
“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Dr. Fox reported.
He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.”
In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group vs 1.6% in the placebo group.
A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. Fox.
However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment.
Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension.
Weekly Liver Enzyme Testing
Dr. Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”
The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later in 2024.
Commenting on the trial, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.”
“The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added.
Dr. Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
GEMINI Trials Also Show Slowed Disability
Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug with teriflunomide, a standard of care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates, compared with teriflunomide.
However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial.
“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Dr. Fox said.
The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.
A version of this article first appeared on Medscape.com.
COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).
In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.
However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.
The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting.
“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said.
Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said.
He estimated that up to 30% of patients with MS at his clinic may fall into this category.
A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained.
“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.
Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.
He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting.
He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses.
Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
Trial Results
The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months.
They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required.
About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.
The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years.
“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.
Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88).
Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.
In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).
A ‘Head-scratcher’ Finding
Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy.
“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Dr. Fox reported.
He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.”
In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group vs 1.6% in the placebo group.
A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. Fox.
However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment.
Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension.
Weekly Liver Enzyme Testing
Dr. Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”
The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later in 2024.
Commenting on the trial, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.”
“The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added.
Dr. Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
GEMINI Trials Also Show Slowed Disability
Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug with teriflunomide, a standard of care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates, compared with teriflunomide.
However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial.
“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Dr. Fox said.
The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2024
No Signal of Benefit for Simvastatin in Progressive MS
COPENHAGEN — There were high hopes that simvastatin, a well-tolerated lipid-lowering therapy, would reduce disability progression in patients with nonflaring secondary progressive multiple sclerosis (SPMS), but a definitive multicenter double-blind randomized trial found no benefit at all.
“There was no effect on the primary outcome of confirmed progression or on any of the secondary outcomes,” reported Jeremy Chataway, MD, PhD, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College of London, England.
For the primary outcome of progression on the Expanded Disability Status Scale (EDSS), the nonsignificant hazard ratio (HR) was, in fact, in favor of placebo (HR, 1.13; P = .26) over 45 months of follow-up and 365 progression events.
No Meaningful Difference Between Study Arms
“There were wide confidence intervals [95% CI, 0.91-1.39], so, really, there were no differences between the two arms,” reported Dr. Chataway, who presented the simvastatin trial, called MS-STAT2, during the late-breaker session of the 2024 ECTRIMS annual meeting.
Over a period of more than 20 years, a series of experimental and clinical studies have indicated that simvastatin and other CoA reductase inhibitors have anti-inflammatory and neuroprotective effects. These studies were the basis for the first MED-STAT study, which was a placebo-controlled randomized trial published in 2014.
Although this study did not have a clinical endpoint, it associated simvastatin with a 43% reduction (P = .003) in the annualized rate of brain atrophy, which has been widely accepted as a surrogate measure of MS progression.
In MS-STAT2, 964 patients were available for the intention-to-treat analysis. An established diagnosis of SPMS, an age of 25-65, and an EDSS score of 4.0-6.5 were among the inclusion criteria. Patients were required to be relapse-free for at least 3 months prior to study entry.
Importantly, patients were excluded if they were taking statin-lowering therapies or were candidates for these therapies due to the presence of cardiovascular disease. They were also excluded from entering the trial if taking immunosuppressants, such as methotrexate or azathioprine, or had exposure to monoclonal antibodies employed in the treatment of MS, such as natalizumab and alemtuzumab, in the prior 12 months.
Randomized to 80 mg of simvastatin (40 mg in the first month followed by rapid upward titration) or placebo in a 1:1 fashion, patients remained on their assigned therapy for 3 years in the absence of progression. At the end of this time, patients who remained progression-free could continue for up to 45 months while still blinded to treatment assignment.
Even though a large proportion of patients who were eligible to remain in the study for the full 45 months did so, the retention did not reflect clinical improvement.
Indeed, the secondary endpoints also produced no signal of benefit. On a composite secondary endpoint of EDSS, ambulation in the form of the 25-foot walk, and upper extremity function in the form of the 9-hole peg test (9-HPT), the numerical odds ratio (OR) went in the wrong direction for simvastatin although the difference was not significant (OR, 1.17; P = .26).
Annualized Relapse Rate Numerically Higher on Simvastatin
The annualized relapse rate, another secondary endpoint, was low in both arms of the study at 0.05 relapses/year for placebo and 0.7 relapses/year for simvastatin. Again, this result, although numerically unfavorable for simvastatin did not reach statistical significance (OR, 1.43; P = .04).
Simvastatin had a placebo-like safety profile. The single case of rhabdomyolysis in the simvastatin arm, which occurred early after randomization, resolved. Otherwise, simvastatin was well tolerated.
Conducted before and through the period of the COVID-19 pandemic, the number of progression events tripled in the year after the COVID-19 pandemic started relative to the prior year. At the end of the pandemic, progression events returned to a level similar to that before its onset. However, although Dr. Chataway noted this was an interesting example of comorbidities exacerbating MS, he emphasized that this increase was similar in the simvastatin and placebo arms.
There are more analyses to come, including patient-reported outcomes, biomarker analyses, and further comparisons of change in MRIs, but Dr. Chataway acknowledged that the study provided no support for the underlying hypothesis.
Several experts commenting after the study was presented, including Ludwig Kappos, MD, PhD, Chair of Neurology at the University Hospital, Basel, Switzerland, agreed.
“Unfortunately, these results are quite disappointing,” he said. When asked if there is any rationale for further pursuing studies of simvastatin for the treatment of SPMS, he said no.
“These data are quite convincing that there is no benefit. I do not see where you could go from here,” Dr. Kappos said in an interview.
Dr. Chataway, asked the same question, reiterated that there are a number of preplanned analyses that will be completed, but he does not foresee further studies with simvastatin for the indication studied in MS-STAT-2 trial.
However, he also emphasized strongly that simvastatin or any other lipid-lowering therapy should not be withheld from MS patients that need these drugs for a cardiovascular indication.
“We saw no benefit seen from simvastatin for patients with stable SPMS, but these drugs were well tolerated and they can be life-saving therapies for patients with increased cardiovascular risk,” Dr. Chataway said.
Dr, Chataway reported financial relationships with Biogen, Genzyme, Ionis, Lucid, Merck NerveGen, Novartis, Roche, and Sanofi. Dr. Kappos reports financial relationships with more than 20 pharmaceutical companies. The MS-STAT2 trial received no funding from industry.
COPENHAGEN — There were high hopes that simvastatin, a well-tolerated lipid-lowering therapy, would reduce disability progression in patients with nonflaring secondary progressive multiple sclerosis (SPMS), but a definitive multicenter double-blind randomized trial found no benefit at all.
“There was no effect on the primary outcome of confirmed progression or on any of the secondary outcomes,” reported Jeremy Chataway, MD, PhD, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College of London, England.
For the primary outcome of progression on the Expanded Disability Status Scale (EDSS), the nonsignificant hazard ratio (HR) was, in fact, in favor of placebo (HR, 1.13; P = .26) over 45 months of follow-up and 365 progression events.
No Meaningful Difference Between Study Arms
“There were wide confidence intervals [95% CI, 0.91-1.39], so, really, there were no differences between the two arms,” reported Dr. Chataway, who presented the simvastatin trial, called MS-STAT2, during the late-breaker session of the 2024 ECTRIMS annual meeting.
Over a period of more than 20 years, a series of experimental and clinical studies have indicated that simvastatin and other CoA reductase inhibitors have anti-inflammatory and neuroprotective effects. These studies were the basis for the first MED-STAT study, which was a placebo-controlled randomized trial published in 2014.
Although this study did not have a clinical endpoint, it associated simvastatin with a 43% reduction (P = .003) in the annualized rate of brain atrophy, which has been widely accepted as a surrogate measure of MS progression.
In MS-STAT2, 964 patients were available for the intention-to-treat analysis. An established diagnosis of SPMS, an age of 25-65, and an EDSS score of 4.0-6.5 were among the inclusion criteria. Patients were required to be relapse-free for at least 3 months prior to study entry.
Importantly, patients were excluded if they were taking statin-lowering therapies or were candidates for these therapies due to the presence of cardiovascular disease. They were also excluded from entering the trial if taking immunosuppressants, such as methotrexate or azathioprine, or had exposure to monoclonal antibodies employed in the treatment of MS, such as natalizumab and alemtuzumab, in the prior 12 months.
Randomized to 80 mg of simvastatin (40 mg in the first month followed by rapid upward titration) or placebo in a 1:1 fashion, patients remained on their assigned therapy for 3 years in the absence of progression. At the end of this time, patients who remained progression-free could continue for up to 45 months while still blinded to treatment assignment.
Even though a large proportion of patients who were eligible to remain in the study for the full 45 months did so, the retention did not reflect clinical improvement.
Indeed, the secondary endpoints also produced no signal of benefit. On a composite secondary endpoint of EDSS, ambulation in the form of the 25-foot walk, and upper extremity function in the form of the 9-hole peg test (9-HPT), the numerical odds ratio (OR) went in the wrong direction for simvastatin although the difference was not significant (OR, 1.17; P = .26).
Annualized Relapse Rate Numerically Higher on Simvastatin
The annualized relapse rate, another secondary endpoint, was low in both arms of the study at 0.05 relapses/year for placebo and 0.7 relapses/year for simvastatin. Again, this result, although numerically unfavorable for simvastatin did not reach statistical significance (OR, 1.43; P = .04).
Simvastatin had a placebo-like safety profile. The single case of rhabdomyolysis in the simvastatin arm, which occurred early after randomization, resolved. Otherwise, simvastatin was well tolerated.
Conducted before and through the period of the COVID-19 pandemic, the number of progression events tripled in the year after the COVID-19 pandemic started relative to the prior year. At the end of the pandemic, progression events returned to a level similar to that before its onset. However, although Dr. Chataway noted this was an interesting example of comorbidities exacerbating MS, he emphasized that this increase was similar in the simvastatin and placebo arms.
There are more analyses to come, including patient-reported outcomes, biomarker analyses, and further comparisons of change in MRIs, but Dr. Chataway acknowledged that the study provided no support for the underlying hypothesis.
Several experts commenting after the study was presented, including Ludwig Kappos, MD, PhD, Chair of Neurology at the University Hospital, Basel, Switzerland, agreed.
“Unfortunately, these results are quite disappointing,” he said. When asked if there is any rationale for further pursuing studies of simvastatin for the treatment of SPMS, he said no.
“These data are quite convincing that there is no benefit. I do not see where you could go from here,” Dr. Kappos said in an interview.
Dr. Chataway, asked the same question, reiterated that there are a number of preplanned analyses that will be completed, but he does not foresee further studies with simvastatin for the indication studied in MS-STAT-2 trial.
However, he also emphasized strongly that simvastatin or any other lipid-lowering therapy should not be withheld from MS patients that need these drugs for a cardiovascular indication.
“We saw no benefit seen from simvastatin for patients with stable SPMS, but these drugs were well tolerated and they can be life-saving therapies for patients with increased cardiovascular risk,” Dr. Chataway said.
Dr, Chataway reported financial relationships with Biogen, Genzyme, Ionis, Lucid, Merck NerveGen, Novartis, Roche, and Sanofi. Dr. Kappos reports financial relationships with more than 20 pharmaceutical companies. The MS-STAT2 trial received no funding from industry.
COPENHAGEN — There were high hopes that simvastatin, a well-tolerated lipid-lowering therapy, would reduce disability progression in patients with nonflaring secondary progressive multiple sclerosis (SPMS), but a definitive multicenter double-blind randomized trial found no benefit at all.
“There was no effect on the primary outcome of confirmed progression or on any of the secondary outcomes,” reported Jeremy Chataway, MD, PhD, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College of London, England.
For the primary outcome of progression on the Expanded Disability Status Scale (EDSS), the nonsignificant hazard ratio (HR) was, in fact, in favor of placebo (HR, 1.13; P = .26) over 45 months of follow-up and 365 progression events.
No Meaningful Difference Between Study Arms
“There were wide confidence intervals [95% CI, 0.91-1.39], so, really, there were no differences between the two arms,” reported Dr. Chataway, who presented the simvastatin trial, called MS-STAT2, during the late-breaker session of the 2024 ECTRIMS annual meeting.
Over a period of more than 20 years, a series of experimental and clinical studies have indicated that simvastatin and other CoA reductase inhibitors have anti-inflammatory and neuroprotective effects. These studies were the basis for the first MED-STAT study, which was a placebo-controlled randomized trial published in 2014.
Although this study did not have a clinical endpoint, it associated simvastatin with a 43% reduction (P = .003) in the annualized rate of brain atrophy, which has been widely accepted as a surrogate measure of MS progression.
In MS-STAT2, 964 patients were available for the intention-to-treat analysis. An established diagnosis of SPMS, an age of 25-65, and an EDSS score of 4.0-6.5 were among the inclusion criteria. Patients were required to be relapse-free for at least 3 months prior to study entry.
Importantly, patients were excluded if they were taking statin-lowering therapies or were candidates for these therapies due to the presence of cardiovascular disease. They were also excluded from entering the trial if taking immunosuppressants, such as methotrexate or azathioprine, or had exposure to monoclonal antibodies employed in the treatment of MS, such as natalizumab and alemtuzumab, in the prior 12 months.
Randomized to 80 mg of simvastatin (40 mg in the first month followed by rapid upward titration) or placebo in a 1:1 fashion, patients remained on their assigned therapy for 3 years in the absence of progression. At the end of this time, patients who remained progression-free could continue for up to 45 months while still blinded to treatment assignment.
Even though a large proportion of patients who were eligible to remain in the study for the full 45 months did so, the retention did not reflect clinical improvement.
Indeed, the secondary endpoints also produced no signal of benefit. On a composite secondary endpoint of EDSS, ambulation in the form of the 25-foot walk, and upper extremity function in the form of the 9-hole peg test (9-HPT), the numerical odds ratio (OR) went in the wrong direction for simvastatin although the difference was not significant (OR, 1.17; P = .26).
Annualized Relapse Rate Numerically Higher on Simvastatin
The annualized relapse rate, another secondary endpoint, was low in both arms of the study at 0.05 relapses/year for placebo and 0.7 relapses/year for simvastatin. Again, this result, although numerically unfavorable for simvastatin did not reach statistical significance (OR, 1.43; P = .04).
Simvastatin had a placebo-like safety profile. The single case of rhabdomyolysis in the simvastatin arm, which occurred early after randomization, resolved. Otherwise, simvastatin was well tolerated.
Conducted before and through the period of the COVID-19 pandemic, the number of progression events tripled in the year after the COVID-19 pandemic started relative to the prior year. At the end of the pandemic, progression events returned to a level similar to that before its onset. However, although Dr. Chataway noted this was an interesting example of comorbidities exacerbating MS, he emphasized that this increase was similar in the simvastatin and placebo arms.
There are more analyses to come, including patient-reported outcomes, biomarker analyses, and further comparisons of change in MRIs, but Dr. Chataway acknowledged that the study provided no support for the underlying hypothesis.
Several experts commenting after the study was presented, including Ludwig Kappos, MD, PhD, Chair of Neurology at the University Hospital, Basel, Switzerland, agreed.
“Unfortunately, these results are quite disappointing,” he said. When asked if there is any rationale for further pursuing studies of simvastatin for the treatment of SPMS, he said no.
“These data are quite convincing that there is no benefit. I do not see where you could go from here,” Dr. Kappos said in an interview.
Dr. Chataway, asked the same question, reiterated that there are a number of preplanned analyses that will be completed, but he does not foresee further studies with simvastatin for the indication studied in MS-STAT-2 trial.
However, he also emphasized strongly that simvastatin or any other lipid-lowering therapy should not be withheld from MS patients that need these drugs for a cardiovascular indication.
“We saw no benefit seen from simvastatin for patients with stable SPMS, but these drugs were well tolerated and they can be life-saving therapies for patients with increased cardiovascular risk,” Dr. Chataway said.
Dr, Chataway reported financial relationships with Biogen, Genzyme, Ionis, Lucid, Merck NerveGen, Novartis, Roche, and Sanofi. Dr. Kappos reports financial relationships with more than 20 pharmaceutical companies. The MS-STAT2 trial received no funding from industry.
FROM ECTRIMS 2024
Disability Reduction Is a Twist in Negative BTKi RRMS Trial
COPENHAGEN — In two phase 3 head-to-head comparing the Bruton tyrosine kinase inhibitor (BTKi) tolebrutinib to the immunomodulatory teriflunomide for relapsing-remitting multiple sclerosis (RRMS), there was no advantage on the primary endpoint of relapse, but the greater protection against disability, a secondary endpoint, might change thinking about BTKis as a potential MS therapy.
For annualized relapse rate (ARR), which is the basis on which these two drugs were compared, “there was no difference between tolebrutinib and teriflunomide,” reported Jiwon Oh, MD, Medical Director, Barlo Multiple Sclerosis Program, St. Michael’s Hospital, University of Toronto, Canada.
In the similar GEMINI 1 and 2 trials, the ARRs were nearly identical in the first, (0.13 and 0.12), and completely identical in the second (0.11) for tolebrutinib and teriflunomide, respectively.
Although Negative, GEMINI Trials Offer Intriguing Data
These data rule out the study hypothesis that a BTKi offers greater protection against relapse than a commonly used immunomodulator, but Dr. Oh suggested the study is still potentially relevant to MS research.
“There is hope,” Dr. Oh said, when reporting the findings of the GEMINI I and II trials during the latebreaker session at the 2024 ECTRIMS annual meeting. Ultimately, a substantial part of this hope was derived from the consistency of the GEMINI data with the placebo-controlled HERCULES trial of tolebrutinib presented immediately afterwards, but the disparity between the primary and secondary outcomes of GEMINI are, by themselves, relevant, suggesting that targets of treatment change as MS progresses from an acute to a chronic inflammatory process.
BTKi Associated With Reduced Disability
At 3 months, the rate of confirmed disability worsening (CDW) in the pooled GEMINI trials was 18.5% and 14.7% for tolebrutinib and teriflunomide, respectively, producing at 27% reduction in hazard ratio (HR) for this outcome (HR 0.73; P = .0018). At 6 months, the protection against disability (13.2% vs. 9.9%) persisted for tolebrutinib relative to teriflunomide (HR 0.71; P = .023).*
For the outcome of a confirmed disability improvement at 6 months, the higher rate in the tolebrutinib arm did not reach statistical significance (12.8% vs. 12.0%), but it did suggest a favorable trend (HR 1.22; P = .17).
While Dr. Oh acknowledged that secondary outcomes can only be considered hypothesis generating when the primary outcome is negative, she said these outcomes provide intriguing support for the potential of this BTKi drug to inhibit “smoldering inflammation.” Even if tolebrutinib was no more effective than teriflunomide against the acute inflammation that drives relapse, the GEMINI trials data support greater inhibition of the chronic inflammation implicated in progression in the absence of flares.
On MRI, the annualized rate of new and enlarging T2 lesions, although numerically higher in the tolebrutinib group, did not differ significantly in either GEMINI 1 (5.6 vs. 5.2; P = .46) or GEMINI 2 (5.1 vs. 4.4; P = .24). The least mean square difference in brain volume at end of study relative to 6 months into the study was 0.2% less in the tolebrutinib arm than the teriflunomide arm (P = .0002) in GEMINI 1, but the 0.04 numerical advantage for tolebrutinib did not reach statistical significance in GEMINI 2 (P = .43).
Of the 974 patients randomized in GEMINI 1 and 899 randomized in GEMINI 2, about 85% completed the 3-year trial. Almost all had RRMS (99%) rather than progressing MS. The median age was approximately 36 years, the baseline EDSS score was approximately 1.2, and the median time since diagnosis was about 6.5 years. The mean number of relapses in the prior year was approximately 0.6.
In GEMINI, the secondary outcomes foreshadowed the positive findings in the phase 3 HERCULES trial that came immediately after Dr. Oh’s GEMINI trials presentation. The HERCULES trial associated tolebrutinib with a 31% reduction in the risk of confirmed disability progression (CDW) relative to placebo in patients with non-relapsing secondary progressive MS (nrSPMS).
In HERCULES, 1172 patients with nrSPMS were randomized in a 2:1 fashion to tolebrutinib or placebo. For the primary endpoint of CDW at 6 months, tolebrutinib demonstrated a major and highly significant reduction in this primary endpoint (HR 0.69; P = .00026).
BTKi Disability Protection Supported By Progressive MS Trial
“This is the first trial to show significant slowing of disability in people with nrSPMS,” reported the principal investigator Robert J. Fox, MD, Vice Chair of the Neurological Institute at Cleveland Clinic, Cleveland, Ohio.
For disability improvement at 6 months, tolebrutinib was associated with a nearly 2-fold improvement (HR 1.88; P = .021). According to both Dr. Oh and Dr. Fox the results of these two major phase 3 tolebrutinib studies support the principle that the BTKi, which was shown to offer inhibition of relapse comparable to teriflunomide in the GEMINI trials, offers a greater inhibition of chronic inflammation.
“These results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes,” Dr. Oh said.
Dr. Fox said that the HERCULES results will be submitted to regulatory authorities with the goal of securing an indication for tolebrutinib for nrSPMS.
Both Dr. Oh and Dr. Fox suggested these results are likely to reorient thinking about the pathophysiology of MS progression and how different processes can be targeted in the future. Other experts agreed.
“I think we are starting to look at different endpoints than ARR, particularly at those that might better reflect progression in later stages of MS and that are independent of ARR,” said Dalia Rotstein, MD, MS researcher and an assistant professor of neurology, University of Toronto, Canada.
A moderator of the ECTRIMS latebreaker session, she suggested that the differences between outcomes of the GEMINI trials and HERCULES trials might have relevance to each other even if the GEMINI trials did not meet their primary endpoint.
Dr. Oh reported financial relationships with Amgen, Biogen, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi, which provided funding for the GEMINI trials. Dr. Fox reported financial relationships with more than 15 pharmaceutical companies, including Sanofi, which also provided funding for the HERCULES trial. Dr. Rotstein reported financial relationships with Alexion, Biogen, EMD Serono, Horizon, Novartis, Roche, Sanofi, and Touch IME.
*Correction, 9/26/24: A previous version of this article contained an incorrect P value.
COPENHAGEN — In two phase 3 head-to-head comparing the Bruton tyrosine kinase inhibitor (BTKi) tolebrutinib to the immunomodulatory teriflunomide for relapsing-remitting multiple sclerosis (RRMS), there was no advantage on the primary endpoint of relapse, but the greater protection against disability, a secondary endpoint, might change thinking about BTKis as a potential MS therapy.
For annualized relapse rate (ARR), which is the basis on which these two drugs were compared, “there was no difference between tolebrutinib and teriflunomide,” reported Jiwon Oh, MD, Medical Director, Barlo Multiple Sclerosis Program, St. Michael’s Hospital, University of Toronto, Canada.
In the similar GEMINI 1 and 2 trials, the ARRs were nearly identical in the first, (0.13 and 0.12), and completely identical in the second (0.11) for tolebrutinib and teriflunomide, respectively.
Although Negative, GEMINI Trials Offer Intriguing Data
These data rule out the study hypothesis that a BTKi offers greater protection against relapse than a commonly used immunomodulator, but Dr. Oh suggested the study is still potentially relevant to MS research.
“There is hope,” Dr. Oh said, when reporting the findings of the GEMINI I and II trials during the latebreaker session at the 2024 ECTRIMS annual meeting. Ultimately, a substantial part of this hope was derived from the consistency of the GEMINI data with the placebo-controlled HERCULES trial of tolebrutinib presented immediately afterwards, but the disparity between the primary and secondary outcomes of GEMINI are, by themselves, relevant, suggesting that targets of treatment change as MS progresses from an acute to a chronic inflammatory process.
BTKi Associated With Reduced Disability
At 3 months, the rate of confirmed disability worsening (CDW) in the pooled GEMINI trials was 18.5% and 14.7% for tolebrutinib and teriflunomide, respectively, producing at 27% reduction in hazard ratio (HR) for this outcome (HR 0.73; P = .0018). At 6 months, the protection against disability (13.2% vs. 9.9%) persisted for tolebrutinib relative to teriflunomide (HR 0.71; P = .023).*
For the outcome of a confirmed disability improvement at 6 months, the higher rate in the tolebrutinib arm did not reach statistical significance (12.8% vs. 12.0%), but it did suggest a favorable trend (HR 1.22; P = .17).
While Dr. Oh acknowledged that secondary outcomes can only be considered hypothesis generating when the primary outcome is negative, she said these outcomes provide intriguing support for the potential of this BTKi drug to inhibit “smoldering inflammation.” Even if tolebrutinib was no more effective than teriflunomide against the acute inflammation that drives relapse, the GEMINI trials data support greater inhibition of the chronic inflammation implicated in progression in the absence of flares.
On MRI, the annualized rate of new and enlarging T2 lesions, although numerically higher in the tolebrutinib group, did not differ significantly in either GEMINI 1 (5.6 vs. 5.2; P = .46) or GEMINI 2 (5.1 vs. 4.4; P = .24). The least mean square difference in brain volume at end of study relative to 6 months into the study was 0.2% less in the tolebrutinib arm than the teriflunomide arm (P = .0002) in GEMINI 1, but the 0.04 numerical advantage for tolebrutinib did not reach statistical significance in GEMINI 2 (P = .43).
Of the 974 patients randomized in GEMINI 1 and 899 randomized in GEMINI 2, about 85% completed the 3-year trial. Almost all had RRMS (99%) rather than progressing MS. The median age was approximately 36 years, the baseline EDSS score was approximately 1.2, and the median time since diagnosis was about 6.5 years. The mean number of relapses in the prior year was approximately 0.6.
In GEMINI, the secondary outcomes foreshadowed the positive findings in the phase 3 HERCULES trial that came immediately after Dr. Oh’s GEMINI trials presentation. The HERCULES trial associated tolebrutinib with a 31% reduction in the risk of confirmed disability progression (CDW) relative to placebo in patients with non-relapsing secondary progressive MS (nrSPMS).
In HERCULES, 1172 patients with nrSPMS were randomized in a 2:1 fashion to tolebrutinib or placebo. For the primary endpoint of CDW at 6 months, tolebrutinib demonstrated a major and highly significant reduction in this primary endpoint (HR 0.69; P = .00026).
BTKi Disability Protection Supported By Progressive MS Trial
“This is the first trial to show significant slowing of disability in people with nrSPMS,” reported the principal investigator Robert J. Fox, MD, Vice Chair of the Neurological Institute at Cleveland Clinic, Cleveland, Ohio.
For disability improvement at 6 months, tolebrutinib was associated with a nearly 2-fold improvement (HR 1.88; P = .021). According to both Dr. Oh and Dr. Fox the results of these two major phase 3 tolebrutinib studies support the principle that the BTKi, which was shown to offer inhibition of relapse comparable to teriflunomide in the GEMINI trials, offers a greater inhibition of chronic inflammation.
“These results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes,” Dr. Oh said.
Dr. Fox said that the HERCULES results will be submitted to regulatory authorities with the goal of securing an indication for tolebrutinib for nrSPMS.
Both Dr. Oh and Dr. Fox suggested these results are likely to reorient thinking about the pathophysiology of MS progression and how different processes can be targeted in the future. Other experts agreed.
“I think we are starting to look at different endpoints than ARR, particularly at those that might better reflect progression in later stages of MS and that are independent of ARR,” said Dalia Rotstein, MD, MS researcher and an assistant professor of neurology, University of Toronto, Canada.
A moderator of the ECTRIMS latebreaker session, she suggested that the differences between outcomes of the GEMINI trials and HERCULES trials might have relevance to each other even if the GEMINI trials did not meet their primary endpoint.
Dr. Oh reported financial relationships with Amgen, Biogen, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi, which provided funding for the GEMINI trials. Dr. Fox reported financial relationships with more than 15 pharmaceutical companies, including Sanofi, which also provided funding for the HERCULES trial. Dr. Rotstein reported financial relationships with Alexion, Biogen, EMD Serono, Horizon, Novartis, Roche, Sanofi, and Touch IME.
*Correction, 9/26/24: A previous version of this article contained an incorrect P value.
COPENHAGEN — In two phase 3 head-to-head comparing the Bruton tyrosine kinase inhibitor (BTKi) tolebrutinib to the immunomodulatory teriflunomide for relapsing-remitting multiple sclerosis (RRMS), there was no advantage on the primary endpoint of relapse, but the greater protection against disability, a secondary endpoint, might change thinking about BTKis as a potential MS therapy.
For annualized relapse rate (ARR), which is the basis on which these two drugs were compared, “there was no difference between tolebrutinib and teriflunomide,” reported Jiwon Oh, MD, Medical Director, Barlo Multiple Sclerosis Program, St. Michael’s Hospital, University of Toronto, Canada.
In the similar GEMINI 1 and 2 trials, the ARRs were nearly identical in the first, (0.13 and 0.12), and completely identical in the second (0.11) for tolebrutinib and teriflunomide, respectively.
Although Negative, GEMINI Trials Offer Intriguing Data
These data rule out the study hypothesis that a BTKi offers greater protection against relapse than a commonly used immunomodulator, but Dr. Oh suggested the study is still potentially relevant to MS research.
“There is hope,” Dr. Oh said, when reporting the findings of the GEMINI I and II trials during the latebreaker session at the 2024 ECTRIMS annual meeting. Ultimately, a substantial part of this hope was derived from the consistency of the GEMINI data with the placebo-controlled HERCULES trial of tolebrutinib presented immediately afterwards, but the disparity between the primary and secondary outcomes of GEMINI are, by themselves, relevant, suggesting that targets of treatment change as MS progresses from an acute to a chronic inflammatory process.
BTKi Associated With Reduced Disability
At 3 months, the rate of confirmed disability worsening (CDW) in the pooled GEMINI trials was 18.5% and 14.7% for tolebrutinib and teriflunomide, respectively, producing at 27% reduction in hazard ratio (HR) for this outcome (HR 0.73; P = .0018). At 6 months, the protection against disability (13.2% vs. 9.9%) persisted for tolebrutinib relative to teriflunomide (HR 0.71; P = .023).*
For the outcome of a confirmed disability improvement at 6 months, the higher rate in the tolebrutinib arm did not reach statistical significance (12.8% vs. 12.0%), but it did suggest a favorable trend (HR 1.22; P = .17).
While Dr. Oh acknowledged that secondary outcomes can only be considered hypothesis generating when the primary outcome is negative, she said these outcomes provide intriguing support for the potential of this BTKi drug to inhibit “smoldering inflammation.” Even if tolebrutinib was no more effective than teriflunomide against the acute inflammation that drives relapse, the GEMINI trials data support greater inhibition of the chronic inflammation implicated in progression in the absence of flares.
On MRI, the annualized rate of new and enlarging T2 lesions, although numerically higher in the tolebrutinib group, did not differ significantly in either GEMINI 1 (5.6 vs. 5.2; P = .46) or GEMINI 2 (5.1 vs. 4.4; P = .24). The least mean square difference in brain volume at end of study relative to 6 months into the study was 0.2% less in the tolebrutinib arm than the teriflunomide arm (P = .0002) in GEMINI 1, but the 0.04 numerical advantage for tolebrutinib did not reach statistical significance in GEMINI 2 (P = .43).
Of the 974 patients randomized in GEMINI 1 and 899 randomized in GEMINI 2, about 85% completed the 3-year trial. Almost all had RRMS (99%) rather than progressing MS. The median age was approximately 36 years, the baseline EDSS score was approximately 1.2, and the median time since diagnosis was about 6.5 years. The mean number of relapses in the prior year was approximately 0.6.
In GEMINI, the secondary outcomes foreshadowed the positive findings in the phase 3 HERCULES trial that came immediately after Dr. Oh’s GEMINI trials presentation. The HERCULES trial associated tolebrutinib with a 31% reduction in the risk of confirmed disability progression (CDW) relative to placebo in patients with non-relapsing secondary progressive MS (nrSPMS).
In HERCULES, 1172 patients with nrSPMS were randomized in a 2:1 fashion to tolebrutinib or placebo. For the primary endpoint of CDW at 6 months, tolebrutinib demonstrated a major and highly significant reduction in this primary endpoint (HR 0.69; P = .00026).
BTKi Disability Protection Supported By Progressive MS Trial
“This is the first trial to show significant slowing of disability in people with nrSPMS,” reported the principal investigator Robert J. Fox, MD, Vice Chair of the Neurological Institute at Cleveland Clinic, Cleveland, Ohio.
For disability improvement at 6 months, tolebrutinib was associated with a nearly 2-fold improvement (HR 1.88; P = .021). According to both Dr. Oh and Dr. Fox the results of these two major phase 3 tolebrutinib studies support the principle that the BTKi, which was shown to offer inhibition of relapse comparable to teriflunomide in the GEMINI trials, offers a greater inhibition of chronic inflammation.
“These results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes,” Dr. Oh said.
Dr. Fox said that the HERCULES results will be submitted to regulatory authorities with the goal of securing an indication for tolebrutinib for nrSPMS.
Both Dr. Oh and Dr. Fox suggested these results are likely to reorient thinking about the pathophysiology of MS progression and how different processes can be targeted in the future. Other experts agreed.
“I think we are starting to look at different endpoints than ARR, particularly at those that might better reflect progression in later stages of MS and that are independent of ARR,” said Dalia Rotstein, MD, MS researcher and an assistant professor of neurology, University of Toronto, Canada.
A moderator of the ECTRIMS latebreaker session, she suggested that the differences between outcomes of the GEMINI trials and HERCULES trials might have relevance to each other even if the GEMINI trials did not meet their primary endpoint.
Dr. Oh reported financial relationships with Amgen, Biogen, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi, which provided funding for the GEMINI trials. Dr. Fox reported financial relationships with more than 15 pharmaceutical companies, including Sanofi, which also provided funding for the HERCULES trial. Dr. Rotstein reported financial relationships with Alexion, Biogen, EMD Serono, Horizon, Novartis, Roche, Sanofi, and Touch IME.
*Correction, 9/26/24: A previous version of this article contained an incorrect P value.
FROM ECTRIMS 2024
High-Dose Vitamin D Linked to Lower Disease Activity in CIS
COPENHAGEN — , results of a randomized, controlled trial suggest. In addition, cholecalciferol had a favorable safety profile and was well tolerated.
“These data support high-dose vitamin D supplementation in early MS and make vitamin D the best candidate for add-on therapy evaluation in the therapeutic strategy for multiple sclerosis [MS],” said study author Eric Thouvenot, MD, PhD, University Hospital of Nimes, Neurology Department, Nimes, France.
The study was presented at the 2024 ECTRIMS annual meeting.
Vitamin D Supplementation Versus Placebo
Research shows vitamin D deficiency is a risk factor for MS. However, results of previous research investigating vitamin D supplementation in MS, with different regimens and durations, have been contradictory.
The current double-blind study included 303 adults newly diagnosed with CIS (within 90 days) and a serum 25-hydroxy vitamin D concentration of less than 100 nmol/L at baseline. Participants had a median age of 34 years, and 70% were women.
About one third of participants had optic neuritis, two thirds had oligoclonal bands from cerebrospinal fluid analysis, and the median Expanded Disability Status Scale (EDSS) score was 1.0. Of the total, 89% fulfilled 2017 McDonald criteria for the diagnosis of relapsing-remitting MS (RRMS).
Participants were randomly assigned to receive high-dose (100,000 international units) oral cholecalciferol or placebo every 2 weeks for 24 months. Participants had a clinical visit at 3, 6, 12, 18, and 24 months, and brain and spinal cord MRI with and without gadolinium at 3, 12, and 24 months.
The primary outcome was occurrence of disease activity — relapse, new or enlarging T2 lesions, and presence of contrast-enhancing lesions.
Significant Difference
During follow-up, 60.3% in the vitamin group showed evidence of disease activity versus 74.1% in the placebo group (hazard ratio [HR], 0.66; 95% CI, 0.50-0.87; P = .004). In addition, the median time to evidence of disease activity was 432 days in the vitamin D group versus 224 days in the placebo group (P = .003).
“As you can see, the difference is really, really significant,” said Dr. Thouvenot, referring to a Kaplan-Meier curve. He said he was somewhat surprised by the “very rapid” effect of vitamin D.
He noted that the 34% reduction in relative risk for disease activity is “similar to that of some published platform therapies for CIS patients.”
An analysis of the 247 patients who met 2017 McDonald criteria for RRMS at baseline showed the same results.
Secondary analyses showed no significant reduction in relapses and no significant differences for annual change in EDSS, quality of life, fatigue, anxiety, or depression.
Additional analyses showed the HR was unchanged after adjusting for known prognostic factors including age, sex, number of lesions (< 9 vs ≥ 9), EDSS score at baseline, and delay between CIS and treatment onset.
Results showed vitamin D3 supplementation was safe and well tolerated. Dr. Thouvenot noted that 95% of participants completed the trial, and none of the 33 severe adverse events in 30 patients suggested hypercalcemia or were related to the study drug.
These encouraging new data support further studies of high-dose vitamin D supplementation as an add-on therapy in early MS, said Dr. Thouvenot. He noted that animal models suggest vitamin D added to interferon beta has a synergistic effect on the immune system.
‘Fabulous’ Research
During a question-and-answer session, delegates praised the study, with some describing it as “fantastic” or “fabulous.”
Addressing a query about why this study succeeded in showing the benefits of vitamin D while numerous previous studies did not, Dr. Thouvenot said it may be due to the longer duration or a design that was better powered to show differences.
Asked if researchers examined vitamin D blood levels during the study, Dr. Thouvenot said these measures are “ongoing.”
Responding to a question of whether high-dose vitamin D could be a lifelong treatment, he referred again to the “excellent” safety of the intervention. Not only is it well tolerated, but vitamin D benefits bones and the risk for hypercalcemia is low except perhaps for patients with tuberculosis or sarcoidosis, he said.
“When you exclude those patients, the safety is huge, so I don’t know why we should stop it once it’s started.”
This study was funded in part by the French Ministry of Health. Dr. Thouvenot reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
COPENHAGEN — , results of a randomized, controlled trial suggest. In addition, cholecalciferol had a favorable safety profile and was well tolerated.
“These data support high-dose vitamin D supplementation in early MS and make vitamin D the best candidate for add-on therapy evaluation in the therapeutic strategy for multiple sclerosis [MS],” said study author Eric Thouvenot, MD, PhD, University Hospital of Nimes, Neurology Department, Nimes, France.
The study was presented at the 2024 ECTRIMS annual meeting.
Vitamin D Supplementation Versus Placebo
Research shows vitamin D deficiency is a risk factor for MS. However, results of previous research investigating vitamin D supplementation in MS, with different regimens and durations, have been contradictory.
The current double-blind study included 303 adults newly diagnosed with CIS (within 90 days) and a serum 25-hydroxy vitamin D concentration of less than 100 nmol/L at baseline. Participants had a median age of 34 years, and 70% were women.
About one third of participants had optic neuritis, two thirds had oligoclonal bands from cerebrospinal fluid analysis, and the median Expanded Disability Status Scale (EDSS) score was 1.0. Of the total, 89% fulfilled 2017 McDonald criteria for the diagnosis of relapsing-remitting MS (RRMS).
Participants were randomly assigned to receive high-dose (100,000 international units) oral cholecalciferol or placebo every 2 weeks for 24 months. Participants had a clinical visit at 3, 6, 12, 18, and 24 months, and brain and spinal cord MRI with and without gadolinium at 3, 12, and 24 months.
The primary outcome was occurrence of disease activity — relapse, new or enlarging T2 lesions, and presence of contrast-enhancing lesions.
Significant Difference
During follow-up, 60.3% in the vitamin group showed evidence of disease activity versus 74.1% in the placebo group (hazard ratio [HR], 0.66; 95% CI, 0.50-0.87; P = .004). In addition, the median time to evidence of disease activity was 432 days in the vitamin D group versus 224 days in the placebo group (P = .003).
“As you can see, the difference is really, really significant,” said Dr. Thouvenot, referring to a Kaplan-Meier curve. He said he was somewhat surprised by the “very rapid” effect of vitamin D.
He noted that the 34% reduction in relative risk for disease activity is “similar to that of some published platform therapies for CIS patients.”
An analysis of the 247 patients who met 2017 McDonald criteria for RRMS at baseline showed the same results.
Secondary analyses showed no significant reduction in relapses and no significant differences for annual change in EDSS, quality of life, fatigue, anxiety, or depression.
Additional analyses showed the HR was unchanged after adjusting for known prognostic factors including age, sex, number of lesions (< 9 vs ≥ 9), EDSS score at baseline, and delay between CIS and treatment onset.
Results showed vitamin D3 supplementation was safe and well tolerated. Dr. Thouvenot noted that 95% of participants completed the trial, and none of the 33 severe adverse events in 30 patients suggested hypercalcemia or were related to the study drug.
These encouraging new data support further studies of high-dose vitamin D supplementation as an add-on therapy in early MS, said Dr. Thouvenot. He noted that animal models suggest vitamin D added to interferon beta has a synergistic effect on the immune system.
‘Fabulous’ Research
During a question-and-answer session, delegates praised the study, with some describing it as “fantastic” or “fabulous.”
Addressing a query about why this study succeeded in showing the benefits of vitamin D while numerous previous studies did not, Dr. Thouvenot said it may be due to the longer duration or a design that was better powered to show differences.
Asked if researchers examined vitamin D blood levels during the study, Dr. Thouvenot said these measures are “ongoing.”
Responding to a question of whether high-dose vitamin D could be a lifelong treatment, he referred again to the “excellent” safety of the intervention. Not only is it well tolerated, but vitamin D benefits bones and the risk for hypercalcemia is low except perhaps for patients with tuberculosis or sarcoidosis, he said.
“When you exclude those patients, the safety is huge, so I don’t know why we should stop it once it’s started.”
This study was funded in part by the French Ministry of Health. Dr. Thouvenot reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
COPENHAGEN — , results of a randomized, controlled trial suggest. In addition, cholecalciferol had a favorable safety profile and was well tolerated.
“These data support high-dose vitamin D supplementation in early MS and make vitamin D the best candidate for add-on therapy evaluation in the therapeutic strategy for multiple sclerosis [MS],” said study author Eric Thouvenot, MD, PhD, University Hospital of Nimes, Neurology Department, Nimes, France.
The study was presented at the 2024 ECTRIMS annual meeting.
Vitamin D Supplementation Versus Placebo
Research shows vitamin D deficiency is a risk factor for MS. However, results of previous research investigating vitamin D supplementation in MS, with different regimens and durations, have been contradictory.
The current double-blind study included 303 adults newly diagnosed with CIS (within 90 days) and a serum 25-hydroxy vitamin D concentration of less than 100 nmol/L at baseline. Participants had a median age of 34 years, and 70% were women.
About one third of participants had optic neuritis, two thirds had oligoclonal bands from cerebrospinal fluid analysis, and the median Expanded Disability Status Scale (EDSS) score was 1.0. Of the total, 89% fulfilled 2017 McDonald criteria for the diagnosis of relapsing-remitting MS (RRMS).
Participants were randomly assigned to receive high-dose (100,000 international units) oral cholecalciferol or placebo every 2 weeks for 24 months. Participants had a clinical visit at 3, 6, 12, 18, and 24 months, and brain and spinal cord MRI with and without gadolinium at 3, 12, and 24 months.
The primary outcome was occurrence of disease activity — relapse, new or enlarging T2 lesions, and presence of contrast-enhancing lesions.
Significant Difference
During follow-up, 60.3% in the vitamin group showed evidence of disease activity versus 74.1% in the placebo group (hazard ratio [HR], 0.66; 95% CI, 0.50-0.87; P = .004). In addition, the median time to evidence of disease activity was 432 days in the vitamin D group versus 224 days in the placebo group (P = .003).
“As you can see, the difference is really, really significant,” said Dr. Thouvenot, referring to a Kaplan-Meier curve. He said he was somewhat surprised by the “very rapid” effect of vitamin D.
He noted that the 34% reduction in relative risk for disease activity is “similar to that of some published platform therapies for CIS patients.”
An analysis of the 247 patients who met 2017 McDonald criteria for RRMS at baseline showed the same results.
Secondary analyses showed no significant reduction in relapses and no significant differences for annual change in EDSS, quality of life, fatigue, anxiety, or depression.
Additional analyses showed the HR was unchanged after adjusting for known prognostic factors including age, sex, number of lesions (< 9 vs ≥ 9), EDSS score at baseline, and delay between CIS and treatment onset.
Results showed vitamin D3 supplementation was safe and well tolerated. Dr. Thouvenot noted that 95% of participants completed the trial, and none of the 33 severe adverse events in 30 patients suggested hypercalcemia or were related to the study drug.
These encouraging new data support further studies of high-dose vitamin D supplementation as an add-on therapy in early MS, said Dr. Thouvenot. He noted that animal models suggest vitamin D added to interferon beta has a synergistic effect on the immune system.
‘Fabulous’ Research
During a question-and-answer session, delegates praised the study, with some describing it as “fantastic” or “fabulous.”
Addressing a query about why this study succeeded in showing the benefits of vitamin D while numerous previous studies did not, Dr. Thouvenot said it may be due to the longer duration or a design that was better powered to show differences.
Asked if researchers examined vitamin D blood levels during the study, Dr. Thouvenot said these measures are “ongoing.”
Responding to a question of whether high-dose vitamin D could be a lifelong treatment, he referred again to the “excellent” safety of the intervention. Not only is it well tolerated, but vitamin D benefits bones and the risk for hypercalcemia is low except perhaps for patients with tuberculosis or sarcoidosis, he said.
“When you exclude those patients, the safety is huge, so I don’t know why we should stop it once it’s started.”
This study was funded in part by the French Ministry of Health. Dr. Thouvenot reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2024
Positive Stem Cell Transplant Data Is Increasing Its Use
COPENHAGEN —
With only one completed randomized trial available, HSCT remains experimental but the number of patients treated with this approach has now reached substantial numbers over 20 years of experience at multiple centers, according to two representative real-world studies presented at the 2024 ECTRIMS annual meeting.
The latest data are wholly consistent with a 2019 multinational randomized trial that found HSCT, which is a one-time intervention, to be relatively well tolerated and more effective than disease-modifying therapy (DMT) for median time to progression in patients refractory to DMT.
Relative to 24 months in the DMT group, median time to relapse was not reached among those randomized to HSCT because there were too few events. The hazard ratio (HR) reduction for progression was greater than 90% (HR, 0.07; P < 0.001). Other endpoints, such as EDSS, which improved in the group receiving HSCT but declined on DMT, also favored the single-treatment therapy.
Two Real-World Experiences With HSCT Reported
Of the two multicenter real world studies presented at ECTRIMS, one included 363 patients treated at one of 14 participating public hospitals in the United Kingdom since 2002. This analysis was uncontrolled. The other, with 97 patients treated at one of 20 participating centers in Italy since 1999, compared HSCT to alemtuzumab retrospectively.
In the UK data, presented by Paolo Muraro, MD, PhD, Senior Consultant, Division of Brain Sciences, Imperial College, London, England, 94.6% were in relapse-free survival (RFS) at 2 years and 88.6% at 5 years after undergoing HSCT. He called these numbers “impressive.”
In addition, MRI-free activity survival (MFS) was 88.2% and 78.8% at 2 and 5 years, respectively, Dr. Muraro said.
On the Expanded Disability Status Scale (EDSS), the cumulative incidence of improvement was 24.6% at 2 years and 28.6% at 5 years. There was no evidence of disease activity on the endpoints of symptoms, relapse, and MRI (NEDA-3) in 72% of patients at 2 years and 48.5% at 5 years.
Relative to historical response rates in a refractory population, Dr. Muraro considered these results favorable. Although there were four deaths, producing a treatment-related mortality of 1.1%, all occurred at an early stage of the HSCT program when there was limited experience in the management of cytopenias and other acute complications of HSCT.
“In this real-world cohort, stem cell transplant led to a durable remission of inflammatory activity and to clinical stability even though this included patients with a high EDSS at baseline [median 6.0] and a substantial proportion [39%) with progressive disease,” Dr. Muraro said.
In the Italian data, presented by Alessio Signori, MD, PhD, associate professor, Department of Health Sciences, University of Genoa, Italy, the 97 HSCT patients were matched with 314 treated with alemtuzumab over the same period and compared with propensity score overlap weighting. Baseline features were comparable.
HSCT Outperforms Alemtuzumab on All Measures
After a median follow-up of 62 months in the HSCT group and 30 months in the alemtuzumab group, HSCT outperformed drug therapy on all efficacy measures. When translated into HR, HSCT relative to alemtuzumab was associated with a 50% reduction in the probability of disability progression (HR, 0.50; P = 0.025), a 66% reduction in probability of relapse (HR, 0.34; P < 0.001), and a 62% reduction in the probability of MRI activity (HR, 0.38; P < 0.001).
“At 5 years, 58.3% of patients in the HSCT group versus 22.3% of the patients in the alemtuzumab group maintained NEDA-3,” said Dr. Signori, who reported that this difference represented a greater than 50% reduction (HR, 0.48; P < 0.001).
In this study there were two treatment-related deaths. Both occurred within 30 days of HSCT and, again, were confined to the early experience with HSCT.
There are questions that remain unanswered, such as whether there are predictors of response to HSCT. Although sustained responses have been greater on HSCT than drug therapy on average, poor responses appeared to be more common among those with a progressive phenotype in the UK experience.
Although patients with progressive disease were excluded from the Italian study, a real-world experience published 2 years ago also indicated that patients with progressive forms of MS respond less well to HSCT. Conducted in the United States at a single center (Northwestern University, Chicago) with 414 patients of whom 93 had progressive disease, EDSS progressively declined over the 5 years of follow-up among those with secondary progressive MS even as it improved in those with relapsing-remitting multiple sclerosis.
HSCT Considered on Compassionate Basis
Overall, the HSCT experience as a rescue therapy for MS patients with an inadequate response to DMT has led a growing number of centers active in this area to offer this option on a compassionate basis, according to Dr. Muraro and Dr. Signori. Joachim Burman, MD, PhD, who was the moderator of the scientific session at ECTRIMS and the leader of a research program into HSCT for MS at Uppsala University, Uppsala, Sweden, agreed.
The increasing number of centers offering HSCT to MS patients does not preclude the need or the value of the ongoing phase 3 trials, according to Dr. Burman, but he suggested that there is a growing focus of how it should be used, not whether it will be used.
Ultimately, he speculated that HSCT, once accepted as a mainstream option for MS, will probably be confined to the 5%-10% of patients with very aggressive disease. This is not for lack of safety or efficacy, but he sees several barriers to using this approach first-line, outside of special situations.
“You need a team of several different specialists to offer HSCT,” he said, suggesting that this approach to MS is much more complicated than a visit to a neurologist’s office for a DMT prescription. However, he thinks other barriers, such as concern about safety, are dissipating.
HSCT “is still being characterized as a high-risk procedure, but I would object to that,” he said. “The deaths associated with HSCT largely occurred 20 years ago when the field was new.”
Dr. Muraro reported a financial relationship with Cellerys AG that is unrelated to this study. Dr. Signori reported financial relationships with Chiesi, Horizon, and Novartis. Dr. Burman reports no potential conflicts of interest.
COPENHAGEN —
With only one completed randomized trial available, HSCT remains experimental but the number of patients treated with this approach has now reached substantial numbers over 20 years of experience at multiple centers, according to two representative real-world studies presented at the 2024 ECTRIMS annual meeting.
The latest data are wholly consistent with a 2019 multinational randomized trial that found HSCT, which is a one-time intervention, to be relatively well tolerated and more effective than disease-modifying therapy (DMT) for median time to progression in patients refractory to DMT.
Relative to 24 months in the DMT group, median time to relapse was not reached among those randomized to HSCT because there were too few events. The hazard ratio (HR) reduction for progression was greater than 90% (HR, 0.07; P < 0.001). Other endpoints, such as EDSS, which improved in the group receiving HSCT but declined on DMT, also favored the single-treatment therapy.
Two Real-World Experiences With HSCT Reported
Of the two multicenter real world studies presented at ECTRIMS, one included 363 patients treated at one of 14 participating public hospitals in the United Kingdom since 2002. This analysis was uncontrolled. The other, with 97 patients treated at one of 20 participating centers in Italy since 1999, compared HSCT to alemtuzumab retrospectively.
In the UK data, presented by Paolo Muraro, MD, PhD, Senior Consultant, Division of Brain Sciences, Imperial College, London, England, 94.6% were in relapse-free survival (RFS) at 2 years and 88.6% at 5 years after undergoing HSCT. He called these numbers “impressive.”
In addition, MRI-free activity survival (MFS) was 88.2% and 78.8% at 2 and 5 years, respectively, Dr. Muraro said.
On the Expanded Disability Status Scale (EDSS), the cumulative incidence of improvement was 24.6% at 2 years and 28.6% at 5 years. There was no evidence of disease activity on the endpoints of symptoms, relapse, and MRI (NEDA-3) in 72% of patients at 2 years and 48.5% at 5 years.
Relative to historical response rates in a refractory population, Dr. Muraro considered these results favorable. Although there were four deaths, producing a treatment-related mortality of 1.1%, all occurred at an early stage of the HSCT program when there was limited experience in the management of cytopenias and other acute complications of HSCT.
“In this real-world cohort, stem cell transplant led to a durable remission of inflammatory activity and to clinical stability even though this included patients with a high EDSS at baseline [median 6.0] and a substantial proportion [39%) with progressive disease,” Dr. Muraro said.
In the Italian data, presented by Alessio Signori, MD, PhD, associate professor, Department of Health Sciences, University of Genoa, Italy, the 97 HSCT patients were matched with 314 treated with alemtuzumab over the same period and compared with propensity score overlap weighting. Baseline features were comparable.
HSCT Outperforms Alemtuzumab on All Measures
After a median follow-up of 62 months in the HSCT group and 30 months in the alemtuzumab group, HSCT outperformed drug therapy on all efficacy measures. When translated into HR, HSCT relative to alemtuzumab was associated with a 50% reduction in the probability of disability progression (HR, 0.50; P = 0.025), a 66% reduction in probability of relapse (HR, 0.34; P < 0.001), and a 62% reduction in the probability of MRI activity (HR, 0.38; P < 0.001).
“At 5 years, 58.3% of patients in the HSCT group versus 22.3% of the patients in the alemtuzumab group maintained NEDA-3,” said Dr. Signori, who reported that this difference represented a greater than 50% reduction (HR, 0.48; P < 0.001).
In this study there were two treatment-related deaths. Both occurred within 30 days of HSCT and, again, were confined to the early experience with HSCT.
There are questions that remain unanswered, such as whether there are predictors of response to HSCT. Although sustained responses have been greater on HSCT than drug therapy on average, poor responses appeared to be more common among those with a progressive phenotype in the UK experience.
Although patients with progressive disease were excluded from the Italian study, a real-world experience published 2 years ago also indicated that patients with progressive forms of MS respond less well to HSCT. Conducted in the United States at a single center (Northwestern University, Chicago) with 414 patients of whom 93 had progressive disease, EDSS progressively declined over the 5 years of follow-up among those with secondary progressive MS even as it improved in those with relapsing-remitting multiple sclerosis.
HSCT Considered on Compassionate Basis
Overall, the HSCT experience as a rescue therapy for MS patients with an inadequate response to DMT has led a growing number of centers active in this area to offer this option on a compassionate basis, according to Dr. Muraro and Dr. Signori. Joachim Burman, MD, PhD, who was the moderator of the scientific session at ECTRIMS and the leader of a research program into HSCT for MS at Uppsala University, Uppsala, Sweden, agreed.
The increasing number of centers offering HSCT to MS patients does not preclude the need or the value of the ongoing phase 3 trials, according to Dr. Burman, but he suggested that there is a growing focus of how it should be used, not whether it will be used.
Ultimately, he speculated that HSCT, once accepted as a mainstream option for MS, will probably be confined to the 5%-10% of patients with very aggressive disease. This is not for lack of safety or efficacy, but he sees several barriers to using this approach first-line, outside of special situations.
“You need a team of several different specialists to offer HSCT,” he said, suggesting that this approach to MS is much more complicated than a visit to a neurologist’s office for a DMT prescription. However, he thinks other barriers, such as concern about safety, are dissipating.
HSCT “is still being characterized as a high-risk procedure, but I would object to that,” he said. “The deaths associated with HSCT largely occurred 20 years ago when the field was new.”
Dr. Muraro reported a financial relationship with Cellerys AG that is unrelated to this study. Dr. Signori reported financial relationships with Chiesi, Horizon, and Novartis. Dr. Burman reports no potential conflicts of interest.
COPENHAGEN —
With only one completed randomized trial available, HSCT remains experimental but the number of patients treated with this approach has now reached substantial numbers over 20 years of experience at multiple centers, according to two representative real-world studies presented at the 2024 ECTRIMS annual meeting.
The latest data are wholly consistent with a 2019 multinational randomized trial that found HSCT, which is a one-time intervention, to be relatively well tolerated and more effective than disease-modifying therapy (DMT) for median time to progression in patients refractory to DMT.
Relative to 24 months in the DMT group, median time to relapse was not reached among those randomized to HSCT because there were too few events. The hazard ratio (HR) reduction for progression was greater than 90% (HR, 0.07; P < 0.001). Other endpoints, such as EDSS, which improved in the group receiving HSCT but declined on DMT, also favored the single-treatment therapy.
Two Real-World Experiences With HSCT Reported
Of the two multicenter real world studies presented at ECTRIMS, one included 363 patients treated at one of 14 participating public hospitals in the United Kingdom since 2002. This analysis was uncontrolled. The other, with 97 patients treated at one of 20 participating centers in Italy since 1999, compared HSCT to alemtuzumab retrospectively.
In the UK data, presented by Paolo Muraro, MD, PhD, Senior Consultant, Division of Brain Sciences, Imperial College, London, England, 94.6% were in relapse-free survival (RFS) at 2 years and 88.6% at 5 years after undergoing HSCT. He called these numbers “impressive.”
In addition, MRI-free activity survival (MFS) was 88.2% and 78.8% at 2 and 5 years, respectively, Dr. Muraro said.
On the Expanded Disability Status Scale (EDSS), the cumulative incidence of improvement was 24.6% at 2 years and 28.6% at 5 years. There was no evidence of disease activity on the endpoints of symptoms, relapse, and MRI (NEDA-3) in 72% of patients at 2 years and 48.5% at 5 years.
Relative to historical response rates in a refractory population, Dr. Muraro considered these results favorable. Although there were four deaths, producing a treatment-related mortality of 1.1%, all occurred at an early stage of the HSCT program when there was limited experience in the management of cytopenias and other acute complications of HSCT.
“In this real-world cohort, stem cell transplant led to a durable remission of inflammatory activity and to clinical stability even though this included patients with a high EDSS at baseline [median 6.0] and a substantial proportion [39%) with progressive disease,” Dr. Muraro said.
In the Italian data, presented by Alessio Signori, MD, PhD, associate professor, Department of Health Sciences, University of Genoa, Italy, the 97 HSCT patients were matched with 314 treated with alemtuzumab over the same period and compared with propensity score overlap weighting. Baseline features were comparable.
HSCT Outperforms Alemtuzumab on All Measures
After a median follow-up of 62 months in the HSCT group and 30 months in the alemtuzumab group, HSCT outperformed drug therapy on all efficacy measures. When translated into HR, HSCT relative to alemtuzumab was associated with a 50% reduction in the probability of disability progression (HR, 0.50; P = 0.025), a 66% reduction in probability of relapse (HR, 0.34; P < 0.001), and a 62% reduction in the probability of MRI activity (HR, 0.38; P < 0.001).
“At 5 years, 58.3% of patients in the HSCT group versus 22.3% of the patients in the alemtuzumab group maintained NEDA-3,” said Dr. Signori, who reported that this difference represented a greater than 50% reduction (HR, 0.48; P < 0.001).
In this study there were two treatment-related deaths. Both occurred within 30 days of HSCT and, again, were confined to the early experience with HSCT.
There are questions that remain unanswered, such as whether there are predictors of response to HSCT. Although sustained responses have been greater on HSCT than drug therapy on average, poor responses appeared to be more common among those with a progressive phenotype in the UK experience.
Although patients with progressive disease were excluded from the Italian study, a real-world experience published 2 years ago also indicated that patients with progressive forms of MS respond less well to HSCT. Conducted in the United States at a single center (Northwestern University, Chicago) with 414 patients of whom 93 had progressive disease, EDSS progressively declined over the 5 years of follow-up among those with secondary progressive MS even as it improved in those with relapsing-remitting multiple sclerosis.
HSCT Considered on Compassionate Basis
Overall, the HSCT experience as a rescue therapy for MS patients with an inadequate response to DMT has led a growing number of centers active in this area to offer this option on a compassionate basis, according to Dr. Muraro and Dr. Signori. Joachim Burman, MD, PhD, who was the moderator of the scientific session at ECTRIMS and the leader of a research program into HSCT for MS at Uppsala University, Uppsala, Sweden, agreed.
The increasing number of centers offering HSCT to MS patients does not preclude the need or the value of the ongoing phase 3 trials, according to Dr. Burman, but he suggested that there is a growing focus of how it should be used, not whether it will be used.
Ultimately, he speculated that HSCT, once accepted as a mainstream option for MS, will probably be confined to the 5%-10% of patients with very aggressive disease. This is not for lack of safety or efficacy, but he sees several barriers to using this approach first-line, outside of special situations.
“You need a team of several different specialists to offer HSCT,” he said, suggesting that this approach to MS is much more complicated than a visit to a neurologist’s office for a DMT prescription. However, he thinks other barriers, such as concern about safety, are dissipating.
HSCT “is still being characterized as a high-risk procedure, but I would object to that,” he said. “The deaths associated with HSCT largely occurred 20 years ago when the field was new.”
Dr. Muraro reported a financial relationship with Cellerys AG that is unrelated to this study. Dr. Signori reported financial relationships with Chiesi, Horizon, and Novartis. Dr. Burman reports no potential conflicts of interest.
FROM ECTRIMS 2024
Comorbidity Control Might Slow MS Activity
COPENHAGEN — The largest and perhaps most rigorous study to demonstrate an association between the presence of comorbidities and accelerated progression of multiple sclerosis (MS) is sufficiently compelling that both the study author and an independent expert maintained clinical practice should be adjusted.
Even while acknowledging that “it is hard to make causative statements” on the basis of these types of data, the findings are sufficiently compelling to suggest that comorbidities “should be a pressing concern” in MS management, according to Amber Salter, PhD, an associate professor of biostatistics at the University of Texas Southwestern Medical School, Dallas.
The strong association in this meta-analysis, presented at the 2024 ECTRIMS annual meeting, were drawn from 15 multicenter phase 3 treatment trials with 16,794 participants followed for at least 2 years, Dr. Salter reported. Her data were published simultaneously in JAMA Neurology.
“One of the strengths of this study is that the data on comorbidities were collected prospectively as part of these trials,” explained Mark S. Freedman, MD, director of the Multiple Sclerosis Research Center at Ottawa Hospital in Canada. He agreed with Dr. Salter that it is reasonable to apply these findings to clinical practice given their consistency with numerous other studies and the value of what he termed as “a holistic approach” to improving outcomes in MS.
Meta-Analysis Avoids Weaknesses of Previous Data
There are many potential weaknesses of past observational studies that the authors of this meta-analysis hoped to avoid. These include the possibility that MS patients with comorbidities might be less likely to take or adhere to disease-modifying therapies (DMT) or that comorbidity burden might masquerade or be misinterpreted as MS progression. By employing data from phase 3 DMT trials, Dr. Salter maintained that prospectively collected data monitored carefully over an extended follow-up allows the impact of comorbidities on outcome to be evaluated in a more controlled fashion.
Dr. Freedman liked the design of this study, but he admitted that he was surprised by the result.
“Phase 3 trials typically include exclusion criteria for significant comorbidities, so I did not think they would be able to show any meaningful differences,” Dr. Freedman said in an interview.
For the main outcome of evidence of disease activity (EDA), defined as confirmed disability worsening measured with the Expanded Disability Status Scale (EDSS), relapse activity, or any new or enlarging lesions on MRI, the differences reached significance even after adjustments for multiple potentially confounding factors.
MS Activity Increases Significantly with More Comorbidities
Compared with no comorbidity, the presence of three or more comorbidities were associated with a significant 14% increase in the adjusted hazard ratio (aHR) of EDA (aHR, 1.14; 95% CI, 1.02-1.28), Dr. Salter reported. If there were two or more cardiometabolic comorbidities, the risk of EDA was increased 21% (aHR, 1.21; 95% CI 1.08-1.37).
The list of comorbidities considered in this study was drawn from the International Advisory Committee on Clinical Trials in MS. It included numerous cardiometabolic comorbidities, such as hypertension, hyperlipidemia, diabetes, ischemic heart disease, cerebrovascular disease, and peripheral vascular disease. It also included chronic lung diseases, such as asthma and chronic obstructive pulmonary disease; psychiatric diseases, such as depression and anxiety; and miscellaneous autoimmune conditions.
The number of comorbidities was categorized for analysis as zero, one, two, or three or more. However, Dr. Salter acknowledged that these phase 3 trials did include comorbidity exclusion criteria. In fact, severe forms of most of these comorbidities were exclusion criteria in at least some studies. Yet, the prevalence of one or more comorbidities was still 45.4% in the total population from this meta-analysis.
By themselves alone, ischemic heart disease (aHR, 1.63), cerebrovascular disease (aHR, 1.70) and at least one psychiatric disorder (aHR, 1.14) were all significant for increased MS activity at the end of 2 years by a 95% confidence interval that did not cross the line of unity.
When the EDA endpoints were evaluated individually, not even three or more comorbidities was associated with an increased rate of active lesions on MRI at the end of follow-up, but two or more and three or more comorbidities were associated with a significantly increased risk of disability worsening (aHR, 1.16 and aHR, 1.31, respectively) and relapse (aHR, 1.16 for both).
An Underestimation of Associations?
Prospective trials are still needed to show that treating comorbidities improves outcome in MS, but randomization will be problematic if it means withholding treatment for conditions with risks independent of MS, Dr. Salter said. Although the data from this analysis did not permit an analysis of how relative severity of comorbidities affected MS outcome, she reiterated that most patients with severe comorbidities were likely excluded from inclusion in the studies anyway.
“We think that we are probably seeing an underestimation of an associations between comorbidity and increased MS activity,” Dr. Salter said. While she reported that confounding cannot be ruled out, the robust associations identified in a meta-analysis “limit the possibility of bias or chance findings.”
Asked if the message that clinicians should treat comorbidities to reduce MS activity is a reasonable conclusion in the absence of proof that treatment is beneficial, Dr. Freedman looked both to the body of evidence and to the common sense behind the recommendation.
Basically, Dr. Freedman believes that comorbidities should be addressed routinely and rigorously even if there was no evidence that they improve MS outcome. These data provide just one other source of support for a practice that should be conducted anyway.
Dr. Salter reported financial relationships with Abata Therapeutics, Gryphon Bio, and Owl Therapeutics. Dr. Freedman reported financial relationships with more than 10 pharmaceutical companies.
COPENHAGEN — The largest and perhaps most rigorous study to demonstrate an association between the presence of comorbidities and accelerated progression of multiple sclerosis (MS) is sufficiently compelling that both the study author and an independent expert maintained clinical practice should be adjusted.
Even while acknowledging that “it is hard to make causative statements” on the basis of these types of data, the findings are sufficiently compelling to suggest that comorbidities “should be a pressing concern” in MS management, according to Amber Salter, PhD, an associate professor of biostatistics at the University of Texas Southwestern Medical School, Dallas.
The strong association in this meta-analysis, presented at the 2024 ECTRIMS annual meeting, were drawn from 15 multicenter phase 3 treatment trials with 16,794 participants followed for at least 2 years, Dr. Salter reported. Her data were published simultaneously in JAMA Neurology.
“One of the strengths of this study is that the data on comorbidities were collected prospectively as part of these trials,” explained Mark S. Freedman, MD, director of the Multiple Sclerosis Research Center at Ottawa Hospital in Canada. He agreed with Dr. Salter that it is reasonable to apply these findings to clinical practice given their consistency with numerous other studies and the value of what he termed as “a holistic approach” to improving outcomes in MS.
Meta-Analysis Avoids Weaknesses of Previous Data
There are many potential weaknesses of past observational studies that the authors of this meta-analysis hoped to avoid. These include the possibility that MS patients with comorbidities might be less likely to take or adhere to disease-modifying therapies (DMT) or that comorbidity burden might masquerade or be misinterpreted as MS progression. By employing data from phase 3 DMT trials, Dr. Salter maintained that prospectively collected data monitored carefully over an extended follow-up allows the impact of comorbidities on outcome to be evaluated in a more controlled fashion.
Dr. Freedman liked the design of this study, but he admitted that he was surprised by the result.
“Phase 3 trials typically include exclusion criteria for significant comorbidities, so I did not think they would be able to show any meaningful differences,” Dr. Freedman said in an interview.
For the main outcome of evidence of disease activity (EDA), defined as confirmed disability worsening measured with the Expanded Disability Status Scale (EDSS), relapse activity, or any new or enlarging lesions on MRI, the differences reached significance even after adjustments for multiple potentially confounding factors.
MS Activity Increases Significantly with More Comorbidities
Compared with no comorbidity, the presence of three or more comorbidities were associated with a significant 14% increase in the adjusted hazard ratio (aHR) of EDA (aHR, 1.14; 95% CI, 1.02-1.28), Dr. Salter reported. If there were two or more cardiometabolic comorbidities, the risk of EDA was increased 21% (aHR, 1.21; 95% CI 1.08-1.37).
The list of comorbidities considered in this study was drawn from the International Advisory Committee on Clinical Trials in MS. It included numerous cardiometabolic comorbidities, such as hypertension, hyperlipidemia, diabetes, ischemic heart disease, cerebrovascular disease, and peripheral vascular disease. It also included chronic lung diseases, such as asthma and chronic obstructive pulmonary disease; psychiatric diseases, such as depression and anxiety; and miscellaneous autoimmune conditions.
The number of comorbidities was categorized for analysis as zero, one, two, or three or more. However, Dr. Salter acknowledged that these phase 3 trials did include comorbidity exclusion criteria. In fact, severe forms of most of these comorbidities were exclusion criteria in at least some studies. Yet, the prevalence of one or more comorbidities was still 45.4% in the total population from this meta-analysis.
By themselves alone, ischemic heart disease (aHR, 1.63), cerebrovascular disease (aHR, 1.70) and at least one psychiatric disorder (aHR, 1.14) were all significant for increased MS activity at the end of 2 years by a 95% confidence interval that did not cross the line of unity.
When the EDA endpoints were evaluated individually, not even three or more comorbidities was associated with an increased rate of active lesions on MRI at the end of follow-up, but two or more and three or more comorbidities were associated with a significantly increased risk of disability worsening (aHR, 1.16 and aHR, 1.31, respectively) and relapse (aHR, 1.16 for both).
An Underestimation of Associations?
Prospective trials are still needed to show that treating comorbidities improves outcome in MS, but randomization will be problematic if it means withholding treatment for conditions with risks independent of MS, Dr. Salter said. Although the data from this analysis did not permit an analysis of how relative severity of comorbidities affected MS outcome, she reiterated that most patients with severe comorbidities were likely excluded from inclusion in the studies anyway.
“We think that we are probably seeing an underestimation of an associations between comorbidity and increased MS activity,” Dr. Salter said. While she reported that confounding cannot be ruled out, the robust associations identified in a meta-analysis “limit the possibility of bias or chance findings.”
Asked if the message that clinicians should treat comorbidities to reduce MS activity is a reasonable conclusion in the absence of proof that treatment is beneficial, Dr. Freedman looked both to the body of evidence and to the common sense behind the recommendation.
Basically, Dr. Freedman believes that comorbidities should be addressed routinely and rigorously even if there was no evidence that they improve MS outcome. These data provide just one other source of support for a practice that should be conducted anyway.
Dr. Salter reported financial relationships with Abata Therapeutics, Gryphon Bio, and Owl Therapeutics. Dr. Freedman reported financial relationships with more than 10 pharmaceutical companies.
COPENHAGEN — The largest and perhaps most rigorous study to demonstrate an association between the presence of comorbidities and accelerated progression of multiple sclerosis (MS) is sufficiently compelling that both the study author and an independent expert maintained clinical practice should be adjusted.
Even while acknowledging that “it is hard to make causative statements” on the basis of these types of data, the findings are sufficiently compelling to suggest that comorbidities “should be a pressing concern” in MS management, according to Amber Salter, PhD, an associate professor of biostatistics at the University of Texas Southwestern Medical School, Dallas.
The strong association in this meta-analysis, presented at the 2024 ECTRIMS annual meeting, were drawn from 15 multicenter phase 3 treatment trials with 16,794 participants followed for at least 2 years, Dr. Salter reported. Her data were published simultaneously in JAMA Neurology.
“One of the strengths of this study is that the data on comorbidities were collected prospectively as part of these trials,” explained Mark S. Freedman, MD, director of the Multiple Sclerosis Research Center at Ottawa Hospital in Canada. He agreed with Dr. Salter that it is reasonable to apply these findings to clinical practice given their consistency with numerous other studies and the value of what he termed as “a holistic approach” to improving outcomes in MS.
Meta-Analysis Avoids Weaknesses of Previous Data
There are many potential weaknesses of past observational studies that the authors of this meta-analysis hoped to avoid. These include the possibility that MS patients with comorbidities might be less likely to take or adhere to disease-modifying therapies (DMT) or that comorbidity burden might masquerade or be misinterpreted as MS progression. By employing data from phase 3 DMT trials, Dr. Salter maintained that prospectively collected data monitored carefully over an extended follow-up allows the impact of comorbidities on outcome to be evaluated in a more controlled fashion.
Dr. Freedman liked the design of this study, but he admitted that he was surprised by the result.
“Phase 3 trials typically include exclusion criteria for significant comorbidities, so I did not think they would be able to show any meaningful differences,” Dr. Freedman said in an interview.
For the main outcome of evidence of disease activity (EDA), defined as confirmed disability worsening measured with the Expanded Disability Status Scale (EDSS), relapse activity, or any new or enlarging lesions on MRI, the differences reached significance even after adjustments for multiple potentially confounding factors.
MS Activity Increases Significantly with More Comorbidities
Compared with no comorbidity, the presence of three or more comorbidities were associated with a significant 14% increase in the adjusted hazard ratio (aHR) of EDA (aHR, 1.14; 95% CI, 1.02-1.28), Dr. Salter reported. If there were two or more cardiometabolic comorbidities, the risk of EDA was increased 21% (aHR, 1.21; 95% CI 1.08-1.37).
The list of comorbidities considered in this study was drawn from the International Advisory Committee on Clinical Trials in MS. It included numerous cardiometabolic comorbidities, such as hypertension, hyperlipidemia, diabetes, ischemic heart disease, cerebrovascular disease, and peripheral vascular disease. It also included chronic lung diseases, such as asthma and chronic obstructive pulmonary disease; psychiatric diseases, such as depression and anxiety; and miscellaneous autoimmune conditions.
The number of comorbidities was categorized for analysis as zero, one, two, or three or more. However, Dr. Salter acknowledged that these phase 3 trials did include comorbidity exclusion criteria. In fact, severe forms of most of these comorbidities were exclusion criteria in at least some studies. Yet, the prevalence of one or more comorbidities was still 45.4% in the total population from this meta-analysis.
By themselves alone, ischemic heart disease (aHR, 1.63), cerebrovascular disease (aHR, 1.70) and at least one psychiatric disorder (aHR, 1.14) were all significant for increased MS activity at the end of 2 years by a 95% confidence interval that did not cross the line of unity.
When the EDA endpoints were evaluated individually, not even three or more comorbidities was associated with an increased rate of active lesions on MRI at the end of follow-up, but two or more and three or more comorbidities were associated with a significantly increased risk of disability worsening (aHR, 1.16 and aHR, 1.31, respectively) and relapse (aHR, 1.16 for both).
An Underestimation of Associations?
Prospective trials are still needed to show that treating comorbidities improves outcome in MS, but randomization will be problematic if it means withholding treatment for conditions with risks independent of MS, Dr. Salter said. Although the data from this analysis did not permit an analysis of how relative severity of comorbidities affected MS outcome, she reiterated that most patients with severe comorbidities were likely excluded from inclusion in the studies anyway.
“We think that we are probably seeing an underestimation of an associations between comorbidity and increased MS activity,” Dr. Salter said. While she reported that confounding cannot be ruled out, the robust associations identified in a meta-analysis “limit the possibility of bias or chance findings.”
Asked if the message that clinicians should treat comorbidities to reduce MS activity is a reasonable conclusion in the absence of proof that treatment is beneficial, Dr. Freedman looked both to the body of evidence and to the common sense behind the recommendation.
Basically, Dr. Freedman believes that comorbidities should be addressed routinely and rigorously even if there was no evidence that they improve MS outcome. These data provide just one other source of support for a practice that should be conducted anyway.
Dr. Salter reported financial relationships with Abata Therapeutics, Gryphon Bio, and Owl Therapeutics. Dr. Freedman reported financial relationships with more than 10 pharmaceutical companies.
FROM ECTRIMS 2024
FDA Okays Subcutaneous Ocrelizumab for MS
The subcutaneous (SC) injection can be administered by a healthcare professional in approximately 10 minutes and is the first and only twice-a-year SC injection approved for both RMS and PPMS, according to a company news release.
The FDA approval is based on pivotal data from the phase 3 OCARINA II trial, which showed no clinically significant difference in blood levels of ocrelizumab when administered subcutaneously and an efficacy profile consistent with the intravenous (IV) formulation.
“The trial met its primary and secondary endpoints, demonstrating SC injection was noninferior to IV infusion based on [ocrelizumab] levels in the blood, and consistent control of clinical (relapses) and radiological (MRI lesions) disease activity,” the company said in the release.
The safety profile of SC ocrelizumab was consistent with the safety profile of IV ocrelizumab, with the exception of injection site reactions, the most common adverse event.
Injection reactions were more often reported with the first injection, with 49% of trial participants experiencing an injection reaction after the first injection. All injection reactions were mild or moderate, and none led to treatment withdrawal.
Ocrevus Zunovo “may offer greater flexibility for healthcare providers and people living with multiple sclerosis, based on their individual treatment needs,” Levi Garraway, MD, PhD, chief medical officer for Genentech, said in the press release. “We are pleased that with a new method of delivery, there is now an additional option for those who need flexibility in the route of administration or treatment time,” Natalie Blake, executive director of the MS Foundation, said in the release.
The SC formulation of ocrelizumab was approved by the European Commission in June.
Complete prescribing information is available online.
A version of this article appeared on Medscape.com.
The subcutaneous (SC) injection can be administered by a healthcare professional in approximately 10 minutes and is the first and only twice-a-year SC injection approved for both RMS and PPMS, according to a company news release.
The FDA approval is based on pivotal data from the phase 3 OCARINA II trial, which showed no clinically significant difference in blood levels of ocrelizumab when administered subcutaneously and an efficacy profile consistent with the intravenous (IV) formulation.
“The trial met its primary and secondary endpoints, demonstrating SC injection was noninferior to IV infusion based on [ocrelizumab] levels in the blood, and consistent control of clinical (relapses) and radiological (MRI lesions) disease activity,” the company said in the release.
The safety profile of SC ocrelizumab was consistent with the safety profile of IV ocrelizumab, with the exception of injection site reactions, the most common adverse event.
Injection reactions were more often reported with the first injection, with 49% of trial participants experiencing an injection reaction after the first injection. All injection reactions were mild or moderate, and none led to treatment withdrawal.
Ocrevus Zunovo “may offer greater flexibility for healthcare providers and people living with multiple sclerosis, based on their individual treatment needs,” Levi Garraway, MD, PhD, chief medical officer for Genentech, said in the press release. “We are pleased that with a new method of delivery, there is now an additional option for those who need flexibility in the route of administration or treatment time,” Natalie Blake, executive director of the MS Foundation, said in the release.
The SC formulation of ocrelizumab was approved by the European Commission in June.
Complete prescribing information is available online.
A version of this article appeared on Medscape.com.
The subcutaneous (SC) injection can be administered by a healthcare professional in approximately 10 minutes and is the first and only twice-a-year SC injection approved for both RMS and PPMS, according to a company news release.
The FDA approval is based on pivotal data from the phase 3 OCARINA II trial, which showed no clinically significant difference in blood levels of ocrelizumab when administered subcutaneously and an efficacy profile consistent with the intravenous (IV) formulation.
“The trial met its primary and secondary endpoints, demonstrating SC injection was noninferior to IV infusion based on [ocrelizumab] levels in the blood, and consistent control of clinical (relapses) and radiological (MRI lesions) disease activity,” the company said in the release.
The safety profile of SC ocrelizumab was consistent with the safety profile of IV ocrelizumab, with the exception of injection site reactions, the most common adverse event.
Injection reactions were more often reported with the first injection, with 49% of trial participants experiencing an injection reaction after the first injection. All injection reactions were mild or moderate, and none led to treatment withdrawal.
Ocrevus Zunovo “may offer greater flexibility for healthcare providers and people living with multiple sclerosis, based on their individual treatment needs,” Levi Garraway, MD, PhD, chief medical officer for Genentech, said in the press release. “We are pleased that with a new method of delivery, there is now an additional option for those who need flexibility in the route of administration or treatment time,” Natalie Blake, executive director of the MS Foundation, said in the release.
The SC formulation of ocrelizumab was approved by the European Commission in June.
Complete prescribing information is available online.
A version of this article appeared on Medscape.com.
Does MS Protect Against Alzheimer’s Disease?
In a recent study, Understanding how MS does this may drive new treatment strategies, said the authors of the study, which was published online in Annals of Neurology. Regarding current treatments, they added, the availability of new disease-modifying Alzheimer’s disease therapies increases the importance of early diagnosis in cognitively impaired people including those with MS.
Confirmatory Studies Needed
“Replication and confirmation of these findings, including in studies representative of the real-world Alzheimer’s population in race/ethnicity and sex/gender, are needed before any clinical implications can be drawn,” said Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach. She was not involved with the study but was asked to comment.
The study’s most important immediate implication, said Dr. Sexton, is that it “opens the door to questions about why MS may be associated with Alzheimer’s risk.”
Anecdotal Observation
Although life expectancy for people with MS is increasing, the authors, led by Matthew R. Brier, MD, PhD, an assistant professor at Washington University in St. Louis, Missouri, said they have seen no concomitant rise in Alzheimer’s disease dementia among their patients with MS. This anecdotal observation fueled their hypothesis that Alzheimer’s disease pathology occurs less frequently in this population.
To test their hypothesis, the investigators sequentially enrolled 100 patients with MS (age 60 years or older), along with 300 non-MS controls matched for age, sex, apolipoprotein E (apoE) proteotype, and cognitive status. All participants underwent the Mini-Mental State Examination (MMSE) and PrecivityAD2 (C2N Diagnostics) blood testing.
Overall, patients with MS had lower p-tau217 (t = 3.76, P = .00019) and amyloid probability score 2 (APS2; t = 3.83, P = .00015) ratios than did those without MS. APS2 combines p-tau217 ratio with Abeta42/40 ratio. In addition, APS2 and p-tau217 ratios were lower in patients with MS and ApoE3/apoE3 or apoE3/apoE4 proteotype. MMSE scores were also slightly lower in the MS cohort: 27.6 versus 28.44 for controls. Of 11 patients with MS who underwent Pittsburgh Compound B (PiB) positron emission tomography (PET), nine had congruent PiB PET and plasma results.
When the investigators applied clinical cutoffs, 7.1% of patients with MS were APS2-positive, versus 15.3% of controls (P = .0043). The corresponding figures for p-tau217 ratio positivity were 9% and 18.3%, respectively (P = .0024). Mean Abeta42/40 scores showed no difference between groups.
Patients with MS and positive amyloid biomarkers often had atypical MS features at diagnosis. Compared with biomarker-negative patients with MS, odds ratios for having at least two atypical MS features at diagnosis among APS2-positive and p-tau217 ratio-positive patients with MS were 23.3 and 11.38, respectively.
Data regarding the actual incidence of Alzheimer’s disease among people with MS are scarce and conflicting. An autopsy study published in Annals of Neurology in 2008 revealed the expected rate of amyloid pathology in MS brain tissue, along with extensive microglia activation. In a PET study published in Annals of Neurology in 2020, however, researchers found less amyloid pathology among patients with MS than those without, but little difference in tau pathology.
Because MS and Alzheimer’s disease can each cause cognitive impairment, the rate of co-occurrence of MS and Alzheimer’s disease has been difficult to ascertain without accurate biomarkers. But, the authors said, the advent of disease-modifying therapies makes identifying early Alzheimer’s dementia in MS patients relevant.
Possible Explanations
The authors hypothesized that the lower rate of amyloid pathology observed in their patients with MS may stem from the following possibly overlapping mechanisms:
- MS components, such as persistent perilesional immune activity, may inhibit amyloid beta deposition or facilitate its clearance.
- Exposure to MS drugs may impact Alzheimer’s disease pathology. Most study patients with MS were exposed to beta interferons or glatiramer acetate, the authors noted, and 39 had switched to high-efficacy medications such as B-cell depleting therapies and natalizumab.
- MS’s genetic signature may protect against AD.
“Investigating these ideas would advance our understanding of the relationship between MS and Alzheimer’s, and potentially inform avenues for treatment,” said Dr. Sexton. In this regard, the Alzheimer’s Association has funded an ongoing study examining a drug currently used to promote myelin formation in individuals with MS in genetically engineered Alzheimer’s-like mice. Additional Association-funded studies that examine inflammation also may improve understanding of the mechanisms that may link these diseases, said Dr. Sexton.
The study authors added that unusual cases, such as a study patient who had high amyloid burden by PET but negative APS2 and tau PET, also may shed light on interactions between MS, amyloid pathology, and tau pathology.
Limitations of the present study include the fact that plasma Alzheimer’s disease biomarkers are potentially affected by other conditions as well, according to a study published in Nature Medicine. Additional shortcomings include the MS cohort’s relatively small size and lack of diagnostic confirmation by cerebrospinal fluid. Although MMSE scores among patients with MS were slightly lower, the authors added, this disparity would lead one to expect more, not less, amyloid pathology among these patients if their cognitive impairment resulted from Alzheimer’s disease.
Dr. Sexton reported no relevant financial interests.
The study was supported by the Hope Center for Neurological Disorders at Washington University in St. Louis and by C2N Diagnostics. Washington University in St. Louis holds equity in C2N Diagnostics and may receive royalties resulting from use of PrecivityAD2.
In a recent study, Understanding how MS does this may drive new treatment strategies, said the authors of the study, which was published online in Annals of Neurology. Regarding current treatments, they added, the availability of new disease-modifying Alzheimer’s disease therapies increases the importance of early diagnosis in cognitively impaired people including those with MS.
Confirmatory Studies Needed
“Replication and confirmation of these findings, including in studies representative of the real-world Alzheimer’s population in race/ethnicity and sex/gender, are needed before any clinical implications can be drawn,” said Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach. She was not involved with the study but was asked to comment.
The study’s most important immediate implication, said Dr. Sexton, is that it “opens the door to questions about why MS may be associated with Alzheimer’s risk.”
Anecdotal Observation
Although life expectancy for people with MS is increasing, the authors, led by Matthew R. Brier, MD, PhD, an assistant professor at Washington University in St. Louis, Missouri, said they have seen no concomitant rise in Alzheimer’s disease dementia among their patients with MS. This anecdotal observation fueled their hypothesis that Alzheimer’s disease pathology occurs less frequently in this population.
To test their hypothesis, the investigators sequentially enrolled 100 patients with MS (age 60 years or older), along with 300 non-MS controls matched for age, sex, apolipoprotein E (apoE) proteotype, and cognitive status. All participants underwent the Mini-Mental State Examination (MMSE) and PrecivityAD2 (C2N Diagnostics) blood testing.
Overall, patients with MS had lower p-tau217 (t = 3.76, P = .00019) and amyloid probability score 2 (APS2; t = 3.83, P = .00015) ratios than did those without MS. APS2 combines p-tau217 ratio with Abeta42/40 ratio. In addition, APS2 and p-tau217 ratios were lower in patients with MS and ApoE3/apoE3 or apoE3/apoE4 proteotype. MMSE scores were also slightly lower in the MS cohort: 27.6 versus 28.44 for controls. Of 11 patients with MS who underwent Pittsburgh Compound B (PiB) positron emission tomography (PET), nine had congruent PiB PET and plasma results.
When the investigators applied clinical cutoffs, 7.1% of patients with MS were APS2-positive, versus 15.3% of controls (P = .0043). The corresponding figures for p-tau217 ratio positivity were 9% and 18.3%, respectively (P = .0024). Mean Abeta42/40 scores showed no difference between groups.
Patients with MS and positive amyloid biomarkers often had atypical MS features at diagnosis. Compared with biomarker-negative patients with MS, odds ratios for having at least two atypical MS features at diagnosis among APS2-positive and p-tau217 ratio-positive patients with MS were 23.3 and 11.38, respectively.
Data regarding the actual incidence of Alzheimer’s disease among people with MS are scarce and conflicting. An autopsy study published in Annals of Neurology in 2008 revealed the expected rate of amyloid pathology in MS brain tissue, along with extensive microglia activation. In a PET study published in Annals of Neurology in 2020, however, researchers found less amyloid pathology among patients with MS than those without, but little difference in tau pathology.
Because MS and Alzheimer’s disease can each cause cognitive impairment, the rate of co-occurrence of MS and Alzheimer’s disease has been difficult to ascertain without accurate biomarkers. But, the authors said, the advent of disease-modifying therapies makes identifying early Alzheimer’s dementia in MS patients relevant.
Possible Explanations
The authors hypothesized that the lower rate of amyloid pathology observed in their patients with MS may stem from the following possibly overlapping mechanisms:
- MS components, such as persistent perilesional immune activity, may inhibit amyloid beta deposition or facilitate its clearance.
- Exposure to MS drugs may impact Alzheimer’s disease pathology. Most study patients with MS were exposed to beta interferons or glatiramer acetate, the authors noted, and 39 had switched to high-efficacy medications such as B-cell depleting therapies and natalizumab.
- MS’s genetic signature may protect against AD.
“Investigating these ideas would advance our understanding of the relationship between MS and Alzheimer’s, and potentially inform avenues for treatment,” said Dr. Sexton. In this regard, the Alzheimer’s Association has funded an ongoing study examining a drug currently used to promote myelin formation in individuals with MS in genetically engineered Alzheimer’s-like mice. Additional Association-funded studies that examine inflammation also may improve understanding of the mechanisms that may link these diseases, said Dr. Sexton.
The study authors added that unusual cases, such as a study patient who had high amyloid burden by PET but negative APS2 and tau PET, also may shed light on interactions between MS, amyloid pathology, and tau pathology.
Limitations of the present study include the fact that plasma Alzheimer’s disease biomarkers are potentially affected by other conditions as well, according to a study published in Nature Medicine. Additional shortcomings include the MS cohort’s relatively small size and lack of diagnostic confirmation by cerebrospinal fluid. Although MMSE scores among patients with MS were slightly lower, the authors added, this disparity would lead one to expect more, not less, amyloid pathology among these patients if their cognitive impairment resulted from Alzheimer’s disease.
Dr. Sexton reported no relevant financial interests.
The study was supported by the Hope Center for Neurological Disorders at Washington University in St. Louis and by C2N Diagnostics. Washington University in St. Louis holds equity in C2N Diagnostics and may receive royalties resulting from use of PrecivityAD2.
In a recent study, Understanding how MS does this may drive new treatment strategies, said the authors of the study, which was published online in Annals of Neurology. Regarding current treatments, they added, the availability of new disease-modifying Alzheimer’s disease therapies increases the importance of early diagnosis in cognitively impaired people including those with MS.
Confirmatory Studies Needed
“Replication and confirmation of these findings, including in studies representative of the real-world Alzheimer’s population in race/ethnicity and sex/gender, are needed before any clinical implications can be drawn,” said Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach. She was not involved with the study but was asked to comment.
The study’s most important immediate implication, said Dr. Sexton, is that it “opens the door to questions about why MS may be associated with Alzheimer’s risk.”
Anecdotal Observation
Although life expectancy for people with MS is increasing, the authors, led by Matthew R. Brier, MD, PhD, an assistant professor at Washington University in St. Louis, Missouri, said they have seen no concomitant rise in Alzheimer’s disease dementia among their patients with MS. This anecdotal observation fueled their hypothesis that Alzheimer’s disease pathology occurs less frequently in this population.
To test their hypothesis, the investigators sequentially enrolled 100 patients with MS (age 60 years or older), along with 300 non-MS controls matched for age, sex, apolipoprotein E (apoE) proteotype, and cognitive status. All participants underwent the Mini-Mental State Examination (MMSE) and PrecivityAD2 (C2N Diagnostics) blood testing.
Overall, patients with MS had lower p-tau217 (t = 3.76, P = .00019) and amyloid probability score 2 (APS2; t = 3.83, P = .00015) ratios than did those without MS. APS2 combines p-tau217 ratio with Abeta42/40 ratio. In addition, APS2 and p-tau217 ratios were lower in patients with MS and ApoE3/apoE3 or apoE3/apoE4 proteotype. MMSE scores were also slightly lower in the MS cohort: 27.6 versus 28.44 for controls. Of 11 patients with MS who underwent Pittsburgh Compound B (PiB) positron emission tomography (PET), nine had congruent PiB PET and plasma results.
When the investigators applied clinical cutoffs, 7.1% of patients with MS were APS2-positive, versus 15.3% of controls (P = .0043). The corresponding figures for p-tau217 ratio positivity were 9% and 18.3%, respectively (P = .0024). Mean Abeta42/40 scores showed no difference between groups.
Patients with MS and positive amyloid biomarkers often had atypical MS features at diagnosis. Compared with biomarker-negative patients with MS, odds ratios for having at least two atypical MS features at diagnosis among APS2-positive and p-tau217 ratio-positive patients with MS were 23.3 and 11.38, respectively.
Data regarding the actual incidence of Alzheimer’s disease among people with MS are scarce and conflicting. An autopsy study published in Annals of Neurology in 2008 revealed the expected rate of amyloid pathology in MS brain tissue, along with extensive microglia activation. In a PET study published in Annals of Neurology in 2020, however, researchers found less amyloid pathology among patients with MS than those without, but little difference in tau pathology.
Because MS and Alzheimer’s disease can each cause cognitive impairment, the rate of co-occurrence of MS and Alzheimer’s disease has been difficult to ascertain without accurate biomarkers. But, the authors said, the advent of disease-modifying therapies makes identifying early Alzheimer’s dementia in MS patients relevant.
Possible Explanations
The authors hypothesized that the lower rate of amyloid pathology observed in their patients with MS may stem from the following possibly overlapping mechanisms:
- MS components, such as persistent perilesional immune activity, may inhibit amyloid beta deposition or facilitate its clearance.
- Exposure to MS drugs may impact Alzheimer’s disease pathology. Most study patients with MS were exposed to beta interferons or glatiramer acetate, the authors noted, and 39 had switched to high-efficacy medications such as B-cell depleting therapies and natalizumab.
- MS’s genetic signature may protect against AD.
“Investigating these ideas would advance our understanding of the relationship between MS and Alzheimer’s, and potentially inform avenues for treatment,” said Dr. Sexton. In this regard, the Alzheimer’s Association has funded an ongoing study examining a drug currently used to promote myelin formation in individuals with MS in genetically engineered Alzheimer’s-like mice. Additional Association-funded studies that examine inflammation also may improve understanding of the mechanisms that may link these diseases, said Dr. Sexton.
The study authors added that unusual cases, such as a study patient who had high amyloid burden by PET but negative APS2 and tau PET, also may shed light on interactions between MS, amyloid pathology, and tau pathology.
Limitations of the present study include the fact that plasma Alzheimer’s disease biomarkers are potentially affected by other conditions as well, according to a study published in Nature Medicine. Additional shortcomings include the MS cohort’s relatively small size and lack of diagnostic confirmation by cerebrospinal fluid. Although MMSE scores among patients with MS were slightly lower, the authors added, this disparity would lead one to expect more, not less, amyloid pathology among these patients if their cognitive impairment resulted from Alzheimer’s disease.
Dr. Sexton reported no relevant financial interests.
The study was supported by the Hope Center for Neurological Disorders at Washington University in St. Louis and by C2N Diagnostics. Washington University in St. Louis holds equity in C2N Diagnostics and may receive royalties resulting from use of PrecivityAD2.
FROM ANNALS OF NEUROLOGY
EMA Warns of Anaphylactic Reactions to MS Drug
Such reactions could occur even years after the start of treatment, the European Medicines Agency (EMA) warned.
Glatiramer acetate is a disease-modifying therapy (DMT) for relapsing MS that is given by injection.
The drug has been used for treating MS for more than 20 years, during which time, it has had a good safety profile. Common side effects are known to include vasodilation, arthralgia, anxiety, hypertonia, palpitations, and lipoatrophy.
A meeting of the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC), held on July 8-11, considered evidence from an EU-wide review of all available data concerning anaphylactic reactions with glatiramer acetate. As a result, the committee concluded that the medicine is associated with a risk for anaphylactic reactions, which may occur shortly after administration or even months or years later.
Risk for Delays to Treatment
Cases involving the use of glatiramer acetate with a fatal outcome have been reported, PRAC noted.
The committee cautioned that because the initial symptoms could overlap with those of postinjection reaction, there was a risk for delay in identifying an anaphylactic reaction.
PRAC has sanctioned a direct healthcare professional communication (DHPC) to inform healthcare professionals about the risk. Patients and caregivers should be advised of the signs and symptoms of an anaphylactic reaction and the need to seek emergency care if this should occur, the committee added. In the event of such a reaction, treatment with glatiramer acetate must be discontinued, PRAC stated.
Once adopted, the DHPC for glatiramer acetate will be disseminated to healthcare professionals by the marketing authorization holders.
Anaphylactic reactions associated with the use of glatiramer acetate have been noted in medical literature for some years. A letter by members of the department of neurology at Albert Ludwig University Freiburg, Freiburg im Bresigau, Germany, published in the journal European Neurology in 2011, detailed six cases of anaphylactoid or anaphylactic reactions in patients while they were undergoing treatment with glatiramer acetate.
The authors highlighted that in one of the cases, a grade 1 anaphylactic reaction occurred 3 months after treatment with the drug was initiated.
A version of this article first appeared on Medscape.com.
Such reactions could occur even years after the start of treatment, the European Medicines Agency (EMA) warned.
Glatiramer acetate is a disease-modifying therapy (DMT) for relapsing MS that is given by injection.
The drug has been used for treating MS for more than 20 years, during which time, it has had a good safety profile. Common side effects are known to include vasodilation, arthralgia, anxiety, hypertonia, palpitations, and lipoatrophy.
A meeting of the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC), held on July 8-11, considered evidence from an EU-wide review of all available data concerning anaphylactic reactions with glatiramer acetate. As a result, the committee concluded that the medicine is associated with a risk for anaphylactic reactions, which may occur shortly after administration or even months or years later.
Risk for Delays to Treatment
Cases involving the use of glatiramer acetate with a fatal outcome have been reported, PRAC noted.
The committee cautioned that because the initial symptoms could overlap with those of postinjection reaction, there was a risk for delay in identifying an anaphylactic reaction.
PRAC has sanctioned a direct healthcare professional communication (DHPC) to inform healthcare professionals about the risk. Patients and caregivers should be advised of the signs and symptoms of an anaphylactic reaction and the need to seek emergency care if this should occur, the committee added. In the event of such a reaction, treatment with glatiramer acetate must be discontinued, PRAC stated.
Once adopted, the DHPC for glatiramer acetate will be disseminated to healthcare professionals by the marketing authorization holders.
Anaphylactic reactions associated with the use of glatiramer acetate have been noted in medical literature for some years. A letter by members of the department of neurology at Albert Ludwig University Freiburg, Freiburg im Bresigau, Germany, published in the journal European Neurology in 2011, detailed six cases of anaphylactoid or anaphylactic reactions in patients while they were undergoing treatment with glatiramer acetate.
The authors highlighted that in one of the cases, a grade 1 anaphylactic reaction occurred 3 months after treatment with the drug was initiated.
A version of this article first appeared on Medscape.com.
Such reactions could occur even years after the start of treatment, the European Medicines Agency (EMA) warned.
Glatiramer acetate is a disease-modifying therapy (DMT) for relapsing MS that is given by injection.
The drug has been used for treating MS for more than 20 years, during which time, it has had a good safety profile. Common side effects are known to include vasodilation, arthralgia, anxiety, hypertonia, palpitations, and lipoatrophy.
A meeting of the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC), held on July 8-11, considered evidence from an EU-wide review of all available data concerning anaphylactic reactions with glatiramer acetate. As a result, the committee concluded that the medicine is associated with a risk for anaphylactic reactions, which may occur shortly after administration or even months or years later.
Risk for Delays to Treatment
Cases involving the use of glatiramer acetate with a fatal outcome have been reported, PRAC noted.
The committee cautioned that because the initial symptoms could overlap with those of postinjection reaction, there was a risk for delay in identifying an anaphylactic reaction.
PRAC has sanctioned a direct healthcare professional communication (DHPC) to inform healthcare professionals about the risk. Patients and caregivers should be advised of the signs and symptoms of an anaphylactic reaction and the need to seek emergency care if this should occur, the committee added. In the event of such a reaction, treatment with glatiramer acetate must be discontinued, PRAC stated.
Once adopted, the DHPC for glatiramer acetate will be disseminated to healthcare professionals by the marketing authorization holders.
Anaphylactic reactions associated with the use of glatiramer acetate have been noted in medical literature for some years. A letter by members of the department of neurology at Albert Ludwig University Freiburg, Freiburg im Bresigau, Germany, published in the journal European Neurology in 2011, detailed six cases of anaphylactoid or anaphylactic reactions in patients while they were undergoing treatment with glatiramer acetate.
The authors highlighted that in one of the cases, a grade 1 anaphylactic reaction occurred 3 months after treatment with the drug was initiated.
A version of this article first appeared on Medscape.com.
COMBAT-MS: Therapy Choice for Relapsing-Remitting MS Has ‘Small’ Impact on Disability Progression, Patient-Reported Outcomes
, according to recent research published in Annals of Neurology.
Fredrik Piehl, MD, PhD, of the department of clinical neuroscience at Karolinska Institutet in Stockholm, and colleagues analyzed results from a cohort study in Sweden of 2449 patients with relapsing-remitting MS who started an initial disease-modifying therapy (DMT), and 2463 patients who switched from their first therapy between 2011 and 2018, with 1148 patients overlapping in both groups. DMTs evaluated in the group that started an initial treatment included rituximab (591 patients), natalizumab (334 patients), dimethyl fumarate (416 patients), interferon (992 patients), and glatiramer acetate (116 patients), while DMTs included in the group switching therapies were rituximab (748 patients), natalizumab (541 patients), dimethyl fumarate (570 patients), fingolimod (443 patients), and teriflunomide (161 patients).
The researchers compared patients receiving low-dose rituximab with other MS therapies, with confirmed disability worsening (CDW) over 12 months and change in disease-related impact on daily life as measured by MS Impact Scale-29 (MSIS-29) subscales as primary outcomes at 3 years after therapy initiation or switching. They also assessed the rate of relapse, discontinuation of therapy, and serious adverse events as secondary outcomes.
At 3 years, among patients who received rituximab, 9.1% of patients who initiated therapy and 5.1% who switched therapy experienced CDW, and there were no significant differences in disease worsening between patients who received rituximab and those who received other MS therapies. “Most instances of CDW on rituximab were in subjects with no relapse within 3 years of treatment start,” the researchers said.
Patient MSIS-29 physical subscores at 3 years improved by 1.3 points in the initial DMT group and by 0.4 points in the DMT-switching group, while MSIS-29 psychological scores improved by 8.4 points in the initial DMT and by 3.6 points in the DMT-switching group. “Adjusted for baseline characteristics, MSIS-29 physical subscale scores decreased more with natalizumab, both as a first DMT and after a DMT switch, compared with rituximab, although absolute differences were small,” Dr. Piehl and colleagues said.
With regard to secondary outcomes, there was a reduction in mean overall Expanded Disability Status Scale (EDSS) score compared with baseline in the initial rituximab group at 3 years (–0.2 points), with 28.7% of patients experiencing improvement and 19.0% experiencing worsening, while there was no overall change in mean EDSS score in the rituximab-switching group. At 5 years, mean EDSS scores decreased compared with baseline in the initial rituximab group (–0.1 point), with 27.1% patients experiencing improvement and 20.8% experiencing worsening, and there was an increase in overall EDSS score (0.1 point) at 5 years for the rituximab-switching group, with improvement in 17.9% of patients and worsening in 26.4% of patients. However, there were no significant differences between rituximab and other DMTs.
Patients in both initial and switching rituximab groups had a lower annualized relapse rate (ARR) compared with other DMTs, with the exception of natalizumab in the initial DMT group (3 vs 2 additional relapses per 100 patients per year). The highest ARR in the initial DMT group belonged to interferon (13 additional relapses per 100 patients per year) and teriflunomide (8 additional relapses per 100 patients per year). “Similar differences were evident also at 5 years, with significantly higher ARRs with all other DMTs compared with rituximab, except for natalizumab, in both the first DMT and DMT switch groups,” Dr. Piehl and colleagues said.
In the group of patients who received rituximab, 75.7% of patients had no evidence of disease activity (NEDA-3) at 3 years in the initial DMT group and 82.1% of patients in the DMT-switching group, which was “greater than for all comparators, except natalizumab as a first DMT,” the researchers said. “Proportions fulfilling NEDA-3 status at 5 years were higher with rituximab than with all comparators in both cohorts,” they noted.
Concerning safety, the researchers said there were minor differences in safety outcomes between rituximab and comparators, but patients in the DMT-switching group who received rituximab had a higher risk of severe infections compared with other groups.
Unanswered Questions About MS Therapies
In an interview, Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates, New York, who was not involved in the study, emphasized the importance of high-potency DMTs and adherence for treatment success.
“Lower-efficacy DMT might result in insufficient suppression of disease activity that might not be clinically apparent,” he said. “Routine examination is not sufficient to detect cognitive impairment or change in cognitive impact of disease. Adherence is critical to therapy success, and infusion therapies or treatment not self-administered have higher likelihood of higher adherence rates.”
Commenting on the study by Piehl et al, Dr. Gudesblatt said it “provides important real-world information” on how infusion therapies are tolerated, their effectiveness, and their adherence compared with oral or self-administered treatments. For rituximab, “just as importantly, this therapy provides effective disease control with less accumulated disability and disability related health care costs,” he said.
Dr. Gudesblatt said there are several unanswered issues in the study, including the uncertain nature of the incidence and development of rituximab-blocking antibodies, which could potentially differ by biosimilar. “[H]ow this impacts therapy efficacy is unclear,” he said. “The presence of blocking antibodies should be routinely monitored.”
Another issue is the between-patient variation in degree of B-cell depletion and speed of B-cell repletion, which might differ based on therapy duration. “The timing and frequency of dosing is an issue that also needs further critical analysis and improved guidelines,” he noted.
Dr. Gudesblatt said up to 25% of patients with MS might have unrecognized immune deficiency. “[I]mmune deficiency unrelated to DMT as well as the development of immune deficiency related to DMT are issues of concern, as the rate of infections in B-cell depleting agents are higher than other class of DMT,” he explained. Patients with MS who develop infections carry significant risk of morbidity and mortality, he added.
“Lastly, the issue of vaccination failure is extremely high in B-cell depleting agents, and with the recent viral pandemic and lingering concerns about recurrent similar scenarios, this is another issue of great concern with use of this highly adherent and effective DMT choice,” Dr. Gudesblatt said.
Several authors reported personal and institutional relationships in the form of grants, consultancies, research support, honoraria, advisory board positions, travel support, and other fees for Bayer, Biogen, Merck, Novartis, Roche, and Teva. Dr. Gudesblatt reports no relevant conflicts of interest.
, according to recent research published in Annals of Neurology.
Fredrik Piehl, MD, PhD, of the department of clinical neuroscience at Karolinska Institutet in Stockholm, and colleagues analyzed results from a cohort study in Sweden of 2449 patients with relapsing-remitting MS who started an initial disease-modifying therapy (DMT), and 2463 patients who switched from their first therapy between 2011 and 2018, with 1148 patients overlapping in both groups. DMTs evaluated in the group that started an initial treatment included rituximab (591 patients), natalizumab (334 patients), dimethyl fumarate (416 patients), interferon (992 patients), and glatiramer acetate (116 patients), while DMTs included in the group switching therapies were rituximab (748 patients), natalizumab (541 patients), dimethyl fumarate (570 patients), fingolimod (443 patients), and teriflunomide (161 patients).
The researchers compared patients receiving low-dose rituximab with other MS therapies, with confirmed disability worsening (CDW) over 12 months and change in disease-related impact on daily life as measured by MS Impact Scale-29 (MSIS-29) subscales as primary outcomes at 3 years after therapy initiation or switching. They also assessed the rate of relapse, discontinuation of therapy, and serious adverse events as secondary outcomes.
At 3 years, among patients who received rituximab, 9.1% of patients who initiated therapy and 5.1% who switched therapy experienced CDW, and there were no significant differences in disease worsening between patients who received rituximab and those who received other MS therapies. “Most instances of CDW on rituximab were in subjects with no relapse within 3 years of treatment start,” the researchers said.
Patient MSIS-29 physical subscores at 3 years improved by 1.3 points in the initial DMT group and by 0.4 points in the DMT-switching group, while MSIS-29 psychological scores improved by 8.4 points in the initial DMT and by 3.6 points in the DMT-switching group. “Adjusted for baseline characteristics, MSIS-29 physical subscale scores decreased more with natalizumab, both as a first DMT and after a DMT switch, compared with rituximab, although absolute differences were small,” Dr. Piehl and colleagues said.
With regard to secondary outcomes, there was a reduction in mean overall Expanded Disability Status Scale (EDSS) score compared with baseline in the initial rituximab group at 3 years (–0.2 points), with 28.7% of patients experiencing improvement and 19.0% experiencing worsening, while there was no overall change in mean EDSS score in the rituximab-switching group. At 5 years, mean EDSS scores decreased compared with baseline in the initial rituximab group (–0.1 point), with 27.1% patients experiencing improvement and 20.8% experiencing worsening, and there was an increase in overall EDSS score (0.1 point) at 5 years for the rituximab-switching group, with improvement in 17.9% of patients and worsening in 26.4% of patients. However, there were no significant differences between rituximab and other DMTs.
Patients in both initial and switching rituximab groups had a lower annualized relapse rate (ARR) compared with other DMTs, with the exception of natalizumab in the initial DMT group (3 vs 2 additional relapses per 100 patients per year). The highest ARR in the initial DMT group belonged to interferon (13 additional relapses per 100 patients per year) and teriflunomide (8 additional relapses per 100 patients per year). “Similar differences were evident also at 5 years, with significantly higher ARRs with all other DMTs compared with rituximab, except for natalizumab, in both the first DMT and DMT switch groups,” Dr. Piehl and colleagues said.
In the group of patients who received rituximab, 75.7% of patients had no evidence of disease activity (NEDA-3) at 3 years in the initial DMT group and 82.1% of patients in the DMT-switching group, which was “greater than for all comparators, except natalizumab as a first DMT,” the researchers said. “Proportions fulfilling NEDA-3 status at 5 years were higher with rituximab than with all comparators in both cohorts,” they noted.
Concerning safety, the researchers said there were minor differences in safety outcomes between rituximab and comparators, but patients in the DMT-switching group who received rituximab had a higher risk of severe infections compared with other groups.
Unanswered Questions About MS Therapies
In an interview, Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates, New York, who was not involved in the study, emphasized the importance of high-potency DMTs and adherence for treatment success.
“Lower-efficacy DMT might result in insufficient suppression of disease activity that might not be clinically apparent,” he said. “Routine examination is not sufficient to detect cognitive impairment or change in cognitive impact of disease. Adherence is critical to therapy success, and infusion therapies or treatment not self-administered have higher likelihood of higher adherence rates.”
Commenting on the study by Piehl et al, Dr. Gudesblatt said it “provides important real-world information” on how infusion therapies are tolerated, their effectiveness, and their adherence compared with oral or self-administered treatments. For rituximab, “just as importantly, this therapy provides effective disease control with less accumulated disability and disability related health care costs,” he said.
Dr. Gudesblatt said there are several unanswered issues in the study, including the uncertain nature of the incidence and development of rituximab-blocking antibodies, which could potentially differ by biosimilar. “[H]ow this impacts therapy efficacy is unclear,” he said. “The presence of blocking antibodies should be routinely monitored.”
Another issue is the between-patient variation in degree of B-cell depletion and speed of B-cell repletion, which might differ based on therapy duration. “The timing and frequency of dosing is an issue that also needs further critical analysis and improved guidelines,” he noted.
Dr. Gudesblatt said up to 25% of patients with MS might have unrecognized immune deficiency. “[I]mmune deficiency unrelated to DMT as well as the development of immune deficiency related to DMT are issues of concern, as the rate of infections in B-cell depleting agents are higher than other class of DMT,” he explained. Patients with MS who develop infections carry significant risk of morbidity and mortality, he added.
“Lastly, the issue of vaccination failure is extremely high in B-cell depleting agents, and with the recent viral pandemic and lingering concerns about recurrent similar scenarios, this is another issue of great concern with use of this highly adherent and effective DMT choice,” Dr. Gudesblatt said.
Several authors reported personal and institutional relationships in the form of grants, consultancies, research support, honoraria, advisory board positions, travel support, and other fees for Bayer, Biogen, Merck, Novartis, Roche, and Teva. Dr. Gudesblatt reports no relevant conflicts of interest.
, according to recent research published in Annals of Neurology.
Fredrik Piehl, MD, PhD, of the department of clinical neuroscience at Karolinska Institutet in Stockholm, and colleagues analyzed results from a cohort study in Sweden of 2449 patients with relapsing-remitting MS who started an initial disease-modifying therapy (DMT), and 2463 patients who switched from their first therapy between 2011 and 2018, with 1148 patients overlapping in both groups. DMTs evaluated in the group that started an initial treatment included rituximab (591 patients), natalizumab (334 patients), dimethyl fumarate (416 patients), interferon (992 patients), and glatiramer acetate (116 patients), while DMTs included in the group switching therapies were rituximab (748 patients), natalizumab (541 patients), dimethyl fumarate (570 patients), fingolimod (443 patients), and teriflunomide (161 patients).
The researchers compared patients receiving low-dose rituximab with other MS therapies, with confirmed disability worsening (CDW) over 12 months and change in disease-related impact on daily life as measured by MS Impact Scale-29 (MSIS-29) subscales as primary outcomes at 3 years after therapy initiation or switching. They also assessed the rate of relapse, discontinuation of therapy, and serious adverse events as secondary outcomes.
At 3 years, among patients who received rituximab, 9.1% of patients who initiated therapy and 5.1% who switched therapy experienced CDW, and there were no significant differences in disease worsening between patients who received rituximab and those who received other MS therapies. “Most instances of CDW on rituximab were in subjects with no relapse within 3 years of treatment start,” the researchers said.
Patient MSIS-29 physical subscores at 3 years improved by 1.3 points in the initial DMT group and by 0.4 points in the DMT-switching group, while MSIS-29 psychological scores improved by 8.4 points in the initial DMT and by 3.6 points in the DMT-switching group. “Adjusted for baseline characteristics, MSIS-29 physical subscale scores decreased more with natalizumab, both as a first DMT and after a DMT switch, compared with rituximab, although absolute differences were small,” Dr. Piehl and colleagues said.
With regard to secondary outcomes, there was a reduction in mean overall Expanded Disability Status Scale (EDSS) score compared with baseline in the initial rituximab group at 3 years (–0.2 points), with 28.7% of patients experiencing improvement and 19.0% experiencing worsening, while there was no overall change in mean EDSS score in the rituximab-switching group. At 5 years, mean EDSS scores decreased compared with baseline in the initial rituximab group (–0.1 point), with 27.1% patients experiencing improvement and 20.8% experiencing worsening, and there was an increase in overall EDSS score (0.1 point) at 5 years for the rituximab-switching group, with improvement in 17.9% of patients and worsening in 26.4% of patients. However, there were no significant differences between rituximab and other DMTs.
Patients in both initial and switching rituximab groups had a lower annualized relapse rate (ARR) compared with other DMTs, with the exception of natalizumab in the initial DMT group (3 vs 2 additional relapses per 100 patients per year). The highest ARR in the initial DMT group belonged to interferon (13 additional relapses per 100 patients per year) and teriflunomide (8 additional relapses per 100 patients per year). “Similar differences were evident also at 5 years, with significantly higher ARRs with all other DMTs compared with rituximab, except for natalizumab, in both the first DMT and DMT switch groups,” Dr. Piehl and colleagues said.
In the group of patients who received rituximab, 75.7% of patients had no evidence of disease activity (NEDA-3) at 3 years in the initial DMT group and 82.1% of patients in the DMT-switching group, which was “greater than for all comparators, except natalizumab as a first DMT,” the researchers said. “Proportions fulfilling NEDA-3 status at 5 years were higher with rituximab than with all comparators in both cohorts,” they noted.
Concerning safety, the researchers said there were minor differences in safety outcomes between rituximab and comparators, but patients in the DMT-switching group who received rituximab had a higher risk of severe infections compared with other groups.
Unanswered Questions About MS Therapies
In an interview, Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates, New York, who was not involved in the study, emphasized the importance of high-potency DMTs and adherence for treatment success.
“Lower-efficacy DMT might result in insufficient suppression of disease activity that might not be clinically apparent,” he said. “Routine examination is not sufficient to detect cognitive impairment or change in cognitive impact of disease. Adherence is critical to therapy success, and infusion therapies or treatment not self-administered have higher likelihood of higher adherence rates.”
Commenting on the study by Piehl et al, Dr. Gudesblatt said it “provides important real-world information” on how infusion therapies are tolerated, their effectiveness, and their adherence compared with oral or self-administered treatments. For rituximab, “just as importantly, this therapy provides effective disease control with less accumulated disability and disability related health care costs,” he said.
Dr. Gudesblatt said there are several unanswered issues in the study, including the uncertain nature of the incidence and development of rituximab-blocking antibodies, which could potentially differ by biosimilar. “[H]ow this impacts therapy efficacy is unclear,” he said. “The presence of blocking antibodies should be routinely monitored.”
Another issue is the between-patient variation in degree of B-cell depletion and speed of B-cell repletion, which might differ based on therapy duration. “The timing and frequency of dosing is an issue that also needs further critical analysis and improved guidelines,” he noted.
Dr. Gudesblatt said up to 25% of patients with MS might have unrecognized immune deficiency. “[I]mmune deficiency unrelated to DMT as well as the development of immune deficiency related to DMT are issues of concern, as the rate of infections in B-cell depleting agents are higher than other class of DMT,” he explained. Patients with MS who develop infections carry significant risk of morbidity and mortality, he added.
“Lastly, the issue of vaccination failure is extremely high in B-cell depleting agents, and with the recent viral pandemic and lingering concerns about recurrent similar scenarios, this is another issue of great concern with use of this highly adherent and effective DMT choice,” Dr. Gudesblatt said.
Several authors reported personal and institutional relationships in the form of grants, consultancies, research support, honoraria, advisory board positions, travel support, and other fees for Bayer, Biogen, Merck, Novartis, Roche, and Teva. Dr. Gudesblatt reports no relevant conflicts of interest.
FROM ANNALS OF NEUROLOGY