News: good and bad

The tolebrutinib results have now been published. High-dose ocrelizumab in relapsing MS is a no.

Tolebrutinib

A short newsletter to highlight news. The tolebrutinib data has finally been published and not only vindicates that BTK (Bruton Tyrosine Kinase) is a valid therapeutic target targeting B-cells and likely CNS macrophages and microglia but also makes the case for CNS penetrant therapies. The tolebrutinib results are a landmark in MS drug development and usher in a new phase of MS therapeutics that goes beyond targeting relapses and focal MRI activity to target smouldering MS. I hope Prof. George Ebers will be happy; this is something he was pushing for in the 1990s, and nobody would listen to him. Tolebrutnib also tells us that relapses and focal MRI activity should not be the primary target in MS; they are not MS. The real MS is what is happening in the tissue of the brain and spinal cord, i.e. smouldering disease and that we should be targeting the disease and not the immune response to the disease. Do you agree?

High-dose ocrelizumab

At the same time, Roche-Genentech released a short press statement last week (2-April-2025) stating that the MUSETTE trial designed to determine whether a higher dose of the currently approved Ocrevus IV 600 mg would provide additional benefit to people living with relapsing multiple sclerosis, did not meet its primary endpoint and that results support ocrelizuab (Ocrevus) IV 600 mg as the optimal dose to slow disability progression. Importantly, high-dose ocrelizumab was well tolerated with an overall comparable safety profile to Ocrevus IV 600 mg, and no new safety signals were observed. These data further support the efficacy and safety profile of Ocrevus IV 600 mg dose for RMS.

I called this one wrong. I thought that, based on the need to target CNS-resident B-cells and plasmablasts, we needed higher, not lower, doses of anti-CD20 to get better CNS penetration. I have not seen the data and can’t comment on specifics. We need to see if there were any signals to suggest that high-dose was superior on secondary outcome measures. There is a possibility that the event rate (confirmed disability progression) may be too low in an early relapsing cohort of trial participants to give a positive result, i.e. the study was underpowered. I will withhold further judgement until the results of the high-dose PPMS or GAVOTTE study (ClinicalTrials ID NCT04548999). Saying this, my predictions of positive results for teh PPMS study have dropped below 50%; I would now say they are at 33% (20-45%). I still think the PPMS trial may be positive because pwPPMS are more likely to get worse in a short study than pwRMS; i.e. the trial is less likely to be underpowered.

So mixed news, good and bad. I assume those of you who have smouldering MS are happy to see the HERCULES results published as we are one step closer to getting a new therapy for people with smouldering MS. People in the US can expect a decision from the FDA in late September and from the EMA and MHRA about 6 months later. However, due to EU and UK rules, the licensing in Europe and the UK doesn’t mean immediate availability; there are still all the market access hoops to go through, which can take 6-12 months. So for people with smouldering MS in the UK, I would not expect tolebrutinib to be available until late 2026.

Papers

Fox et al. Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis. N Engl J Med. Published April 8, 2025. DOI: 10.1056/NEJMoa2415988.

Background: Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for multiple sclerosis have limited effects on disability accrual unrelated to relapses, which is thought to be partially caused by chronic, nonresolving neuroinflammation within the central nervous system. Tolebrutinib is an oral, brain-penetrant Bruton’s tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B cells in both the periphery and central nervous system. There are no approved treatments for nonrelapsing secondary progressive multiple sclerosis.

Methods: In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with nonrelapsing secondary progressive multiple sclerosis, in a 2:1 ratio, to receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed disability progression that was sustained for at least 6 months, assessed in a time-to-event analysis.

Results: A total of 1131 participants underwent randomization: 754 were assigned to receive tolebrutinib and 377 to receive placebo. The median follow-up was 133 weeks. A smaller percentage of participants in the tolebrutinib group than in the placebo group had confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; hazard ratio, 0.69; 95% confidence interval, 0.55 to 0.88; P=0.003). Serious adverse events occurred in 15.0% of the participants in the tolebrutinib group and in 10.4% of those in the placebo group. A total of 4.0% of the participants in the tolebrutinib group and 1.6% of those in the placebo group had increases in alanine aminotransferase levels to more than 3 times the upper limit of the normal range.

Conclusions: In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo. (Funded by Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.)

Oh et al. Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med. Published April 8, 2025. DOI: 10.1056/NEJMoa2415985.

Background: Tolebrutinib is an oral, brain-penetrant, and bioactive Bruton’s tyrosine kinase inhibitor that modulates peripheral inflammation and persistent immune activation within the central nervous system, including disease-associated microglia and B cells. More data are needed on its efficacy and safety in treating relapsing multiple sclerosis.

Methods: In two phase 3, double-blind, double-dummy, event-driven trials (GEMINI 1 and GEMINI 2), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo. The primary end point was the annualized relapse rate. The key secondary end point was confirmed worsening of disability that was sustained for at least 6 months, which was assessed in a time-to-event analysis that was pooled across trials.

Results: A total of 974 participants were enrolled in GEMINI 1, and 899 were enrolled in GEMINI 2. The median follow-up was 139 weeks. The annualized relapse rate in the tolebrutinib and teriflunomide groups was 0.13 and 0.12, respectively, in GEMINI 1 (rate ratio, 1.06; 95% confidence interval [CI], 0.81 to 1.39; P=0.67) and 0.11 and 0.11, respectively, in GEMINI 2 (rate ratio, 1.00; 95% CI, 0.75 to 1.32; P=0.98). The pooled percentage of participants with confirmed disability worsening sustained for at least 6 months was 8.3% with tolebrutinib and 11.3% with teriflunomide (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; no formal hypothesis testing was conducted owing to the prespecified hierarchical testing plan, and the width of the confidence interval is not adjusted for multiple testing). The percentage of participants who had adverse events was similar in the two treatment groups, although the percentage with minor bleeding was higher in the tolebrutinib group than in the teriflunomide group (petechiae occurred in 4.5% vs. 0.3%, and heavy menses in 2.6% vs. 1.0%).

Conclusions: Tolebrutinib was not superior to teriflunomide in decreasing annualized relapse rates among participants with relapsing multiple sclerosis. (Funded by Sanofi; GEMINI 1 and GEMINI 2 ClinicalTrials.gov numbers, NCT04410978 and NCT04410991, respectively.)

I am still away on holiday and will try and get to the long list of questions you have asked next week when I am back home.

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.