Tolebrutinib, a second-generation BTK inhibitor, is the first to show a reduction in disability accumulation in non-relapsing secondary progressive MS or smoldering MS.
Written by: Gavin Giovannoni — Sept 2, 2024
I suspect subscribers of MS-Selfie are tired of me banging on about smouldering MS. I have recently had some very vexatious emails and comments stating my newsletters are too downbeat and that I am destroying any hope that people with MS are living with. Is this true?
I have never wanted to pull my punches and provide a rose-tinted view of the world. My newsletters are designed to be as accurate as possible, to give you my worldview of MS, and to try and empower you to self-manage your MS as best you can and to ask the right questions when you see your MS HCPs (healthcare providers).
So, how do I tell you that one of the first trials designed to target smouldering MS in people with so-called non-relapsing secondary progressive MS is positive? How do I do this without creating false hope and unrealistic expectations? Let me give it a go.
Breaking news
Sanofi, the sponsor, has just released a press statement that Tolebrutinib, a second-generation BTK inhibitor, has met its primary endpoint in the HERCULES phase 3 study. This is the first trial to show a drug reduces disability accumulation in non-relapsing secondary progressive MS or smouldering MS.
I have to put out a disclaimer here that I am a member of the HERCULES steering committee, so anything positive needs to be taken with a pinch of salt.
Excerpts from Sanofi press release (02-Sep-2024)
âIn the HERCULES study, tolebrutinib met the primary endpoint in delaying the time to onset of confirmed disability progression in people with nrSPMS, a population for which there are currently no approved therapies and significant unmet medical needs.
The GEMINI 1 and 2 studies evaluating tolebrutinib in people with relapsing MS (RMS) did not show significance in the primary endpoint of reducing annualized relapse rate over Aubagio (teriflunomide). Analysis of the key secondary endpoint of pooled 6-month confirmed disability worsening (CDW) data showed a considerable delay in time to onset.
Phase 3 study results will form the basis for future discussions with global regulatory authorities.
Study results will be presented at the ECTRIMS medical meeting on September 20, 2024.
Positive results from the HERCULES phase 3 study showed that tolebrutinib, Sanofiâs oral brain-penetrant BTK inhibitor, met the primary endpoint of improvement over placebo in delaying time to onset of confirmed disability progression (CDP) in people with non-relapsing secondary progressive MS (nrSPMS). In the HERCULES study, nrSPMS was defined at baseline as having a SPMS diagnosis with an expanded disability status scale (EDSS) score between 3.0 and 6.5, no clinical relapses for the previous 24 months and documented evidence of disability accumulation in the previous 12 months. Preliminary analysis of liver safety was consistent with previous tolebrutinib studies.
Results from the GEMINI 1 and 2 phase 3 studies evaluating tolebrutinib did not meet the primary endpoint of reducing annualised relapse rate (ARR), compared to teriflunomide, in people with relapsing forms of multiple sclerosis. However, analysis of the key secondary endpoint of pooled 6-month CDW data showed a considerable delay in time to onset, which supports the CDP data observed in HERCULES.â
My thoughts
After the failed evobrutinib phase 3 studies, I predicted the GEMINI 1 and 2 studies would not reach their primary outcome because teriflunomide is a much better anti-inflammatory DMT than we have previously appreciated and that trial populations have changed. In retrospect, the primary outcome for these studies should have been disability progression and not relapse rate. However, the fact that Tolebrutinb was positive on disability progression, or the real MS, in both relapsing and non-relapsing MS supports my claim that relapses and focal MRI activity are not MS. I sincerely hope the regulators come to their senses and allow people with smouldering MS, which includes pwMS across the disease spectrum, to access Tolebrutinb. What do you think?
These studiesâ results support our claim that relapses are not MS and that the real MS is smouldering MS. We have been saying this for some time. I suggest you read the following MS-Selfie Newsletters and papers to learn about some of the issues these trial results raise and support.
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