Nowadays, MS is understood as a continuum of two distinct disease processes. While focal inflammatory disease activity, which is driven by the adaptive immunity, is the underlying pathological substrate for the development of new lesions and classic relapses, smoldering chronic neuroinflammation with the innate immunity as a key player is a driver of slow progression independent of relapse activity (PIRA).
While we have become increasingly proficient in quieting down focal inflammation with our arsenal of highly effective disease-modifying therapies (DMT), there is still an unmet need to develop high-efficacy medications for progressive disease. A potential reason for this gap may be that currently available therapies mainly target adaptive immunity. To date, the B-cell depleting anti-CD20 monoclonal antibody ocrelizumab is the only FDA-approved therapy in Primary Progressive Multiple Sclerosis (PPMS). While its modest efficacy has been reconfirmed in the ORATORIO-HAND trial recently presented at ECTRIMS, there is still a significant proportion of people with PPMS who continue to progress despite DMT with ocrelizumab. Accordingly, our field has been very excited about the class of Bruton’s tyrosine kinase inhibitors (BTKi) due to their mechanism of action with dual modulation of both B-cells and microglia, the resident innate immune cells of the central nervous system. This was further fueled by the promising Phase 2 results of multiple BTKi in MS, including evobrutinib, tolebrutinib, and fenebrutinib, which sparked the initiation of large Phase 3 clinical trial programs for Relapsing Remitting, Secondary Progressive, and Primary Progressive MS. Sharing this enthusiasm, I am participating in multiple BTKi trials as the site-PI here at the University of Florida as well. Unfortunately, initial excitement has been slightly dampened in recent years by the negative results of evobrutinib and tolebrutinib Phase 3 clinical trials in Relapsing Remitting MS (RRMS), which did not meet their primary endpoints to reduce annualized relapse rates compared to teriflunomide. However, tolebrutinib did show promising results in the reduction of 6-month confirmed disability progression (CDP) on the Expanded Disability Status Scale (EDSS) in both RRMS (29% reduction) and non-relapsing Secondary Progressive MS (nrSPMS) as the first medication with a positive clinical trial result in this patient population. Accordingly, the results of two Phase 3 trials for Primary Progressive MS were highly anticipated and finally presented at the ACTRIMS Forum 2026 in San Diego.
In the PERSEUS trial, people with PPMS were randomized to either tolebrutinib or placebo in a 2:1 ratio, with a total of 252 participants on placebo and 515 on tolebrutinib. Inclusion criteria included an age of 18 – 55 years, an EDSS score of 2.0 – 6.5, positive CSF-restricted oligoclonal bands or elevated immunoglobulin G index, and no access to ocrelizumab or safety/efficacy concerns related to ocrelizumab. Of note, a high proportion of enrolled participants were treated with prior DMT (39.3% and 42.5%). The trial did not meet its primary endpoint, with tolebrutinib not significantly decreasing the time to onset of 6-month composite confirmed disability progression (cCDP) on the EDSS, Timed 25-Foot Walk (T25FW), and Nine-Hole-Peg Test (9HPT) compared to placebo. Similarly, there was no appreciable treatment effect in the secondary outcomes of 3-month cCDP, as well as 6-month confirmed disability improvement. Of note, there was a nominal 14% risk reduction in 6-month CDP on the EDSS (HR 0.86 [0.64 – 1.15]). Radiographically, tolebrutinib was associated with a 46% reduction of new/enlarging T2 lesions and less brain volume loss compared to placebo. As already shown in previous tolebrutinib Phase 3 trials, there was a small subgroup of patients (0.8%) that developed severe ALT elevation > 20x ULN, all occurring within the first 90 days of treatment. In summary, tolebrutinib did not meet its primary endpoint in PERSEUS, even though there was some effect on 6-month CDP across the MS disease spectrum.
FenTREPID was designed as a non-inferiority trial with 1:1 randomization of people with PPMS to fenebrutinib (493 participants) or ocrelizumab (492 participants). Inclusion criteria included age 18 – 65 years, an EDSS score from 3.0 to 6.5, disability progression in the 12 months prior to screening, and the ability to complete the performance measures required for the primary endpoint of 3-month cCDP. The proportion of participants with prior DMT use was lower (23.6%) compared to PERSEUS. Fenebrutinib met its primary endpoint with non-inferiority compared to ocrelizumab. Of note, there was a separation of the Kaplan Meyer curves starting at week 24 with a nominal 12% risk reduction compared to placebo. A post-hoc analysis with inclusion of only EDSS and 9HPT showed an even higher nominal risk reduction of 22% compared to placebo. Of note, there were 8 total fatalities in the clinical trial, with seven participants in the fenebrutinib arm, which were determined as unrelated to the study drug by the investigators. Similar to evobrutinib and tolebrutinib, there was also a liver signal with fenebrutinib, with a higher incidence of liver enzyme elevations, treatment withdrawals due to liver enzyme elevations, and a small number (0.6%) of severe ALT elevations >20 ULN. Infection rates were comparable between the two treatment groups. In conclusion, fenebrutinib is the first oral and the only therapy besides ocrelizumab to demonstrate efficacy in PPMS, which is exciting news for our field.
Why were results different for fenebrutinib and tolebrutinib in PPMS? One possible explanation could be the clear differences in trial design. FenTREPID required documented disability progression within the previous year, a similar factor included in the positive tolebrutinib trial for nrSPMS (HERCULES), but not in PERSEUS. Furthermore, there was a very high exposure to prior DMT in PERSEUS, which was higher than in ORATORIO, ORATORIO-HAND, and FenTREPID. Accordingly, there is the potential for ongoing overlapping DMT effects in the placebo group that could interfere with detecting the real treatment effect of tolebrutinib. The recent PPMS trials have shown that EDSS and the 9HPT without inclusion of the T25FW could be a more ideal outcome measure. It is important to emphasize that there are significant differences between the different BTKi. Fenebrutinib’s binding mechanism is non-covalent and reversible, while it is covalent and irreversible in tolebrutinib. Additionally, tolebrutinib, like evobrutinib, has significant off-target effects that likely contribute to the medication’s liver signal and create a barrier for dose maximization.
Dr. Rempe received grant funding from the National Multiple Sclerosis Society. Dr. Rempe served on advisory boards for Genentech, Alexion, Amgen, TG Therapeutics, EMD Serono, and Sanofi-Genzyme. He received institutional contract research support from Sanofi-Genzyme, Novartis, Celgene, TG Therapeutics, and Genentech.
Illustration by April Brust
