About a year ago, I predicted that Fenebrutinib would be the best-in-class of the emerging BTK inhibitors. This was based on the phase 2 extension data of fenebrutinib, which was more effective at suppressing Gd-enhancing lesions than tolebrutinib. Based on that data, I assigned fenebrutinib a ~87.5% (range, 75-95%) chance of being superior to teriflunomide in suppressing relapses and focal MRI activity, and I assigned fenebrutinib a 40% chance (range, 30-50%) of being superior to ocrelizumab in PPMS (please see Battle of the BTKi’s, 23-Sept-2024). My predictions may be correct.
Roche-Genentech has just released the headline results (see press release 20-11-2025).
“The first (FENhance 2) of two pivotal RMS studies met its primary endpoint, showing investigational fenebrutinib significantly reduced relapses compared to teriflunomide. Fenebrutinib substantially reduced the number of relapses in RMS and slowed disability progression in PPMS. These unprecedented results suggest that fenebrutinib could potentially become a best-in-disease medicine as the first high-efficacy, oral treatment for people with RMS or PPMS,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. Therefore, these pivotal results for fenebrutinib may offer new hope for people living with MS, and they reaffirm our enduring commitment to the MS community. Liver safety was consistent with previous fenebrutinib studies. Additional safety data is being further evaluated. The results of the second RMS Phase III trial (FENhance 1) are expected by the first half of 2026.”
Fenebrutinib differs from tolebrutinib in that fenebrutinib is a non-covalent reversible inhibitor that targets the open conformation of the enzyme and acts to trap BTK in an inactive conformation. From a PK perspective, tolebrutinib has a very short half-life (~90 min), while fenebrutinib has a half-life of approximately 4-6 hours. Because tolebrutinib is covalent, the PD actions are long-lasting, and enzyme activity recovers after the last dose within 5-7 days as new enzyme is synthesised (protein turnover). Fenebrutinib is a classical competitive inhibitor; therefore, to maintain “coverage” in vivo, relatively high doses are required, and it must be administered twice daily. Fenebrutinib has a “long residency time”, meaning that the off-rate is slow. The consequence of nanomolar potency with slow dissociation implies that the off-rate defines the steady-state. When measured in a model system, occupancy of BTK within cells is primarily driven by the C trough, with estimates suggesting that fenebrutinib is likely to have modest occupancy within the CNS.
About the FENhance 1 and 2 studies (from press release 20-11-2025)
FENhance 1 and 2 are similarly designed Phase III multicentre, randomised, double-blind, double-dummy, parallel-group studies to evaluate the efficacy and safety of investigational fenebrutinib compared with teriflunomide in a total of 1,497 adult patients with RMS. Eligible participants were randomised 1:1 to receive treatment with either oral fenebrutinib twice a day (and placebo matched to oral teriflunomide once a day) or oral teriflunomide once a day (and placebo matched to oral fenebrutinib twice a day) for at least 96 weeks.
The primary endpoint is annualised relapse rate (ARR). Key secondary endpoints include the time to onset of composite 24-week confirmed disability progression (cCDP24), 12-week confirmed disability progression (CDP12) and 24-week confirmed disability progression (CDP24).
Following the double-blind treatment period, patients have the option to enter an open-label extension (OLE) phase, in which all patients receive treatment with fenebrutinib.
About the FENtrepid study (from press release 20-11-2025)
FENtrepid is a Phase III multicentre, randomised, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of fenebrutinib compared with OCREVUS in 985 adult patients with PPMS. Eligible participants were randomised 1:1 to receive treatment with either daily oral fenebrutinib (and placebo matched to intravenous [IV] OCREVUS) or IV OCREVUS (and placebo matched to oral fenebrutinib) for at least 120 weeks.
The primary endpoint is the time to onset of 12-week composite confirmed disability progression (cCDP12). The cCDP incorporates three measures of disability – total functional disability measured by the Expanded Disability Status Scale (EDSS), walking speed measured by the timed 25-foot walk (T25FW), and upper limb function measured by the nine-hole peg test (9HPT). This comprehensive composite endpoint offers greater sensitivity than the EDSS alone, capturing additional aspects of disability and often earlier. Key secondary endpoints include the time to onset of 24-week composite confirmed disability progression (cCDP24), 12-week confirmed disability progression (CDP12) and 24-week confirmed disability progression (CDP24).
Following the double-blind treatment period, patients have the option to enter an open-label extension (OLE) phase, in which all patients receive treatment with fenebrutinib.
About fenebrutinib (from press release 20-11-2025)
Fenebrutinib is an investigational oral, central nervous system (CNS)-penetrant, reversible and non-covalent Bruton’s tyrosine kinase (BTK) inhibitor with an optimised pharmacokinetics (PK) profile. Fenebrutinib has been shown to be 130 times more selective for BTK vs. other kinases. Fenebrutinib is an inhibitor of both B-cell and microglia activation. This dual inhibition may be able to reduce both multiple sclerosis disease activity and disability progression, thereby potentially addressing the key unmet medical need of disability progression in people living with multiple sclerosis and providing comprehensive multiple sclerosis care. The fenebrutinib Phase III programme includes two similarly designed trials in relapsing multiple sclerosis (RMS) (FENhance 1 and 2), with an active comparator of teriflunomide, and the only trial in primary progressive multiple sclerosis (PPMS) (FENtrepid), in which a BTK inhibitor is being evaluated against OCREVUS.
Final thoughts
How do these results fit in with the EBV hypothesis of MS? They support EBV as the cause and driver of MS disease activity. I have said before that for EBV to remain latent, EBV hijacks BTK, via its latent membrane protein 2a (LMP2a), to provide the B-cell with a prosurvival signal. Inhibiting BTK, you remove this signal, and EBV-infected memory B-cells die. This has been demonstrated with first-generation BTK inhibitors. I suspect if we look in fenebrutinib-treated pwMS, we will see the same thing. Contrary to what people think, these results support, rather than refute, the EBV hypothesis of MS.
Exciting times for pwMS and for those researching the field. Maybe you disagree?
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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.
Prof G- Is it possible to have a newsletter to compare top DMTs - BTKi vs ocrevus vs cladribine vs CAR-T . And practicalities in getting on them etc, hurdles etc.
Exciting news but there are still a couple of hurdles to overcome. NICE to select it and will it be available to me, 71 years old, smouldering MS with no history of relapses but struggling with numerous disabilities.
Sorry to sound a bit negative but I do feel that people like my self are ignored and I suspect there are quite a lot of us who just have to get on with it.