Fenebrutinib

Roche said the strongest treatment effect was seen on a test of upper limb function.\n Roche has shared the numbers behind its phase 3 win in primary progressive multiple sclerosis (PPMS), linking its BTK inhibitor to a 12% reduction in the risk of disability progression compared to Ocrevus.The Swiss drugmaker revealed that the study met its primary endpoint in November, delivering a win for a mechanism that has endured a bumpy ride amid setbacks to programs at companies including Merck KGaA and Sanofi. Yet Roche only showed its BTK inhibitor, fenebrutinib, was noninferior to Ocrevus, despite originally designing (PDF) the study to show superiority to the incumbent MS treatment.Roche shared results from the trial at the Americas Committee for Treatment and Research in Multiple Sclerosis meeting Saturday. Patients taking fenebrutinib performed numerically better on the primary endpoint, which measured the time to onset of 12-week composite confirmed disability progression (cCDP12).While fenebrutinib was only noninferior to Ocrevus on cCDP12, Roche dug into the individual elements of the composite primary endpoint to find areas where its BTK inhibitor may have an advantage. The drugmaker said the strongest fenebrutinib treatment effect was seen on the nine-hole peg test (9HPT) for upper limb function, where the BTK inhibitor cut the risk of worsening by 26% compared to Ocrevus. Roche combined scores on 9HPT and the Expanded Disability Status Scale for functional disability in a post hoc analysis. Fenebrutinib was superior to Ocrevus in the analysis, with a 22% risk reduction. The composite measure used in the primary analysis included a third element, the timed 25-foot walk test. Discussing fenebrutinib’s positioning on an earnings call in January, Roche Pharmaceuticals CEO Teresa Graham said the ability to get Ocrevus-like efficacy in an oral therapy is very attractive to “many patients for many, many different reasons.” While the phase 3 data suggest fenebrutinib has Ocrevus-like efficacy, links between BTK inhibition and liver toxicity have raised questions about the program.The FDA rejected Sanofi’s request to approve a BTK inhibitor, tolebrutinib, in another form of MS in December. Later, the agency published its complete response letter, revealing that management of the risk of severe drug-induced liver injury informed its rejection. Graham cautioned analysts against extrapolating from the tolebrutinib rejection to make predictions about fenebrutinib.“I think we have to be very, very cautious here. If you actually read that CRL, it is incredibly specific to the risk-benefit that was seen with tolebrutinib. And unfortunately, they had a number of failed trials. They had a number of Hy\'s Law cases,” Graham said. “So I think it is very difficult and inappropriate to actually take the language that was applied to tolebrutinib and actually put that forward on to fenebrutinib.” The FDA put fenebrutinib on partial hold in 2023 in response to two cases of elevated liver enzymes in a relapsing MS (RMS) trial. Graham said only one case was deemed by the FDA to be a Hy’s Law case, an indicator for potential severe liver injury. The second case was confounded by alcohol use. Roche hasn’t seen any cases since implementing liver monitoring. In the PPMS trial, Roche reported transient and reversible liver enzyme elevations in 13.3% of patients in the fenebrutinib group, compared to 2.9% of people in the placebo arm. All cases resolved after patients stopped taking fenebrutinib. No Hy’s Law cases were seen.Roche plans to report data from a second phase 3 trial in RMS in the first half of the year. After that, the company will seek approval in PPMS and RMS. Guggenheim Securities analysts said in a note to investors in January that fenebrutinib could become the first BTK inhibitor approved in MS, especially given the unmet need in PPMS, but could face challenges at the FDA and beyond. “Fenebrutinib will face a high bar in establishing a favorable risk/reward due to potential Hy\'s Law cases and likely grade 3 liver enzyme elevations,” the analysts said. “If approved, we believe fenebrutinib may come with liver monitoring requirements, which could set up [Novartis’] remibrutinib to be the BTKi of choice for MS.” The analysts’ prediction rests on remibrutinib maintaining a clean safety profile and delivering positive phase 3 data. Asked about the threat posed by remibrutinib, Graham said “it’s very difficult to compare because we just really haven\'t seen anything” on the molecule in MS. Novartis had the second-mover advantage of starting its trial with liver monitoring, Graham said, but Roche could be first to market. 

Roche on Saturday detailed just how much its BTK inhibitor was deemed non-inferior compared to its blockbuster medicine Ocrevus in a late-stage trial in primary progressive multiple sclerosis. Fenebrutinib cut the risk of disability progression by 12% versus the CD20-targeting antibody Ocrevus in the Phase 3 trial called FENtrepid. The number indicates a “nominal trend toward better efficacy, but the level is modest,” Jefferies analysts wrote in a Sunday note. Roche said in November that fenebrutinib met the trial’s primary endpoint of non-inferiority to Ocrevus in slowing disability progression, but it didn’t share details at the time. The Saturday data were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis forum in San Diego. A lot is riding on fenebrutinib since Ocrevus, which was Roche’s top-selling medicine in 2025, could see biosimilar competition as soon as 2029. GlobalData analysts estimate that fenebrutinib could reach $1.3 billion in annual sales by 2031. Ocrevus pulled in around CHF 7.01 billion ($9.06 billion) in full-year sales in 2025. The medicine was approved for relapsing and primary progressive forms of MS in 2017. Ocrevus is currently the only treatment approved for PPMS, which affects around 15% of the roughly three million people diagnosed with MS worldwide. Fenebrutinib is also being developed for relapsing MS. Roche said it will wait until it has results from the second of two Phase 3 trials testing fenebrutinib in those patients before filing for approval. Topline data from that study, called FENhance 1, are expected in the middle of the first half of the year. In FENtrepid, Ocrevus was associated with a much lower rate of liver enzyme elevations (2.9%) compared with fenebrutinib (13.3%). Roche said the events were transient and reversible, with all elevations resolving after patients discontinued fenebrutinib. There were no cases where patients were deemed at high risk of fatal drug-induced liver injury, the company added. If fenebrutinib is approved in primary progressive and relapsing MS, Roche said it expects the label to feature “the same liver monitoring requirements used in our clinical trials.” The FENtrepid study measured disability progression using a composite of three tests, including the Expanded Disability Status Scale (EDSS), which looks at symptoms like mobility, vision and cognition. The other tests were a timed 25-foot walk test and a nine-hole peg test, which measure walking ability and arm function, respectively. Elsewhere, Sanofi also unveiled detailed results from a failed Phase 3 trial of its BTK inhibitor tolebrutinib in PPMS at ACTRIMS. That trial struggled with slow enrollment due to the availability of Ocrevus as a treatment for the disease.