Data builds on Roche's dominance in primary progressive MS

Roche has revealed the data behind a positive phase 3 trial for its oral BTK inhibitor fenebrutinib in primary progressive multiple sclerosis (PPMS), revealing that it was at least as effective as its blockbuster Ocrevus administered intravenously.

In the FENtrepid trial, the brain-penetrating BTK inhibitor reduced the risk of disability progression by 12% after 24 weeks compared to CD20-targeting antibody Ocrevus (ocrelizumab), which is the only approved therapy for PPMS and approached $8 billion in global sales last year.

The difference was not statistically significant, but it met the primary objective of showing that fenebrutinib was non-inferior to Ocrevus, raising the prospect of an effective, oral treatment alternative for patients with PPMS.

FENtrepid compared the two drugs on the time to onset of 12-week composite confirmed disability progression (cCDP12), which includes the expanded disability status scale (EDSS), timed 25-foot walks (T25FW), and the nine-hole peg test (9PHT) for upper limb function.

Roche said the strongest treatment effect was seen in the 9PHT test, which improved by 26% with fenebrutinib compared to Ocrevus. There was also a 22% improvement with the oral drug on a composite of the EDSS and 9HPT measures.

Roche said it now plans to press ahead with regulatory filings for fenebrutinib in PPMS in the coming weeks, and potentially also in relapsing forms of MS based on the results of the FENhance 1 and FENhance 2 trials.

The company has already reported positive results in FENhance2 and is waiting for a readout from FENhance 1 before submitting fenebrutinib for approval.

"Fenebrutinib showed a consistent clinical benefit as early as week 24, notably in upper limb function, which is essential for preserving independence and daily functioning," said FENtrepid lead investigator Prof Amit Bar-Or of the University of Pennsylvania in the US.

"With only one disease-modifying therapy available for people with PPMS, fenebrutinib has the potential to be a high-efficacy, oral treatment option that acts directly in the brain, targeting progressive biology," he added.

Roche's filing timeline puts it in hot pursuit of Sanofi, which filed its rival brain-penetrant BTK inhibitor tolebrutinib for non-relapsing secondary progressive MS last year, but was turned down by the FDA at the end of last year. It has, however, been approved in the United Arab Emirates (UAE) – becoming the first approved therapy for this form of MS – and is under review in Europe, with a decision due in the first quarter.

Tolebrutinib was also tested as a PPMS treatment, but failed to move the needle in the PERSEUS trial reported in December. Another BTK inhibitor being developed for MS, Merck KGaA's evobrutinib, also failed late-stage testing and was abandoned, while Novartis remibrutinib and InnoCare Pharma's orelabrutinib are in phase 3 testing.

"Fenebrutinib represents the first potential scientific breakthrough for the PPMS community in over a decade," said Roche's head of R&D, Levi Garraway.