After phase 3 clean sweep, Roche plans oral BTK filing in MS

Roche's oral BTK inhibitor fenebrutinib has hit the spot in the final trial in its phase 3 programme, in relapsing multiple sclerosis (RMS), and is now being prepared for regulatory filings.

The FENhance 1 met its primary endpoint, showing that fenebrutinib reduced relapses by 51% compared to teriflunomide in RMS, which Roche said was "consistent" with the 59% reduction seen in its previously reported FENhance 2 trial.

In a statement, Roche said the two results equate to patients having approximately one relapse every 17 years, with accompanying reductions in the number of new brain lesions.

The two studies – along with recently reported FENtrepid in primary progressive multiple sclerosis (PPMS) – will now be submitted to regulatory authorities around the world, according to the Swiss pharma group.

"These pivotal results, together with the earlier data, provide convincing evidence that fenebrutinib can become the first high-efficacy oral treatment for RMS and PPMS," said Roche's chief medical officer, Levi Garraway.

Roche is in a race to become the leading oral BTK therapy for MS, with the broadest label, and it is fair to say that the class has had variable clinical success in recent years.

Fenebrutinib's closest rival is Sanofi's tolebrutinib, which was unable to show a statistically significant benefit in RMS in the GEMINI-1 and GEMINI-2 studies and PPMS in PERSEUS, but did hit the mark in the HERCULES trial involving patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS).

Tolebrutinib has been approved for nrSPMS in the United Arab Emirates (UAE), but in a setback for Sanofi was turned down by the FDA for nrSPMS last year, after a delayed review, over concerns that potential liver side effects (PDF) may not be managed by the company's proposed patient monitoring protocol.

Liver toxicity a concern?

Roche seems to have anticipated regulatory scrutiny of its proposed filings, and noted in its statement today that elevations in transaminase levels – a marker for liver damage – were "comparable" with teriflunomide.

However, there were eight fatalities in the FENhance studies, compared to one in the teriflunomide arm, which will no doubt catch the attention of regulators. The company added that these had various causes and occurred at different points in treatment in the fenebrutinib arms, and further analyses are ongoing to better understand the findings.

Tolebrutinib, meanwhile, remains under regulatory review in other jurisdictions, including Europe, and Sanofi was asked by the EMA to provide oral arguments at a meeting held at the end of January to support its EU application. A decision by the EMA's human medicines committee, the CHMP, is due this quarter.

Shares in Roche were down 1.6% following this morning's announcement.