After safety signals snare rivals, Roche's MS drug clears lesions without the adverse events

Roche’s BTK inhibitor has hit the mark in a midphase multiple sclerosis trial—and without causing the sort of adverse events that sparked partial holds on Merck KGaA and Sanofi’s rival assets. The data boost Roche’s argument that fenebrutinib is differentiated without settling the debate about the drug class.

Concerns that BTK inhibitors have a classwide safety problem have intensified over the past year. The FDA hit Sanofi’s tolebrutinib with a partial clinical hold over reports of drug-induced liver injury in June 2022 and placed similar restrictions on Merck’s evobrutinib in response to a similar safety signal last month. In between those events, Biogen exited the race after its partner received (PDF) its own FDA hold notice for orelabrutinib

As its rivals have stumbled, Roche has made the case that fenebrutinib stands apart from other drugs in the class because, unlike the rival candidates, it is a non-covalent BTK molecule. But the Swiss drugmaker has lacked evidence to support its case, having moved the candidate into phase 3 without releasing any clinical data in MS. Roche ran phase 1/2 trials in other indications before targeting MS.  

The top-line phase 2 MS data paint a positive, albeit limited, picture. Fenebrutinib significantly reduced the total number of new gadolinium-enhancing T1 brain lesions—a measure of active inflammation—compared to placebo, hitting its primary endpoint with a p-value of 0.0022. 

Fenebrutinib significantly reduced the total number of new or enlarging T2 brain lesions—a measure of disease burden—compared to placebo, too. Other secondary endpoints found more participants in the fenebrutinib arm were free from new gadolinium-enhancing T1 brain lesions and new or enlarging T2-weighted brain lesions compared to placebo.

Roche is yet to share a close look at the safety data, only stating that no new concerns were seen in the phase 2 trial. The Swiss drug developer has now given fenebrutinib to more than 2,400 people, including more than 1,000 MS patients, without seeing red flags that would prompt the FDA to step in. 

The key, unanswered question is whether those red flags will arise as Roche doses more MS patients. A phase 3 trial in primary progressive MS is scheduled to read out this year. Roche is also running a pair of phase 3 trials in relapsing MS.