Merck KGaA's BTK drug flunks pivotal multiple sclerosis trials, sending shockwaves through the sector

Merck KGaA just sent shock waves through the BTK inhibitor space. Evobrutinib, the German drugmaker’s contender for a blockbuster opportunity, failed to beat Sanofi’s Aubagio in two phase 3 multiple sclerosis (MS) clinical trials, raising doubts about the prospects of a clutch of heavily backed rival candidates. 

The potential for BTK inhibitors to tackle smoldering MS, chronic inflammation linked to the progression of symptoms in patients who appear to have stable disease, has attracted a who’s who of drugmakers. Sanofi entered the space by paying $3.7 billion to buy Principia Biopharma. Biogen, Novartis and Roche are among the other companies to take candidates into phase 2 and 3 clinical trials.

Now, Merck has published phase 3 data in MS. And the news is bad. In a pair of phase 3 trials in patients with relapsing MS, the annualized relapse rates (ARR) were almost identical in recipients of evobrutinib and the control drug, Sanofi’s Aubagio.

The ARRs in the first trial, evolutionRMS 1, were the same in both cohorts, 0.11. In the second study, evolutionRMS 2, the ARR was 0.15 in the evobrutinib cohort and 0.14 in the Aubagio group. Neither trial met its primary endpoint of ARR for up to 156 weeks. 

In a statement, Merck noted that the ARRs in recipients of Aubagio were lower than those seen in other recent phase 3 studies of the treatment. The ARR in recipients of evobrutinib slipped from the phase 2 trial, when the rate in patients who received 75 mg twice a day was 0.08 at week 24 and 0.11 in a recent long-term analysis. The ARR on the Aubagio label is 0.37; in another phase 3 trial the ARR was 0.29.

The failure of evobrutinib puts a key Merck pipeline prospect in serious jeopardy, with the drugmaker’s statement devoid of silver linings. Last month, the drugmaker outlined plans to support evobrutinib with a major commercialization push, telling investors that launch preparations would drive up costs starting in the fourth quarter and mulling whether to use a voucher to accelerate the FDA review. 

With the phase 3 data scuttling Merck’s plans, the jitters may be spreading to other companies ahead of their own phase 3 readouts. Sanofi expects to complete phase trials of its candidate, tolebrutinib, in April. Roche is aiming to wrap up phase 3 trials late in 2025, with Novartis set to follow in 2026.  

Principia’s work to treat MS via BTK came under attack from a short seller, who called the approach to treatment “misguided," prior to the Sanofi buyout, but in recent times, concerns about the safety of the mechanism have overshadowed doubts about its efficacy. The FDA has placed a series of partial holds on BTK inhibitors in response to questions about whether they cause liver injury.