Understanding How To Develop BTK Inhibitors In MS Is Evolving

The failure of Merck KGaA’s Phase III trials of the BTK inhibitor evobrutinib in multiple sclerosis (MS) raises several questions about the use of this class of compounds to treat the disease. Safety has long been a concern for these molecules: at various times, MS trials of evobrutinib, Sanofi’s tolebrutinib and, most recently, Roche Holding AG’s fenebrutinib have, to some degree, been placed on clinical hold by FDA. Also see "Clinical Hold For Merck KGaA’s BTK Inhibitor Evobrutinib For MS Raises Class Safety Fears" - Scrip, 12 April, 2023. Also see "Sanofi’s MS Candidate Tolebrutinib On Clinical Hold Following Liver Toxicities" - Scrip, 30 June, 2022. New drugs have emerged as compelling treatments for relapsing MS, making the design of late-stage clinical trials increasingly challenging. Similarly, the sweet spot for proving the value of new MS drugs is shifting towards progressive forms of the disease and a focus on treating disability with high-potency drugs, not preventing relapses.

Merck announced the results of its two pivotal EVOLUTION studies of evobrutinib on 6 December, 2023. Neither met the primary endpoint of reducing annualized relapse rates in participants with relapsing multiple sclerosis as compared to Sanofi’s Aubagio (teriflunomide)