For a long time, doctors have struggled to find effective treatments for multiple sclerosis (MS), a disease that affects each patient differently. While the first disease-modifying therapy, Betaseron, was approved in 1993, and other effective drugs followed, many patients still face challenges with treatment resistance. Recently, there was a setback when Sanofi’s lead drug, a type of treatment called a BTK inhibitor, failed a crucial late-stage trial. BTK inhibitors were hoped to be a game-changer, especially for relapsing-remitting MS, which comes and goes. These drugs target an enzyme involved in the body’s immune response and have shown promise in slowing the development of new lesions and reducing inflammation. Unlike approved treatments, they can cross the blood-brain barrier, potentially giving them a significant advantage. However, a few weeks ago, Sanofi announced that its BTK inhibitor, tolbrutinib, did not meet the main goal in a phase 3 trial for primary progressive MS, leading the company to abandon this indication. Then, in late December, the FDA rejected the drug’s approval for the non-relapsing secondary progressive form of MS in adults. The FDA stated that the data did not show enough benefit to outweigh the serious, potentially fatal liver risks associated with the drug, even considering the limited options for patients. This decision surprised company officials. Houman Ashrafian, Sanofi’s executive vice president and head of research and development, said in a press release that the FDA decision was a ‘significant and meaningful change in direction’ from the agency’s earlier feedback, and that the company was now working to find a way forward. But will this setback spell the end for tolbrutinib? And what does this mean for other drugs in the same category? Other BTK drugs are still being tested, including Genentech’s fenebrutinib, now in phase 3 trials for both relapsing and primary progressive MS. The drug met its main goal by significantly reducing the annualized relapse rate over 96 weeks compared with Sanofi’s Aubagio in the first of two phase 3 trials for relapsing MS, the company announced in November. The drug also met its target in a second phase 3 trial for primary progressive MS, showing it was on par with Ocrevus, the only approved drug for the condition, and might have an edge starting at 24 weeks. ‘These unprecedented results suggest that fenebrutinib could potentially become a best-in-disease medicine,’ said Dr. Levi Garraway, Genentech’s chief medical officer and head of global product development, in the written release. But fenebrutinib has also faced liver-related concerns. In 2023, the FDA placed a temporary partial clinical hold after some trial participants showed signs of drug-induced liver injury. Patients recovered after they stopped taking the drug, and the trial resumed. In the current studies, liver safety appeared consistent with earlier work. Zenas Bio is in phase 3 trials with its BTK inhibitor, orelabrutinib, licensed from China’s InnoCare Pharma Limited for primary progressive MS, and plans to start phase 3 trials for secondary progressive MS this year. The drug showed significant reductions in inflammation and the development of new lesions compared with a placebo in a mid-stage trial and has a similar safety profile to other BTK inhibitors, according to the company. Novartis’ remibrutinib, recently approved to treat chronic spontaneous urticaria, a condition causing repeated breakouts of hives, is also in contention. An upcoming phase 3 trial could expand this approval to include relapsing MS by testing how well it performs against Aubagio. BTK drugs are not the only promising approach in development. Other MS research focuses on repairing the damaged nerve coating to improve function, such as remyelination drugs like CNM-AU8, a drinkable solution that could help the body repair damaged myelin. Moderna is testing an mRNA-1195 vaccine for MS. This vaccine targets the Epstein-Barr virus, which lives in the body after the initial infection and is linked to MS risk. Researchers suspect that EBV activity or reactivation may contribute to disease activity in some patients. Other investigational treatments focus on reducing inflammation, such as the phase 3 small molecule, IMU-838 from Immunic Therapeutics. CAR T-cell therapy is another early-stage option being explored for MS and has seen some success in early studies for autoimmune conditions, like lupus.