Doctors have long been hamstrung in their efforts to help patients with multiple sclerosis, and limited to treatments that only target the disease’s highly variable symptoms.
Despite the approval of the first disease-modifying therapy Betaseron in 1993 and the other effective drugs followed, many patients still struggle with treatment resistance.
And recently, the space was delivered another blow when Sanofi’s lead Bruton’s tyrosine kinase inhibitor flunked a critical late-stage trial.
Drug developers have hoped that BTK inhibitors could become gamechangers, especially for relapsing-remitting MS, which waxes and wanes. BTK inhibitors target an enzyme that plays a role in the body’s immune response, and they’ve shown evidence they can slow the development of new lesions and reduce inflammation. Unlike approved disease-modifying options, they cross the blood-brain barrier, potentially giving them a critical advantage.
But a few weeks ago, Sanofi announced its BTK inhibitor tolbrutinib missed the primary endpoint in a phase 3 for primary progressive disease, leading the company to abandon the indication. Then, in late December, the FDA rebuffed the drug’s approval for the non-relapsing secondary progressive form of multiple sclerosis in adults. In a rejection letter, FDA officials said the data didn’t show enough of a benefit to outweigh the serious, potentially fatal liver risks associated with the drug, even considering patients’ limited options.
The decision seemed to catch company officials by surprise. Houman Ashrafian, Sanofi’s executive vice president, 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 path forward.
But will this turn of events become the death knell for tolebrutinib? And what does this mean for other drugs in the category?
A widening approach to MS
Other BTK drugs are still moving through the clinic, including Genentech’s fenebrutinib, now in phase 3 for both relapsing and primary progressive MS. The drug met its primary endpoint 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 hit the mark in a second phase 3 in 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 run into liver-related concerns. In 2023, the FDA levied 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 with its BTK inhibitor orelabrutinib, which it licensed from China’s InnoCare Pharma Limited for primary progressive MS, and has phase 3 hopes in secondary progressive MS this year. The drug showed significant reductions in inflammation and in the development of new lesions compared with placebo in a mid-stage trial, and it has a similar tolerability profile to other BTK inhibitors, according to the company.
Also in contention is Novartis’ remibrutinib, which was recently approved to treat chronic spontaneous urticaria, a condition that causes repeated breakouts of hives, often driven by autoimmunity. An upcoming phase 3 trial could help expand this approval to include relapsing MS by testing how well it performs against Aubagio.
BTK drugs are not the only promising approach in the works. Other MS research is focused on repairing the damaged nerve coating in hopes of improving function, such as remyelination drugs like CNM-AU8, a drinkable solution that could help the body repair damaged myelin.
Moderna, meanwhile, is testing an mRNA-1195 vaccine for the condition. The 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.
