The BTK inhibitor—which was acquired in Sanofi’s $3.7 billion takeover of Principia Biopharma in 2021—was flagged by the FDA last summer after cases of drug-induced liver injury were reported.
Sanofi's multiple sclerosis med tolebrutinib may be under a partial FDA clinical hold after reports of liver injury in a handful of phase 3 studies, but that is not stopping the French pharma from collecting some data to make the case for efficacy and safety.
The BTK inhibitor—which was acquired in Sanofi’s $3.7 billion takeover of Principia Biopharma in 2021—was flagged by the FDA last summer after cases of drug-induced liver injury (DILI) cropped up. Because of the safety concern, the regulatory agency slapped a partial clinical hold on phase 3 trials —four MS trials and a phase 3 myasthenia gravis (MG) program, the latter of which the French pharma ultimately abandoned.
FDA officials imposed the restrictions because of “a limited number of cases of drug-induced liver injury,” Sanofi said at the time. The company added that most patients had “concurrent complications known historically to predispose to drug-induced liver injury,” and the elevated laboratory values were reversible after treatment stopped.
“Sanofi continues to monitor liver safety in the ongoing trials and is working to understand the rare cases of DILI that have been identified with tolebrutinib exposure in phase 3 studies,” Erik Wallström, M.D., Ph.D., Sanofi’s global head of neurology, told Fierce Biotech in an emailed statement.
New long-term extension data presented at the American Academy of Neurology Annual Meeting in Boston gives a deeper look at tolebrutinib's safety and efficacy. On Monday, phase 2b data was shared from a 2.5-year-long study that split patients with relapsing MS into two groups. Part A is a double-blind study in which patients received 5, 15, 30, or 60 mg of tolebrutinib each day, while part B is an open-label study in which patients received 60 mg per day.
Researchers didn’t observe any dosing-related treatment-emergent adverse events (TEAEs) or serious adverse events (AEs) in part A, and no safety signals emerged for patients switching to 60 mg in part B. The most common TEAEs reported were COVID-19, which 24.8% of patients experienced, and headache, which 13.6% of patients reported.
The study had an 85.6% retention rate (107 patients) at the 2.5-year mark, with “lack of efficacy” being the top reason for treatment discontinuation, as cited by five patients.
A hallmark of MS is that patients often relapse, so efficacy outcomes included annualized relapse rate and change from baseline on a disability status scale. For 124 participants receiving 60 mg of tolebrutinib daily for more than eight weeks, 73.4% of patients remained relapse-free. For the duration of the long-term extension, mean disability status levels remained stable. Overall, the data suggests 60 mg of tolebrutinib taken daily still demonstrates a favorable safety profile and is tied to low relapse rate and stable disability, according to Sanofi.
Despite the ongoing hold, Sanofi remains on track to submit the drug for approval to the FDA in relapsing MS in 2024, Wallström confirmed. Under the partial hold, enrollment at U.S. sites stopped and dosing was suspended in existing subjects who had been in the study for less than 60 days. However, three of the four MS phase 3 trials were already enrolled and aren’t impacted by the hold, a company spokesperson told Fierce Biotech.
The pharma’s phase 3 trials in relapsing MS, dubbed Gemini I and Gemini II, are fully enrolled and have estimated completion dates in September and August of this year, respectively. The trials are evaluating 60 mg daily doses of tolebrutinib.
Sanofi is still working with the agency on resolving the partial clinical hold, according to the spokesperson. Previously, Sanofi said new information requested by the FDA would be submitted at the end of September 2022 in hopes the hold would be lifted shortly after.
The FDA wants a deeper understanding of the patient population and benefit-risk data for the investigational drug, Sanofi’s Global Head of R&D Dietmar Berger told analysts on an earnings call yesterday.
The pharma is steamrolling forward in MS, aiming the Principia med at the indication since bowing out of the myasthenia gravis space in February, when the French pharma discontinued its phase 3 clinical trial given the competitive landscape.
The discontinuation “was based on challenges in enrolling participants from a small patient population (MG is a rare disease) in a placebo-controlled trial given the number of newly approved products,” Wallström told Fierce Biotech. “The decision was not based on any assessment of the clinical promise of tolebrutinib in MG.”
The long-term condition that causes muscle weakness has emerged as a focus for several drug developers in recent years. Alexion, now part of AstraZeneca, snagged approval for Soliris in the indication in 2017 and then gained another FDA nod for Ultomiris last year. Meanwhile, argenx secured U.S. approval for Vyvgart in 2021.
Another competitor that has yet to hit the market is UCB, which has zilucoplan and rozanolixizumab currently under FDA review. Johnson & Johnson trails closely behind, with the phase 3 study of challenger nipocalimab scheduled for primary completion by the end of this year.
The MS space also has plenty of competition approved and in development, including Biogen’s Tecfidera, Genentech’s Ocrevus and Bristol Myers Squibb’s Zeposia. Sanofi also has its own approved MS asset called Aubagio, a daily oral therapy for relapsing MS.