The BTK inhibitor showed promise in non-relapsing secondary progressive multiple sclerosis but not relapsing MS. The company said it plans to apply for approval for the former “as soon as possible.”
Sanofi’s investigational BTK inhibitor tolebrutinib missed the primary efficacy endpoints in the Phase III GEMINI 1 and GEMINI 2 studies, failing to significantly improve relapse rates in patients with relapsing multiple sclerosis, according to a company announcement of three late-stage readouts on Monday.
A third trial, however, succeeded. Results from the Phase III HERCULES study showed that tolebrutinib significantly delayed disability progression in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). Early analysis of toxicities also showed that tolebrutinib’s liver safety profile was consistent with what had been established in prior studies, according to Sanofi.
The pharma did not provide specific data from any of the studies in its news release, instead promising to reveal more detailed findings and analyses from the trials at the upcoming European Committee for Treatment and Research in Multiple Sclerosis, happening later this month in Copenhagen.
“Tolebrutinib represents an unprecedented breakthrough as a potential first-in-disease treatment option with clinically meaningful benefit in disability accumulation,” Houman Ashrafian, Sanofi’s head of R&D, said in a statement. The accumulation of disabilities in patients as their disease progresses “remains the greatest unmet medical need” in nrSPMS patients.
In an interview with Fierce Biotech, Ashrafian added that Monday’s triple readouts “bring into sharp focus which patient population we should be treating.” The pharma plans to file for tolebrutinib’s approval in nrSPMS “as soon as possible,” he said.
MS is a chronic, neurodegenerative disorder that arises when the body’s immune system attacks the protective covering of its own nerve cells. It typically manifests as numbness or weakness in the limbs, lack of coordination and unsteady gait and partial or complete blindness.
According to Sanofi’s news release, the accumulation of disabilities is a central and largely under-addressed problem in MS. For instance, in relapsing MS, patients experience episodes of worsening symptoms, also called relapses, alternating with periods of recovery. While nrSPMS does not include relapses, patients continue to accumulate disabilities such as fatigue, impaired cognition and sexual dysfunction.
Tolebrutinib is an orally available and brain-penetrant inhibitor of the BTK protein, which is a central player in the development of the antibody-producing B cells. Through this mechanism of action, tolebrutinib can help temper the activity of B lymphocytes and disease-driving microglia.
In addition to tolebrutinib, Sanofi is also addressing MS with its anti-CD40L antibody frexalimab. In February 2024, the company reported Phase II data for frexalimab, demonstrating a significant reduction in disease activity and active inflammation in patients with relapsing MS.
Tolebrutinib’s road to Monday’s readouts has been rough. In June 2022, the FDA put a partial clinical hold on Phase III trials of the drug, suspending enrollment into these studies. The regulatory pause was triggered by multiple cases of drug-induced liver injuries.
Aside from the HERCULES and the GEMINI studies, Sanofi continues to evaluate tolebrutinib in the Phase III PERSEUS trial, for primary progressive MS. PERSEUS is expected to read out next year.
Monday’s back-to-back Phase III failures for tolebrutinib illustrate the difficulty of advancing BTK inhibitors in MS. In December 2023, for instance, Merck KGaA’s evobrutinib also failed its Phase III evolutinRMS 1 and evolutionRMS 2 studies, unable to significantly curb relapse rates in patients. A few months later, in March 2024, the German pharma announced it had discontinued the development of evobrutinib in MS.
Fellow pharma powerhouse Roche has also struggled with MS, announcing in December 2023 that its investigational BTK inhibitor fenebrutinib was put under partial clinical hold after the FDA detected multiple cases of liver injury.
