Phase 3 Tolebrutinib Trials Pause US Enrollment Over Safety Concerns

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The U.S. Food and Drug Administration (FDA) has placed a partial clinical hold on Phase 3 trials testing the investigational therapy tolebrutinib in people with multiple sclerosis (MS) and myasthenia gravis based on reports of medication-induced liver injury.

Under the clinical hold, new enrollment at U.S. sites will be paused, and any U.S. participants who have been in the trials for fewer than 60 days should stop treatment. Participants who completed at least 60 days in the trials will continue using tolebrutinib.

According to the therapy’s developer, Sanofi, reports of liver injury were limited and reversible after stopping treatment in all cases. Most incidents involved patients with other health complications that can predispose a person to liver injury.

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After discussing these cases with the FDA, the company revised study protocols in May to increase the frequency of the lab tests used to monitor liver injury, and the enrollment criteria were revised to exclude participants with existing risk factors for liver dysfunction.

Enrollment with the revised study protocols will continue in countries outside the U.S., while Sanofi continues to work with investigators and data monitoring committees globally to evaluate whether the added safety measures are effective.

“Sanofi remains confident in the future of tolebrutinib as a potentially transformative oral treatment option for people living with MS,” the company stated in a press release.

Tolebrutinib works by inhibiting the Bruton tyrosine kinase enzyme, a molecule important for the function of multiple immune cell types implicated in MS progression. In doing so, it’s thought to lessen the inflammation that drives both relapsing and progressive MS types.

An earlier Phase 2b trial (NCT03889639) that evaluated tolebrutinib in 130 adults with relapsing forms of MS showed that daily treatment significantly lowered the number of brain lesions after 12 weeks. Tolebrutinib was overall safe and well-tolerated, with no safety-related treatment discontinuations reported.

Sanofi is now running four Phase 3 clinical trials, which will be affected by the clinical hold.

GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) are investigating tolebrutinib against Aubagio (teriflunomide), an approved MS treatment marketed by Sanofi, in about 1,800 adults with relapsing-remitting MS and active secondary-progressive MS (SPMS). Participants will be treated for about three years, and the main goal is to determine changes in relapse rates.

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The other two trials, HERCULES (NCT04411641) and PERSEUS (NCT04458051), are evaluating tolebrutinib in people with non-relapsing MS types over about four years.

HERCULES aims to enroll 1,290 adults with non-active SPMS, or without relapses in the last two years, while PERSEUS will involve about 990 adults with primary progressive MS. The primary goal of both trials is to assess the proportion of patients who experience worsening disability, as measured with the Expanded Disability Status Scale, that is sustained for at least six months — a measure called six-month confirmed disability progression.

The Phase 3 clinical program of tolebrutinib for MS has been enrolling participants since 2019. More than 2,000 patients are currently on tolebrutinib, with some patients treated for up to three years, Sanofi said in the release.

The fifth trial that will also be affected by the clinical hold is a Phase 3 study (NCT05132569), dubbed URSA, which is evaluating tolebrutinib in adults with generalized myasthenia gravis.

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