Sanofi Admits Defeat for Myasthenia Gravis Candidate, Drops Phase III Trial

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Sanofi is discontinuing its Phase III study of tolebrutinib, an investigational BTK inhibitor for myasthenia gravis (MG), the company announced Friday in its full-year 2022 financial report.

According to the French biopharma, the decision to drop its MG program was driven by the “emerging competitive landscape” in this therapeutic space.

Sanofi gained access to tolebrutinib in 2017 when it put up to $765 million on the line to license tolebrutinib from Principia Biopharma. At the time, tolebrutinib was being developed primarily as a drug for multiple sclerosis (MS). Sanofi later bought Principia for $3.68 billion in August 2020.

Tolebrutinib is an oral small molecule inhibitor of the BTK enzyme, a crucial component in the development pathway of the antibody-producing B-cells. Disabling this protein’s function can potentially reduce the excessive activation of B-cells, which are known to play a role in autoimmune conditions such as MG and MS.

This mechanism of action gave tolebrutinib its promising early-stage performance. In 2018, early results from a Phase I study showed that the candidate was safe and well-tolerated and could cross the blood-brain barrier and reach therapeutic concentrations in the cerebrospinal fluid.

Given these findings, Sanofi saw the potential of tolebrutinib as a treatment for MS and other conditions of the central nervous system.

Later-stage trials, however, would not bear this out. Launched in late 2021, URSA was a randomized, double-blinded, placebo-controlled trial of tolebrutinib in more than 150 patients with moderate-to-severe generalized MG treated with standard of care.

In June 2022, the FDA placed tolebrutinib on a partial clinical old, both in MS and MG, following cases of drug-induced liver injury. Though it has scrapped the MG trial, Sanofi will continue to evaluate to ibrutinib in relapsing, primary progressive and secondary progressive MS.

A Race to the Finish

Sanofi’s decision to drop its tolebrutinib MG program was primarily driven by a therapeutic space crowded with solid competition.

In October 2017, the FDA expanded the indication of Alexion’s blockbuster drug Soliris (eculizumab) to include generalized MG in adults positive for anti-acetylcholine receptor antibodies. Last year, the AstraZeneca subsidiary reinforced its leadership in the MG space with a regulatory nod for Ultomiris (ravulizumab-cwvz).

Joining Alexion/AstraZeneca is Netherlands-based argenx withVyvgart (efgartigimod alfa-fcab), which won FDA approval for generalized MG in December 2021.

Other treatment options include cholinesterase inhibitors, corticosteroids and immunosuppressants.