Sanofi announced positive topline results from the global Phase III LEAP2MONO study evaluating its investigational oral glucosylceramide synthase inhibitor venglustat in patients with type 3 Gaucher disease (GD3), with the trial meeting its primary neurological endpoint versus enzyme replacement therapy. The data contrast with the also announced Phase III failure of the same asset in Fabry disease, underscoring both the potential and the limits of substrate reduction approaches across related lysosomal storage disorders.

Trial specifics

The LEAP2MONO trial was a randomized, double-blind, double-dummy Phase III study enrolling adolescents and adults aged 12 years and older with GD3 who were previously stable on enzyme replacement therapy (ERT). Patients were randomized 1:1 to receive once-daily oral venglustat with placebo infusions or continued ERT with oral placebo over a 52-week double-blind period.

The study evaluated two co-primary endpoints assessing neurological outcomes: change from baseline in the modified total score of the Scale for Assessment and Rating of Ataxia and change in cognitive performance using the Repeatable Battery for the Assessment of Neuropsychological Status. Sanofi reported a statistically significant improvement on the combined neurological endpoint for venglustat compared with ERT. Secondary systemic endpoints, including spleen and liver volume, hemoglobin levels, and platelet counts, were reported to be comparable between treatment arms. Venglustat was generally well tolerated, with no new safety signals.

In contrast, Sanofi also confirmed that PERIDOT, a Phase III study of venglustat in Fabry disease, failed to meet its primary patient-reported endpoint. While the company said further analyses are ongoing and a separate Phase III Fabry study (CARAT) remains ongoing, the mixed outcomes complicate the broader clinical positioning of the program.

Research context

Venglustat inhibits glucosylceramide synthase, reducing the production of glycosphingolipids that accumulate in lysosomal storage disorders. Unlike enzyme replacement therapies, the small-molecule approach is designed to cross the blood-brain barrier, making it particularly relevant for neuronopathic conditions such as GD3, where neurological symptoms drive long-term disability.

The divergent Phase III outcomes across GD3 and Fabry disease highlight biological and clinical differences between the disorders, despite shared metabolic pathways. In Fabry disease, where vascular, renal, and cardiac manifestations dominate, neurological benefit may be harder to demonstrate using patient-reported measures over limited trial durations.

Venglustat has received orphan drug designation in the US, EU, and Japan for GD3 and Fabry disease, as well as US FDA Fast Track designation. The asset remains unapproved globally. Sanofi said it plans to pursue regulatory discussions for venglustat in GD3 based on the LEAP2MONO dataset, while reassessing the Fabry strategy as additional data mature.