Sanofi has reported mixed Phase III clinical trial outcomes for venglustat, an oral glucosylceramide synthase inhibitor being studied for rare lysosomal storage disorders. The drug met key objectives in a late-stage trial involving patients with Gaucher disease who have neurological manifestations, while failing to achieve its primary endpoint in a separate Phase III study in Fabry disease.
In Gaucher disease, Sanofi evaluated venglustat in the Phase III LEAP2MONO trial, which enrolled 43 patients with type 3 Gaucher disease. The study compared venglustat with enzyme replacement therapy (ERT), the current standard of care. According to the company, patients receiving venglustat showed statistically significant improvements in neurological symptoms at week 52. These changes were measured using scales for ataxia and neuropsychological status. The difference between the venglustat group and the ERT group reached statistical significance, with a reported p-value of 0.007.
Beyond neurological outcomes, the LEAP2MONO trial also assessed several non-neurological secondary endpoints. These included changes in spleen volume, liver volume, and hemoglobin levels. Sanofi stated that venglustat performed comparably to ERT across these measures. Based on the results from this study, the company said it plans to submit venglustat for regulatory review for Gaucher disease.
Gaucher disease is a rare inherited lysosomal disorder that results in the accumulation of fatty substances in tissues. Sanofi already markets treatments for the disease, including the ERT Cerezyme and the oral glucosylceramide synthase inhibitor Cerdelga.
In contrast, results were less favorable in Fabry disease. Sanofi reported that the Phase III PERIDOT trial, which included 122 patients, did not meet its primary endpoint. The study aimed to demonstrate superiority over placebo in reducing patient-reported neuropathic pain in the upper and lower extremities, as well as abdominal pain. While the trial did not achieve this goal, Sanofi noted that reductions in both neuropathic and abdominal pain markers were observed in participants across both the treatment and placebo arms.
Sanofi attributed the missed endpoint to improvements seen in both groups and said it is continuing to analyze the data. The company has not outlined specific regulatory plans for Fabry disease based on the PERIDOT results. However, it is continuing a separate Phase III study of venglustat in Fabry disease that is examining effects on left cardiac ventricular mass index in both male and female patients.
Across the studies, venglustat was described as well-tolerated. The most frequently reported adverse events included headache, nausea, spleen enlargement, and diarrhea, with headache reported more often among patients receiving ERT.
Venglustat has previously received fast-track designation from the U.S. Food and Drug Administration for both Gaucher and Fabry diseases. Its development history includes several discontinued programs. Sanofi ended a Phase II study in GM2 gangliosidosis in 2024 following a lack of positive clinical trends, and earlier halted midstage trials in kidney disease.
Commenting on the latest results, Sanofi’s head of research and development, Houman Ashrafian, said, “These findings underscore Sanofi’s commitment to rare disease research and the promise we aim to deliver for people living with these conditions.”
Venglustat Success in Type 3 Gaucher Disease
Sanofi recently released Phase III data for its investigational therapy across two rare lysosomal storage disorders, revealing contrasting outcomes. In the Gaucher disease type 3 study, patients experienced meaningful improvements in neurological function and related clinical measures, positioning the therapy as a potential new option for this underserved population.
Conversely, in the Fabry disease trial, the therapy did not meet the primary endpoint of symptom reduction. While certain secondary outcomes showed modest improvement, the results fell short of expectations, underscoring the complexity of designing effective treatments for rare genetic disorders.
These mixed results reflect both the potential and challenges inherent in rare disease drug development. The company plans to focus on regulatory discussions for Gaucher disease while continuing to explore strategies and additional studies in Fabry disease to better understand the therapy’s impact and optimize future trials.
