Sanofi posts a win for venglustat in Gaucher study, but a miss in Fabry disease

Sanofi announced Monday mixed results from a pair of pivotal studies of venglustat in two rare lysosomal storage disorders, with the oral glucosylceramide synthase inhibitor (GCSi) recording a hit in type 3 Gaucher disease (GD3) and a miss in Fabry disease. 

The contrasting outcomes are the latest to emerge from the company's late-stage pipeline, following mixed readouts reported last month for its investigational OX40-ligand-blocking mAb amlitelimab in two atopic dermatitis trials.

The Phase III LEAP2MONO study randomised 43 adult and paediatric patients with neurological manifestations of GD3 to receive venglustat once-daily or enzyme replacement therapy (ERT). The trial's primary endpoints were change in Scale for Assessment and Rating of Ataxia (SARA) modified total score and change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total scale index score, with key secondary goals including percent change in spleen volume, liver volume and platelet count, as well as change in haemoglobin levels.

According to results, venglustat demonstrated statistically significant improvements in neurological symptoms as measured by both SARA and RBANS at week 52 compared to ERT. Sanofi added that the therapy also achieved three out of four key secondary endpoints, performing as well as ERT on non-neurological outcomes, including changes in spleen volume, liver volume and haemoglobin levels.

Regulatory filings in GD3

"What excites us most is the potential to address critical unmet medical needs. A daily pill could make a serious difference for Gaucher patients facing neurological challenges," said Houman Ashrafian, head of R&D at Sanofi. The company indicated that based on the results, it will pursue global regulatory filings for venglustat in GD3.

Sanofi currently markets the injectable therapy Cerezyme (imiglucerase) for Gaucher disease, as well as the oral drug Cerdelga (eliglustat) for those with type 1 disease. 

The drugmaker's portfolio also includes the injectable therapy Fabrazyme (agalsidase beta) for Fabry disease. However, the second Phase III study reported Monday is likely to dent Sanofi's hopes of adding an oral Fabry disease therapy to its arsenal.

Fabry setback

The PERIDOT study randomised 122 patients aged 16 years and older with Fabry disease to receive venglustat or placebo. Sanofi noted that the trial failed to hit its primary endpoint of percent change from baseline on patient-defined most bothersome symptoms, as assessed by the Fabry Disease Patient-Reported Outcome (FD-PRO) instrument.

According to the company, reductions in neuropathic and abdominal pain were observed in both study arms. Additional analyses of the PERIDOT data are ongoing, while the late-stage CARAT trial evaluating the effect of venglustat on left cardiac ventricular mass index in men and women with Fabry disease is also underway.

Findings from both LEAP2MONO and PERIDOT are scheduled to be presented this week at the annual WORLDSymposium.

Aside from the positive results in GD3, venglustat, which works by reducing the abnormal accumulation of sugar-and-fat molecules in cells and organs, has racked up a number of study failures. In 2024, Sanofi disclosed that the Phase III AMETHIST trial for GM2 gangliosidosis was discontinued based on an "absence of positive trends" for clinical endpoints, adding to a pivotal Phase II/III study setback in autosomal dominant polycystic kidney disease and another in Parkinson's disease with GBA mutations.