Sanofi’s rare disease drug venglustat has met the primary endpoint in a Phase III trial in Gaucher disease but missed the same achievement in a Phase III trial in Fabry disease.
In the LEAP2MONO trial (NCT05222906), venglustat met the primary and three out of four key secondary endpoints in adults and paediatric patients aged 12 years and older, with neurological manifestations of type 3 Gaucher disease (GD3), a rare lysosomal storage disorder.
Patients receiving venglustat, a once-daily pill, demonstrated statistically significant improvements in neurological symptoms measured by a global test score for two assessments, the Scale for Assessment and Rating of Ataxia (SARA) modified total score and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) after 52 weeks, compared with those receiving enzyme replacement therapy (ERT).
The glucosylceramide synthase inhibitor also performed as well as ERT on non-neurological outcomes, including changes in spleen volume, liver volume, and haemoglobin levels, three key secondary endpoints of the study.
The results will be shared this week at the 22nd annual WORLDSymposium in San Diego as late-breaking research.
Houman Ashrafian, executive VP and head of R&D at Sanofi, said: "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.”
Based on the LEAP2MONO trial, Sanofi will pursue global regulatory filings for venglustat in GD3.
Fabry disease failure
The news was not positive, however, in Fabry disease. Venglustat was being investigated in this X-linked lysosomal storage disorder in the Phase III PERIDOT trial (NCT05206773). The primary endpoint, reduction in neuropathic and abdominal pain, was observed in both study arms, missing the primary endpoint.
Sanofi now hangs its hopes on the Phase III CARAT trial (NCT05280548), evaluating the effect of venglustat on left cardiac ventricular mass index in men and women with Fabry disease. The study is ongoing.
The drug was well tolerated in both the PERIDOT and LEAP2MONO trials with no new safety signals identified. In LEAP2MONO, the most commonly reported adverse events (AEs) were headache, nausea, spleen enlargement and diarrhoea.
The Fabry disease failure is not the first time that Sanofi has seen failures with venglustat. The drug failed to show benefit in a Phase II Parkinson’s disease trial and there was very little difference between the drug and placebo in a pivotal trial in autosomal dominant polycystic kidney disease.
Sanofi hopes to add to already approved drugs
Sanofi already has drugs on the market for both Fabry disease and Gaucher disease. This includes Fabrazyme (agalsidase beta), an ERT for Fabry disease, which gained approval from the US Food and Drug Administration (FDA) in 2003.
Rival ERTs approved by the FDA include Takeda’s Replagal (agalsidase alfa), and Chiesi and Protalix BioTherapeutics’ Elfabrio (pegunigalsidase alfa-iwxj), which are administered via intravenous infusion.
The only approved oral chaperone therapy for specific amenable genetic mutations is Amicus Therapeutics’ Galafold (migalastat). The drug will soon fall into BioMarin Pharmaceutical’s ownership as the company announced an agreement to acquire Amicus Therapeutics in December 2025.
In Gaucher disease, Sanofi has Cerezyme (imiglucerase) and Cerdelga (eliglustat), an ERT and oral therapy, respectively, on markets around the world. In January 2026, the FDA approved an expanded label for Cerezyme to include non-central nervous system (CNS) manifestations of GD3.
Other drugs approved in Gaucher disease include Takeda’s VPRIV (velaglucerase alfa), Protalix BioTherapeutics and Pfizer’s Elelyso (taliglucerase alfa) and Oxford GlycoSciences (OGS) and Actelion Pharmaceuticals’s Zavesca (miglustat).
The Gaucher disease market is expected to reach $1.3bn across the seven major markets (7MM: US, France, Germany, Italy, Spain, UK, and Israel) by 2032, according to a GlobalData report.
GlobalData is the parent company of the Clinical Trials Arena.
