Mixed data mars Sanofi's venglustat programme

Sanofi has reported positive phase 3 results with venglustat in Gauder disease, setting up regulatory filings, but chalked up another failure for the drug in Fabry disease.

In the LEAP2MONO study, the oral, brain-penetrating glucosylceramide synthase (GCS) inhibitor achieved "clinically meaningful" efficacy in patients with type 3 Gaucher (G3D), a lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase, leading to the build-up of toxic metabolites in organs.

In G3D, the accumulation often manifests as central nervous system symptoms, like a lack of muscle coordination (ataxia) and problems with cognition, which have no approved therapies.

Venglustat is designed to reduce the toxic build-up, and the new trial showed that a daily dose of the drug achieved statistically significant improvements in neurological symptoms over 52 weeks, measured using the SARA and RBANS scales, compared to standard infused enzyme replacement therapy (ERT) for Gaucher disease.

The drug also improved non-neurological symptoms, including changes in spleen volume, liver volume, and haemoglobin levels, that can be managed with current ERT options.

Sanofi said it will now press ahead with regulatory filings for venglustat, which has finally found an indication after earlier failures in autosomal dominant polycystic kidney disease (ADPKD), GM2 gangliosidosis, and Parkinson's disease.

That list of negative results has been extended, however, with news of a failed trial in Fabry disease, another lysosomal storage disorder, which further undermines Sanofi's once-held view that venglustat could be a 'pipeline-in-a-pill' candidate with big sales potential across rare and more common conditions.

In the PERIDOT trial, venglustat was associated with a reduction in neuropathic and abdominal pain, but was not differentiated from a placebo control group. Sanofi still has one more shot on goal for venglustat in Fabry with the CARAT study, which is looking at its potential to reduce heart complications in patients and should generate first results later this year.

Sanofi's head of R&D, Houman Ashrafian, said that venglustat's once-daily, oral dosing "could make a serious difference for Gaucher patients facing neurological challenges."

Sanofi is already a big player in rare diseases via its Sanofi Genzyme subsidiary, which was acquired by the group for $20 billion in 2011 and sells a range of enzyme replacement therapies for Gaucher, Fabry and Pompe diseases.

Along with intravenous ERT therapies for Gaucher, like Sanofi's type 1 and 3 treatment Cerezyme (imiglucerase), there are a couple of oral therapies on the market. The company's Cerdelga (eliglustat) was approved in 2014 as a first-line therapy for certain patients with type 1 disease, while Advanz Pharma's Zavesca (miglustat) is an option for type 1 patients ineligible for ERT.