November date set for FDA decision on Sanofi's Gaucher drug

The FDA has started a priority review of Sanofi's Gaucher disease therapy venglustat, a potentially first-in-class therapy, with an action date of 25th November.

If approved, venglustat – an oral, brain-penetrating glucosylceramide synthase (GCS) inhibitor – would be the first treatment in the US specifically to treat patients with neurological complications associated with type 3 Gaucher disease (G3D).

Gaucher is a type of lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase, which leads to a 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.

Type 1 is the most common in the US and Europe, affecting organs like the liver, spleen, and bone without CNS involvement, and patients typically have a near-normal life expectancy with treatment. Type 2 is a highly rare form that strikes in infancy, has devastating consequences on the brain, and is generally fatal by around age two.

G3D is less common, but the most common form globally, and affects both peripheral organs and the CNS. Since glucocerebrosidase enzyme replacement therapy (ERT) became available, patients can now expect to have near-normal life spans, even though these drugs are not able to cross the blood-brain barrier into the CNS.

In the pivotal LEAP2MONO trial, venglustat – a small-molecule drug which has been specifically designed to cross into the CNS and reduce the production of harmful metabolites before they accumulate – achieved statistically significant improvements in neurological symptoms over 52 weeks, measured using the SARA and RBANS scales, compared to standard infusions of ERT. It also performed as well as ERT on non-CNS symptoms of G3D, including spleen and liver volume and haemoglobin levels.

Venglustat has had a checkered history in R&D, with failed trials in autosomal dominant polycystic kidney disease (ADPKD), GM2 gangliosidosis, Parkinson's disease, and Fabry disease, but now looks to have finally found its indication.

The serial disappointments have, however, undermined Sanofi's once-held view that the drug could be a 'pipeline-in-a-pill' with multiple indications that could collectively deliver blockbuster sales, and sales expectations are now expected to be relatively modest in G3D alone.

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 the ERT Cerezyme (imiglucerase) for Gaucher as well as Cerdelga (eliglustat), an oral therapy used as a first-line therapy for certain patients with type 1 disease.