Venglustat (DB14966): A Comprehensive Analysis of a Glucosylceramide Synthase Inhibitor from Broad Ambition to Niche Application

Executive Summary

Venglustat, also known by its International Nonproprietary Name (INN) Ibiglustat and developmental codes such as Genz-682452 and SAR402671, is an orally bioavailable, brain-penetrant small molecule inhibitor of the enzyme glucosylceramide synthase (GCS).[1] Developed initially by Genzyme and later by Sanofi, Venglustat operates via the mechanism of Substrate Reduction Therapy (SRT). By inhibiting GCS, the first committed enzyme in the biosynthesis of most glycosphingolipids (GSLs), the drug is designed to decrease the production of glucosylceramide (GL-1) and its downstream derivatives.[4] This approach aims to rebalance the synthesis of GSLs with the impaired capacity of cells to degrade them in various lysosomal storage disorders (LSDs).

The drug's potent mechanism and favorable pharmacokinetic profile, including its ability to cross the blood-brain barrier, led Sanofi to position it as a "pipeline in a pill," with a broad development strategy targeting not only rare LSDs but also more prevalent conditions.[7] This ambitious program included pivotal trials in Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Parkinson's disease associated with mutations in the glucocerebrosidase (

GBA) gene (GBA-PD). However, these large-scale programs were terminated due to a lack of clinical efficacy. A critical finding from these studies was a definitive disconnect between successful biomarker engagement—the drug effectively reduced GSL levels—and the desired clinical outcomes, providing strong evidence that the GSL pathway is not the primary driver of pathology in these complex diseases.[7]