Background

Venglustat is a brain-penetrant allosteric inhibitor of the enzyme glucosylceramide synthase. GCS catalyzes an early step in the synthesis of many glycolipids. Venglustat is being developed for lysosomal storage diseases, including Gaucher’s, Fabry, and for Parkinson’s caused by mutations in the GBA1 gene. In all these diseases, failure to degrade the glycolipid glucosylceramide leads to its accumulation, resulting in lysosomal dysfunction and organ damage. Venglustat and other GCS inhibitors reduce accumulation of glucosylceramide by preventing its synthesis.

Mutations in GBA1, which encodes the lysosomal glucocerebrosidase (GCase) enzyme, are the leading genetic risk factor for Parkinson’s disease and for dementia with Lewy bodies, two synucleinopathies. Insufficient GBA1 function causes a buildup of both α-synuclein and glucosylceramide (Jun 2011 news; Jul 2011 news). Some work suggests glucosylceramide promotes α-synuclein oligomerization (Mazzulli et al., 2011; Zunke et al., 2017).

In a cell model of GCase deficiency, the GCS inhibitor miglustat reduced glucosylceramide, slowed the conversion of physiological α-synuclein tetramers into toxic conformations, and protected against α-synuclein fibril-induced toxicity (Kim et al., 2018). 

No preclinical work is published on venglustat. Sanofi has presented and published results with the related compound GZ667161 (Sardi et al., 2017; Dec 2016 conference news). In a Gaucher disease model, mice carrying a homozygous GBA D409V mutation were fed the inhibitor from 1 month to 10 months of age, or from 6 to 13 months. GZ667161 treatment reduced brain glucosylceramide levels, as well as accumulation of hippocampal α-synuclein and tau deposits. Treatment reportedly improved memory deficits. In a model of α-synuclein toxicity, treatment of mice overexpressing the A53T mutant from age 1.5 to 8 months reduced glucosylceramide levels, hippocampal membrane-associated α-synuclein and tau deposits, and improved cognition. 

Two other GCS inhibitors—miglustat and eliglustat—are FDA-approved for treating Gaucher disease. Both drugs are said to poorly penetrate the brain. GZ667161 was selected for its ability to cross the blood-brain barrier in preclinical models (Cabrera-Salazar et al., 2012).

Findings

Two Phase 1 safety, tolerability, and pharmacokinetics studies in 99 healthy volunteers were conducted in 2012 and 2013 under the drug name Genz-682452. Results are published (Peterschmitt et al., 2021).

In December 2016, Sanofi began MOVES-PD, a global Phase 2 trial to evaluate safety and efficacy of venglustat in PD patients who are heterozygous for a GBA1 mutation. In the initial, safety phase of the trial, 13 patients took one of three doses daily for up to 36 weeks; four took placebo capsules. Their mean age was 58, mean disease duration, seven years. At the 2019 WORLD Symposium on lysosomal diseases, investigators reported that venglustat caused no serious adverse events or deaths. Side effects were mild or moderate and disappeared on their own, though two participants on drug dropped out due to side effects. Drug levels in plasma and CSF increased in dose-dependently; plasma and CSF glucosylceramide levels declined by up to 75 percent, also dose-dependently (Peterschmitt et al., 2019).

The second part of MOVES-PD randomized 221 participants to a one-year regimen of once-daily drug or placebo, plus two years of follow-up. The primary outcome was change from baseline to one year on the Unified Parkinson's Disease Rating Scale Part II and III; secondary outcomes were change in the PD Cognitive Rating Scale, UPRDS all parts, and Hoehn and Yahr score. The treatment phase finished in December 2020. On February 5, 2021, the company told investors that the trial had missed its primary endpoint, and development was stopped for PD (press release). According to results presented at the March 2021 AD/PD conference, the primary endpoint of the MDS-UPDRS Part II and III worsened more with venglustat than placebo. A similar trend was seen for the MDS-UPRDS total score. There was no improvement, and possible worsening, in the cognitive rating scale. Target engagement was deemed successful: glucosylceramide GL-1 levels decreased about 75 percent in plasma and CSF within two weeks of starting dosing, and stayed in normal limits during the study.

Venglustat continues in Phase 2 for Gaucher, Fabry, Tay-Sachs and Sandhoff diseases, and in Phase 3 for cystic kidney disease.

In 2015, the FDA fast-tracked this drug for Fabry disease.

For details on venglustat trials, see clinicaltrials.gov.