Synonyms: Ibiglustat, GZ/SAR402671, Genz-682452
Therapy Type: Small Molecule (timeline)
Target Type: alpha-synuclein, Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Inactive)
Company: Genzyme, Sanofi
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).
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 the 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 270 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, with trial completion in early 2023. On February 5, 2021, the company told investors that the trial had missed its primary endpoint, and development was stopped for PD (press release).
Venglustat continues in Phase 2 for Gaucher and Fabry 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.
Last Updated: 25 Feb 2021
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Research Models Citations
- Peterschmitt MJ, Crawford NP, Gaemers SJ, Ji AJ, Sharma J, Pham TT. Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers. Clin Pharmacol Drug Dev. 2021 Jan;10(1):86-98. Epub 2020 Aug 26 PubMed.
- Peterschmitt MJ, Gasser T, Isaacson S, Kulisevsky J, Mir P, Simuni T, Wills AM, Guedes LC, Svenningsson P P, Waters C, Ji AJ, Li J, Minini P, Nembo B, Saubadu S, Sharma J, Fischer T. Safety, tolerability and pharmacokinetics of oral venglustat in Parkinson disease patients with a GBA mutation. Science Direct February 2019
- Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. Epub 2011 Jun 23 PubMed.
- Zunke F, Moise AC, Belur NR, Gelyana E, Stojkovska I, Dzaferbegovic H, Toker NJ, Jeon S, Fredriksen K, Mazzulli JR. Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron. 2017 Dec 20; PubMed.
- Kim S, Yun SP, Lee S, Umanah GE, Bandaru VV, Yin X, Rhee P, Karuppagounder SS, Kwon SH, Lee H, Mao X, Kim D, Pandey A, Lee G, Dawson VL, Dawson TM, Ko HS. GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers. Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):798-803. Epub 2018 Jan 8 PubMed.
- Sardi SP, Viel C, Clarke J, Treleaven CM, Richards AM, Park H, Olszewski MA, Dodge JC, Marshall J, Makino E, Wang B, Sidman RL, Cheng SH, Shihabuddin LS. Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2699-2704. Epub 2017 Feb 21 PubMed.
- Cabrera-Salazar MA, Deriso M, Bercury SD, Li L, Lydon JT, Weber W, Pande N, Cromwell MA, Copeland D, Leonard J, Cheng SH, Scheule RK. Systemic delivery of a glucosylceramide synthase inhibitor reduces CNS substrates and increases lifespan in a mouse model of type 2 Gaucher disease. PLoS One. 2012;7(8):e43310. Epub 2012 Aug 17 PubMed.
- Schneider SA, Alcalay RN. Precision medicine in Parkinson's disease: emerging treatments for genetic Parkinson's disease. J Neurol. 2020 Mar;267(3):860-869. Epub 2020 Jan 23 PubMed.
- Sardi SP, Simuni T. New Era in disease modification in Parkinson's disease: Review of genetically targeted therapeutics. Parkinsonism Relat Disord. 2019 Feb;59:32-38. Epub 2018 Oct 23 PubMed.