Venglustat in GBA1-related Parkinson's disease

We read with interest the long-awaited report by Nir Giladi and colleagues of the phase 2 clinical trial of venglustat for GBA1-related Parkinson's disease (MOVES-PD).1Giladi N Alcalay RN Cutter G et al.Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.Lancet Neurol. 2023; 22: 661-671Summary Full Text Full Text PDF PubMed Google Scholar 221 adults participated in this trial; many more were listed to take part in a multinational, multicentre, phase 3 clinical trial when the decision was made, in January 2021, to stop the development programme for venglustat for this indication, due to a lack of beneficial treatment effect compared with placebo. The venglustat group showed a greater deterioration in Unified Parkinson's Disease Rating Scale part II and III scores compared with the placebo group, and they had more psychiatric and gastrointestinal adverse events compared with placebo. We think that the arguments in the discussion of the Article could have been more compelling about the reasons for the lack of treatment effect and for the safety issues. The authors could have considered the underlying mechanisms of GBA1-related Parkinson's disease in the context of their data, and perhaps acknowledge that their hypothesis was probably wrong. Instead of GBA1 loss-of-function (relating to the reduced glucocerebrosidase activity and the consequence of glucosylceramide accumulation as the underlying mechanism for GBA1-related Parkinson's disease), they should have mentioned the alternative gain-of function mechanism—ie, the abnormal variant of the GBA1 gene creates a misfolded protein that does not hydrolyse the substrate glucosylceramide and that acquires deleterious characteristics, leading to endoplasmic reticulum stress, inflammation, α-synuclein aggregation in dopaminergic neurons, and eventually to cell death.2Sidransky E Arkadir D Bauer P et al.Substrate reduction therapy for GBA1-associated Parkinsonism: are we betting on the wrong mouse?.Mov Disord. 2020; 35: 228-230Crossref PubMed Scopus (9) Google Scholar, 3Horowitz M Braunstein H Zimran A Revel-Vilk S Goker-Alpan O Lysosomal functions and dysfunctions: molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease.Adv Drug Deliv Rev. 2022; 187114402 Crossref PubMed Scopus (15) Google Scholar Accordingly, an appropriate conclusion should have mentioned the greater potential of pharmacological chaperones to benefit individuals with GBA1-related Parkinson's disease, and to support other ongoing pharmacological studies.4Mullin S Smith L Lee K et al.Ambroxol for the treatment of patients with Parkinson disease with and without glucocerebrosidase gene mutations: a nonrandomized, noncontrolled trial.JAMA Neurol. 2020; 77: 427-434Crossref PubMed Scopus (187) Google Scholar AZ declares grant support paid to their institution from Takeda, Sanofi, Pfizer, and Centogene; consulting fees from Takeda, Prevail Therapeutics, BioEvents, Pfizer, AVROBIO, MLC Pharma, and Insighteq; and speaking fees and travel costs from Takeda, BioEvents, and Pfizer. AZ has stock or stock options in Protalix and Agyany Pharmaceuticals. SR-V declares grant support paid to their institution from Takeda, Sanofi, Pfizer, and Centogene; consulting fees, speaking fees, and travel costs from Takeda, Pfizer, and Sanofi; and is a member of the Prevail Therapeutics advisory board. MB-C declares grant support paid to their institution from Takeda, Sanofi, Pfizer, and Centogene; and travel costs from Takeda and BioEvents. MI declares grant support paid to their institution from Takeda, Sanofi, Pfizer, and Centogene; speaking fees from Takeda and Pfizer; and travel costs paid to their institution from Takeda, BioEvents, Pfizer, and Sanofi. AR declares no competing interests. Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trialIn people with GBA1-associated Parkinson's disease in our study, venglustat had a satisfactory safety profile but showed no beneficial treatment effect compared with placebo. These findings indicate that glucosylceramide synthase inhibition with venglustat might not be a viable therapeutic approach for GBA1-associated Parkinson's disease. Full-Text PDF Venglustat in GBA1-related Parkinson's disease – Authors' replyWe thank Ari Zimran and colleagues for their interest in the MOVES-PD trial. The aim of the trial was to show whether lowering glucosylceramide using the CNS-penetrant glucosylceramide synthase inhibitor venglustat was beneficial in GBA1-associated Parkinson's disease.1 No beneficial treatment effect of venglustat was shown compared with placebo and, therefore, the hypothesis was refuted. It is important to remind the reader that, although the trend in treatment effects favoured the placebo group, the differences were not statistically significant. Full-Text PDF