Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND

Variants in the GBA1 gene, which encodes lysosomal acid glucocerebrosidase, are among the most common genetic risk factors for Parkinson's disease and are associated with faster disease progression. The mechanisms involved are unresolved but might include accumulation of glucosylceramide. Venglustat is a brain-penetrant glucosylceramide synthase inhibitor that, in previous studies, reduced amounts of the glycosphingolipid. We aimed to assess the safety, efficacy, and target engagement of venglustat in people with early-stage Parkinson's disease carrying pathogenic GBA1 variants.

METHODS

MOVES-PD part 2 was a randomised, double-blinded, placebo-controlled phase 2 study done at 52 centres (academic sites, specialty clinics, and general neurology centres) in 16 countries. Eligible adults aged 18-80 years with Parkinson's disease (Hoehn and Yahr stage ≤2) and one or more GBA1 variants were randomly assigned using an interactive voice-response system (1:1) to 52 weeks of treatment with oral venglustat (15 mg/day) or matching placebo. Investigators, site personnel, participants, and their caregivers were masked to treatment allocation. The primary outcome measure was the change from baseline to 52 weeks in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III combined score (a higher score indicates greater impairment), and it was analysed in a modified intention-to-treat population (ie, all randomly assigned participants with a baseline and at least one post-baseline measurement during the treatment period). This study was registered with ClinicalTrials.gov (NCT02906020) and is closed to recruitment.

FINDINGS

Between Dec 15, 2016, and May 27, 2021, 221 participants were randomly assigned to venglustat (n=110) or placebo (n=111). The least squares mean change in MDS-UPDRS parts II and III combined score was 7·29 (SE 1·36) for venglustat (n=96) and 4·71 (SE 1·27) for placebo (n=105); the absolute difference between groups was 2·58 (95% CI -1·10 to 6·27; p=0·17). The most common treatment-emergent adverse events (TEAEs) were constipation and nausea (both were reported by 23 [21%] of 110 participants in the venglustat group and eight [7%] of 111 participants in the placebo group). Serious TEAEs were reported for 12 (11%) participants in each group. There was one death in the venglustat group owing to an unrelated cardiopulmonary arrest and there were no deaths in the placebo group.

INTERPRETATION

In 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.

FUNDING

Sanofi.

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests AHVS declares research support from the UK Medical Research Council, Michael J Fox Foundation (MJFF), Aligning Science Across Parkinson's, and Cure Parkinson's; consulting fees from AvroBio, Auxilius, Coave, Destin, Enterin, Escape Bio, Genilac, and Sanofi; and speaking fees from the Prada Foundation. CRS declares research support from American Parkinson's Disease Foundation, MJFF, US National Institutes of Health (NIH), and US Department of Defense; consulting fees from Sanofi; a patent pending for sphingolipid biomarkers with Brigham and Women's Hospital and Sanofi; scientific advisory board participation for American Parkinson's Disease Foundation; other financial interests from Lysosomal Therapies, MJFF, NIH, Opko, Pfizer, Proteome Sciences, Sanofi, and US Department of Defense; and non-financial interests from Google. GC is an employee of Pythagoras; and declares compensation for consulting and advisory board participation from Alexion, Antisense Therapeutics, Biodelivery Sciences International, Biogen, Clinical Trial Solutions, Genentech, GW Pharmaceuticals, Immunic, Klein Buendel, MedImmune–Viela Bio, MedDay, Merck Serono, NeuroGenesis, Osmotica Pharmaceuticals, Perception Neurosciences, Reckover Pharmaceuticals, Recursion-CereXis Pharmaceuticals, Regeneron, Roche, SAb Biotherapeutics, Sanofi, and TG Therapeutics; data safety monitoring board participation for AI Therapeutics, AMO Pharmaceuticals, Applied Therapeutics, AstraZeneca, AveXis Pharmaceuticals, BioLineRx, BrainStorm Cell Therapeutics, Bristol Myers Squibb-Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Mapi Pharma, Merck–Pfizer, Mitsubishi Tanabe Pharma, Neurim, Novartis, Ophazyme, Opko Biologics, Reata Pharmaceuticals, Sanofi, Teva Pharmaceuticals, and VielaBio; and protocol review committee participation for the US National Heart, Lung, and Blood Institute. GUH declares compensation for consulting and advisory board participation from AbbVie, Alzprotect, Asceneuron, Biogen, Biohaven, Lundbeck, Novartis, Retrotope, Roche, Sanofi, UCB, and Weston Brain Institute; speaker honoraria from AbbVie, Biogen, Roche, Teva, UCB, and Zambon; data safety monitoring or advisory board participation for Alzprotect and Kainos Medicine; and is a patent holder for treatment of synucleinopathies (US patent number US 10,918,628 B2: EP 17 787 904.6–1109). KM declares consulting fees from Calico, Coave Therapeutics, Invicro, Lundbeck, Lysosomal Therapeutics, MJFF, NeuroDerm, Neuron23, OrbiMed, Roche, Takeda, and UBC. MJP, PM, and SPS are employees of Sanofi and might hold shares, stock options, or both, in the company. NG declares research support from Biogen, EU, Ionis, Israel Science Foundation, MJFF, and US National Parkinson Foundation; consulting fees from AbbVie, Biogen, BOL, Denali Therapeutics, NeuroDerm, Sanofi, and Sionara; speaker honoraria from AbbVie, Movement Disorders Society, and Sanofi; advisory board participation for Biogen, Denali Therapeutics, NeuroDerm, Sanofi, and Sionara; and stock ownership for BOL Pharma, GaitBetter, Lysosomal Therapeutics, and Vibrant. RNA declares research support from NIH, MJFF, Parkinson's Foundation, and US Department of Defense; and consulting fees from AVROBIO, Caraway, Gain Therapeutics, GlaxoSmithKline, Janssen, Merck, Ono Therapeutics, Sanofi, and Takeda. TGa declares research support from the EU, German Research Foundation, German Federal Ministry of Education and Research, Helmholtz Association, and MJFF; speaker honoraria from Bayer, BlueRock Therapeutics, and Coave Therapeutics; compensation for consulting and advisory board participation for MedUpdate, Novartis, Teva, and UCB; and advisory board participation for the EU. TGu declares grants from International Movement Disorders Society; consulting fees from AbbVie, NeuroDerm, Medison, Teva, and TrueMed; honoraria from AbbVie, Medison, and Teva; travel support from AbbVie, Boston Scientific, Medison, and Medtronic; unpaid advisory role or membership for Ezra Le’Marpeh Parkinson's rehabilitation programme, Israeli Huntington Disease Association, Israeli Movement Disorders Society, and Tikvah for Parkinson; stock options for Cytora; previous medical writing assistance from AbbVie and Teva; and planned patents for automated speech analysis and vocal Parkinson's disease biomarkers. TS declares research support from Biogen, MJFF, NeuroDerm, US National Institute of Neurological Disorders and Stroke, Parkinson's Foundation, and Roche; and consulting fees from Acadia, Anavex, Allergan, NeroDerm, MJFF, PhotoPharmics, Revance, Sanofi, Sunovion, Voyager, and US WorldMeds. CP declares no competing interests.