Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients With Parkinson's Disease and a GBA Mutation: Results From Part 1 of the Randomised, Double-Blinded, Placebo-Controlled MOVES-PD Trial

Background: Glucocerebrosidase gene (GBA) mutations influence the risk and prognosis of Parkinson’s disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat, a glucosylceramide synthase inhibitor, is investigated in patients with PD and GBA mutations. Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) is a randomised, double-blinded, placebo-controlled, dose-escalation study performed at 13 sites in six countries. Eligible participants were 18–80 years old and had PD diagnosis and heterozygous GBA mutation. Per regulatory agency request, Japanese participants were evaluated separately from those outside Japan. Participants were randomised to three doses of once-daily orally administered venglustat or placebo by an interactive voice-response system, in a sequential cohort design, and were followed up to 36 weeks (52 weeks for Japanese participants). The primary endpoint was safety and tolerability of venglustat versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics. Findings: Between Jan 26, 2017, and Oct 17, 2018, 29 participants were randomised to venglustat (Japanese, n=9; non-Japanese, n=13) or placebo (n=3; n=4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate, and no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72·0% in Japanese and 74·3% in non-Japanese participants. Interpretation: Venglustat showed favourable safety and tolerability in MOVES-PD Part 1 and its target engagement was achieved in the CSF. Part 2 will assess the efficacy of venglustat at the dose selected in Part 1. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT02906020. Funding Statement: Supported by Sanofi. Declaration of Interests: MJP, SJMG, PM, SS, JS, SW, and SPS report receiving personal compensation as employees of Sanofi. HS reports receiving grant support from Boehringer Japan, Dainippon Sumitomo, Kyowa Hakko-Kirin, and Otsuka, and honoraria from Dainippon Sumitomo, Kyowa Hakko-Kirin, Medtronic, Novartis Pharma KK, Otsuka FP, and Takeda. TH reports receiving speaker’s honoraria and research funding from Dainippon Sumitomo, Eisai Co, Ltd, Kyowa Hakko-Kirin, Novartis Pharma KK, Otsuka, Sanofi, and Takeda, and grant support from Dainippon Sumitomo, Eisai Co, Ltd, the Setsuro Fujii Memorial, the Osaka Foundation for Promotion of Fundamental Medical Research, and the Japan Agency for Medical Research and Development under grant number 19dm0107156, the Setsuro Fujii Memorial. TG reports receiving speaker’s honoraria from MedUpdate, Novartis, Teva, and UCB Pharma, and grant support from the German Research Foundation, the German Federal Ministry of Education and Research, the European Commission, the Helmholtz Association, and the Michael J Fox Foundation; he also serves as chairman of the Scientific Advisory Board of the “Joint Programming for Neurodegenerative Diseases” program, funded by the European Commission. SHI has received honoraria for CME services, consulting, research grants, and/or promotional speaking on behalf of AbbVie, Acadia, Acorda, Adamas, Addex, Affiris, Alexva, Allergan, Amarantus, Amneal, Aptinyx, Axial, Axovant, Benevolent, Biogen, Britannia, Cadent, Cala, Cerecor, Cerevel, Cipla, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Impel, Intec Pharma, Ipsen, Jazz, Kyowa, Lundbeck, Merz, the Michael J Fox Foundation, Mitsubishi Tanabe, Neuralys, Neurocrine, Neuroderm, Parkinson Study Group, Pharma2B Prilenia, Promentis, Revance, Roche, Sanofi, Sunovion, Sun Pharma, Teva, Theravance, UCB, US WorldMeds and Zambon. RNA reports research support from the NIH, the Department of Defense, the Parkinson’s Foundation, and the Michael J Fox Foundation, and receives consultation fees from Janssen, Restorbio, Roche, and Sanofi. GC reports participating on Data and Safety Monitoring Boards for Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals, Merck, Merck/Pfizer, Neurim, Novartis, Ophazyme, Opko Biologics, Reata Pharmaceuticals, Receptos/Celgene, Sanofi-Aventis, Teva Pharmaceuticals, Vivus, NHLBI(Protocol Review Committee), and NICHD (OPRU oversight committee); reports receiving consulting fees or participating on advisory boards from Biogen, Click Therapeutics, Genentech, Genzyme, Gilgamesh Pharmaceuticals, GW Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, MedDay, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion Pharmaceuticals, Roche, Somahlution, and TG Therapeutics; is employed by the University of Alabama at Birmingham; and is President of Pythagoras, Inc, a private consulting company located in Birmingham, AL, USA. NH reports receiving consulting fees for participating in advisory boards from Dainippon Sumitomo, Eisai, FP, Kyowa Hakko-Kirin, Ono, Otsuka, Tanabe-Mitsubishi, and; grant support from Biogen, Boehringer Japan, Boston Scientific, Eisai, Medtronic, Meiji, Otsuka, and Takeda; and honoraria from Dainippon, FP, Novartis, Otsuka, and Takeda. GUH reports receiving consulting fees or participating on advisory boards from AbbVie, Alzprotect, Asceneuron, Biogen, Biohaven, Lundbeck, Novartis, Retrotope, Roche, Sanofi, UCB, and the Weston Brain Institute, and has received honoraria for scientific presentations from AbbVie, Biogen, Roche, Teva, UCB, and Zambon. KM reports receiving consulting fees from Ceraspir, GE Healthcare, Invicro, LTI, Lundbeck, the Michael J Fox Foundation, Neuroderm, Neuron23, Proclara, Roche, Takeda, and UBC. AHVS reports receiving consulting fees from Inflammazome, Kyowa, Prevail, and Sanofi. CRS is named as co-inventor on a US patent application on sphingolipids biomarkers that is jointly held by Brigham & Women’s Hospital and Sanofi; has consulted for Sanofi; has collaborated with Genzyme, Lysosomal Therapies, Opko, Pfizer, and Proteome Sciences; is on the Scientific Advisory Board of the American Parkinson Disease Association; has served as Advisor to the Michael J Fox Foundation, NIH, Department of Defense, and Google; and has received funding from the NIH, the US Department of Defense, the Michael J Fox Foundation, and the American Parkinson Disease Association. TS reports receiving consulting fees and honoraria from Acadia, Adamas, Teva, and UCB Pharma; consulting fees from AbbVie, Acorda, Anavex, Allergan, NeuroDerm, PhotoPharmics, Revance, Sanofi, Sunovion, Voyager, US WorldMeds, and the Michael J Fox Foundation; and research funding from Biogen, NeuroDerm, Roche, Sanofi, NINDS, the Michael J Fox Foundation, and the Parkinson Foundation. NG reports owning stock from BOL, Lysosomal Therapeutic Ltd and Vibrant; has served as a consultant for AbbVie, Biogen, BOL, Denali, NeuroDerm, Pharma2B, Sanofi Genzyme and Vibrant; has participated in advisory boards for Biogen, Denali, NeuroDerm, Sanofi Genzyme and Sionara; has received honoraria from AbbVie, Sanofi Genzyme and the Movement Disorder Society; and has received grants from Biogen, Ionis, the European Union, the Israel Science Foundation, the Michael J Fox Foundation and the National Parkinson Foundation. TZF received compensation as an employee of Sanofi at the time the study was conducted, and is currently employed by Alnylam Pharmaceuticals (Cambridge, MA, USA). Ethics Approval Statement: This study was conducted in accordance with international ethics guidelines, including the Declaration of Helsinki and the International Council for Harmonisation guidelines for good clinical practice, and all applicable laws, rules, and regulations. All study procedures were approved by local institutional ethics review boards of participating sites, and participants provided written informed consent.