Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in the Japanese and the Rest of the World Parkinson’s Disease Population With a GBA Mutation: Results from Part 1 of the MOVES-PD Study (809)

Objective: Assess safety, pharmacokinetics (PK), and pharmacodynamics of oral venglustat, a glucosylceramide (GL-1) synthase inhibitor, in Parkinson’s disease (PD) patients with a glucocerebrosidase (GBA) mutation from Japan and the rest of the world (ROW). Background: GBA mutations predispose PD patients to cognitive impairment and rapid disease progression at a younger age. Design/Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, placebo-controlled, double-blind, sequential cohort study of venglustat at 3 escalating doses in PD patients ≥18 years with a GBA mutation. Venglustat/placebo was administered for up to 36 weeks in the ROW population and 52 weeks in Japanese patients (evaluated separately per regulatory agency request). Assessments: venglustat safety/tolerability (primary endpoint); plasma and cerebrospinal fluid (CSF) PK and pharmacodynamics. Results: Twenty-nine PD patients were randomized to venglustat (Japan [n=9]; ROW [n=13]) or placebo (Japan [n=3]; ROW [n=4]). Mean age was 54.3 years (Japan) and 58.4 years (ROW). Eight (89%) Japanese venglustat-treated patients and 12 (92%) ROW patients reported ≥1 adverse event (AE) versus 2 (67%) and 4 (100%) from the respective placebo groups; most AEs were mild/moderate. Psychiatric, gastrointestinal, and neurological events, consistent with common motor/non-motor PD symptoms or known AEs of concurrent PD medications, were most frequent in both populations. No serious AEs/deaths occurred. No Japanese patients and 2 venglustat-treated ROW patients discontinued due to AEs after Week 4 (primary timepoint). In both populations, venglustat exposure in plasma and CSF increased in a close to dose-proportional manner; plasma and CSF GL-1 levels decreased from baseline in a dose-dependent manner over 4 weeks. At the highest dose, CSF GL-1 decreased 72.0% in Japanese and 74.3% in ROW patients. Conclusions: All doses of venglustat demonstrated favorable safety/tolerability in Japanese and ROW PD patients, with dose-dependent plasma and CSF exposure, and reduction in plasma and CSF GL-1. Disclosure: Dr. Peterschmitt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Sanofi.. Dr. Saiki has nothing to disclose. Dr. Hatano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dainippon Sumitomo, Takeda, FP, GSK K.K., Kyowa Hakko-Kirin, Nippon Boehringer Ingelheim, Nihon Medi-Physics, Novartis Pharma, and Otsuka. Dr. Gasser has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with MedUpdate, Novartis, Teva, and UCB Pharma. Dr. Gasser has received personal compensation in an editorial capacity for Chairman of the Scientific Advisory Board of the “Joint Programming for Neurodegenerative Diseases” program, funded by the European Commission. Dr. Gasser has received research support from German Research Foundation, German Federal Ministry of Education and Research, the European Commission, the Helmholtz Association, and the Michael J. Fox Foundation. Dr. Isaacson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie, Acadia, Acorda, Adamas, Addex, Allergan, Amarantus, Axovant, Benevolent, Biogen, Britannia, Cerecor, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec, Ipsen, Jazz, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, and NeuroDerm. Dr. Isaacson has received research support from AbbVie, Acadia, Acorda, Adamas, Addex, Allergan, Amarantus, Axovant, Benevolent, Biogen, Britannia, Cerecor, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec, Ipsen, Jazz, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, and NeuroDerm.Dr. Kulisevsky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Honoraria (Sanofi, Zambon, UCB, Teva, and Bial). Dr. Kulisevsky has received research support from Research grants (Fundacio La Marato de TV3, CIBERNED, and Carlos III Institute).. Dr. Simuni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acadia, Adamas, Teva, UCB Pharma, AbbVie, Anavex, Allergan, Acorda, NeuroDerm, PhotoPharmics, Revance, Sanofi, Sunovion, Voyager, US World Meds, and the Michael J. Fox Foundation. Dr. Simuni has received research support from Biogen, Roche, NeuroDerm, Sanofi, NINDS, the Michael J. Fox Foundation, and the Parkinson Foundation. Dr. Takahashi has received research support from Nippon Medical Physics Co., Ltd.. Dr. Wills has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant fees (Accordant, a CVS/Caremark disease management company).. Dr. Wills has received research support from Research funding (ALS Association); clinical trial funding (Acorda, Biogen, Bristol-Myers Squibb, Sanofi, and Pfizer).. Dr. Correia Guedes has nothing to disclose. Dr. Svenningsson has nothing to disclose. Dr. Takahashi has nothing to disclose. Dr. Waters has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees (Acadia, US WorldMeds); speaker’s honoraria (Acadia, Acorda, Adamas, Lundbeck, Sunovion, and US WorldMeds).. Dr. Waters has received research support from Research support (Sanofi).. Dr. Katsuno has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Speaker’s honoraria (Biogen and Takeda).. Dr. Katsuno has received research support from Research funding (Dainippon Sumitomo, Novartis Pharma K.K., Otsuka, Sanofi, and Takeda).. Dr. Ji has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi.Dr. Gaemers has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi.Dr. Minini has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Sanofi.. Dr. Nembo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Sanofi.. Dr. Sardi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Sanofi.. Dr. Saubadu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Sanofi.. Dr. Sharma has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Sanofi.. Dr. Fischer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi.