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

Abstract

Background: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor.

Objective: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD).

Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18-80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics.

Results: Participants (N = 29) received 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; 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.

Conclusion: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF.

Keywords: GBA-PD; MOVES-PD; Parkinson’s disease; Venglustat (GZ/SAR402671); glucocerebrosidase gene (GBA); glucosylceramide (GL-1); glucosylceramide synthase (GCS) inhibition.

Conflict of interest statement

MJP, SJMG, PM, SS, JS, SW, and SPS report receiving personal compensation as employees of Sanofi, and may hold shares and/or stock options in the company. 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 Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Mitsubishi Tanabe Pharma Holdings, Neurim, Novartis, Ophazyme, Opko Biologics, Reata Pharmaceuticals, Sanofi-Aventis, Teva pharmaceuticals, VielaBio Inc, NHLBI (Protocol Review Committee), and NICHD (OPRU oversight committee); reports receiving consulting fees or participating on advisory boards from Alexion, Antisense Therapeutics, Biodelivery Sciences International, Biogen, Clinical Trial Solutions LLC, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Medimmune/Viela Bio, Medday, Merck/Serono, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Reckover Pharmaceuticals, Recursion/Cerexis Pharmaceuticals, Regeneron, Roche, SAB Biotherapeutics, 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).

Figures

Fig. 1

CONSORT diagram: disposition of participants enrolled in Part 1 of the MOVES-PD trial. Two non-Japanese participants permanently discontinued the study due to adverse events after receiving venglustat and post week 4 (one participant [low dose] discontinued due to confusional state, and one participant [high dose] due to a panic attack). aInclusion criterion: male or female patients with a diagnosis of PD (with at least two of the following signs: resting tremor, postural instability, akinesia/hypokinesia, and muscle rigidity) and who are heterozygous carriers of a GBA mutation. bInclusion criterion: patients carrying known sequence variants associated with GBA-PD, in addition to having a diagnosis of PD (with at least two of the following signs: resting tremor, postural instability, akinesia/hypokinesia, or muscle rigidity), must also have a diagnosis of RBD confirmed by historically documented polysomnography or by RBD screening questionnaire. GBA, glucocerebrosidase (glucosylceramidase beta) gene; PD, Parkinson’s disease; RBD, rapid eye movement sleep behavior disorder.

Fig. 2

Percent reduction in plasma and CSF GL-1 levels after venglustat treatment. Mean percent change from baseline in plasma (A) and CSF (B) GL-1 levels in Japanese and non-Japanese participants who received placebo or were treated with venglustat (low, mid, or high dose) in Part 1 of the MOVES-PD trial. GL-1 levels were assessed in plasma samples collected at baseline, end of week 2, and end of week 4, and in CSF samples collected at baseline and end of week 4. aWeek 4 CSF sample was not collected for one participant from the non-Japanese population. CSF, cerebrospinal fluid; GL-1, glucosylceramide.