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

M. Judith Peterschmitt*, Hidemoto Saiki, Taku Hatano, Thomas Gasser, Stuart H. Isaacson, Sebastiaan J.M. Gaemers, Pascal Minini, Stéphane Saubadu, Jyoti Sharma, Samantha Walbillic, Roy N. Alcalay, Gary Cutter, Nobutaka Hattori, Günter U. Höglinger, Kenneth Marek, Anthony H.V. Schapira, Clemens R. Scherzer, Tanya Simuni, Nir Giladi, Sergio Pablo SardiTanya Z. Fischer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)557-570
Number of pages14
JournalJournal of Parkinson's disease
Volume12
Issue number2
DOIs
StatePublished - 2022

Keywords

  • GBA-PD
  • MOVES-PD
  • Parkinson's disease
  • Venglustat (GZ/SAR402671)
  • glucocerebrosidase gene (GBA)
  • glucosylceramide (GL-1)
  • glucosylceramide synthase (GCS) inhibition

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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