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.

• Authors: 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 Sardi, Tanya Z Fischer, MOVES-PD Investigators
• Journal: Journal of Parkinson's disease (J Parkinsons Dis) Vol. 12 Issue 2 Pg. 557-570 ( 2022) ISSN: 1877-718X [Electronic] Netherlands
• PMID: 34897099 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Glucosylceramides
• Glucosylceramidase

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Enzyme Inhibitors (adverse effects)
• Glucosylceramidase (genetics)
• Glucosylceramides
• Humans
• Middle Aged
• Mutation
• Parkinson Disease (drug therapy, genetics)
• Young Adult