Objective: Report outcomes from Part 2 of the phase 2 MOVES-PD trial (NCT02906020) in patients with PD stratified by glucocerebrosidase (GBA) gene mutation severity.

Background: MOVES-PD Part 2 was a 52-week, randomized (1:1), placebo-controlled study of efficacy and safety of oral venglustat in patients with PD and GBA mutations. Venglustat was well tolerated and markedly reduced plasma and cerebrospinal fluid glucosylceramide levels, confirming CNS target engagement. The study did not meet the primary or secondary efficacy endpoints, prompting venglustat development halt in GBA-PD [1].

Method: Primary outcome was change from baseline to Week 52 in MDS-UPDRS Part II+III (OFF state) [1]. Patients were stratified by GBA mutation severity. Dopamine transporter (DAT) scan data were assessed. Safety was evaluated.

Results: Of 221 participants enrolled, 24% (placebo) and 31% (venglustat) carried severe GBA mutations, most commonly L444P. The most common mild mutation was N370S. At Week 52, versus placebo, there was a numerically greater MDS-UPDRS Part II+III progression in venglustat-treated patients with mild GBA mutations (between-group difference, 3.7) than those with severe mutations (-0.7); the largest difference versus placebo was observed for N370S carriers (8.0). Evidence of progression was observed as early as Week 13, suggesting a symptomatic rather than disease-modifying effect. In the placebo group, patients with severe GBA mutations showed faster MDS-UPDRS Part II+III progression than those with mild mutations (least-square mean score change, 9.7 vs 2.9). Striatal DAT showed the expected reduction with placebo and no significant difference between venglustat and placebo groups. The most common treatment-emergent psychiatric disorders were depression and insomnia, reported in 5% (placebo) and 8% (venglustat) of patients.

Conclusion: Venglustat did not reduce the rate of change in MDS-UPDRS score over 52 weeks. An early negative trend in MDS-UPDRS Part II+III in venglustat-treated patients suggests a negative symptomatic effect. This trend was more prominent in a subset of mild GBA mutation carriers versus those with severe mutations, which likely influenced the primary efficacy endpoint outcome favoring placebo. The mechanism for this negative symptomatic effect of venglustat remains to be determined. Imaging analyses showed no impact of venglustat treatment on DAT.

References: [1] Peterschmitt MJ, Giladi N, Alcalay RN, et al. Venglustat In Parkinson’s Disease Patients with a GBA Mutation: Results From Part 2 of the Phase 2 MOVES-PD Trial. Presented at: 15th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD™), Virtual, March 9–14, 2021.

« Back to MDS Virtual Congress 2021

MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-venglustat-by-gba-mutation-severity-in-patients-with-parkinsons-disease/