Safety and Efficacy of Venglustat Assessed in GBA Gene Carriers With Parkinson Disease

In a poster presented at MDS 2021 and as part 2 of the MOVES-PD trial, researchers assessed the safety and efficacy of venglustat, a glucosylceramide synthase inhibitor, in patients stratified by GBA gene variation severity.

The following article is part of conference coverage from the International Congress of Parkinson’s Disease and Movement Disorders (MDS) Virtual Annual Meeting. Neurology Advisor’s staff will be reporting breaking news associated with research conducted by leading experts in neurology. Check back for the latest news from the MDS 2021 Virtual Annual Meeting.


Among patients with Parkinson disease (PD) and glucocerebrosidase (GBA) gene variations, treatment with venglustat was safe and well tolerated, but had a negative symptomatic effect that was more significant in those with nonsevere GBA variations, according to study results presented as a poster at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) Virtual Congress 2021, held from September 17 to 22, 2021.

The risk for PD is increased among patients with variations in the GBA gene. The safety and efficacy of venglustat in these patients were determined in the MOVES-PD trial (Clinical Identifier: NCT02906020); part 1 was a placebo-controlled dose-escalation phase and part 2 was a double-blind, placebo-controlled study of the dose selected in the first part. As part 1 of the study failed to meet the primary and secondary efficacy endpoints, the development of venglustat for this indication was halted.

The current study was focused on outcomes from part 2 of the trial, with the objective of determining the effect of venglustat in patients stratified by GBA gene variation severity.

After the 52-week trial, patients received venglustat for another 104 weeks. The change from baseline to week 52 in MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 2+3 was the primary outcome. Data on the safety of venglustat were also collected.

The study sample included 221 participants, including 110 in the venglustat group and 111 in the placebo group. Severe GBA variations, most commonly L444P, were reported in 24% of the placebo group and 31% of the venglustat group.

At week 52, absolute differences in deterioration in MDS-UPDRS part 2+3 were greater among patients with mild GBA variations treated with venglustat compared with placebo with nonsevere vs severe GBA variations (between group difference, 3.68 vs -0.69, respectively).

Overall, venglustat was well tolerated and had a favorable safety profile. The rate of any treatment-emergent adverse events was 88.3% in the placebo group vs 90.9% in the venglustat group, with serious adverse events reported in 10.8% and 10.9%, respectively. The most common psychiatric disorders in the placebo and venglustat groups were depression and insomnia. The most common treatment-emergent adverse event of special interest was cataract, reported in 12.6% of placebo group and 10.9% of venglustat group.

“Venglustat did not reduce the rate of change in MDS-UPDRS score over 52 weeks. An early negative trend in MDS-UPDRS [part 2+3] in venglustat-treated patients suggests a negative symptomatic effect. This trend was more prominent in a subset of mild GBA [variation] carriers [vs] those with severe [variations], which likely influenced the primary efficacy endpoint outcome favoring placebo,” the researchers concluded.


Peterschmitt MJ, Giladi N, Alcalay RN, et al. Effect of venglustat by GBA mutation severity in patients with Parkinson’s disease. Presented at: MDS Virtual Congress 2021; September 17-22, 2021. Poster 430.