Mutations in GBA, which encodes glucocerebrosidase, are associated with increased risk of developing PD, characterized by a younger onset, higher prevalence of cognitive impairment, and more rapid disease progression.

Assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of once-daily oral venglustat, a CNS-penetrating glucosylceramide (GL-1) synthase inhibitor, in Parkinson’s disease (PD) patients with a GBA mutation.

Part 1 of MOVES-PD (NCT02906020) was an up-to 36-week randomized, placebo-controlled, double-blind, sequential-cohort study of the safety/tolerability of once-daily venglustat at 3 escalating doses. PD patients age 18-80 years with symptoms ≥2 years at baseline who were heterozygous carriers of a GBA mutation were eligible. The primary endpoint was the safety/tolerability of venglustat. Secondary endpoints included plasma and cerebrospinal fluid (CSF) PK. Exploratory endpoints included pharmacodynamics. 

Seventeen patients were randomized to placebo (n=4) or venglustat (n=13). Mean age at enrollment was 58.4 years. Mean years since symptom onset was 6.7, and since diagnosis was 5.2. GBA mutations included N370S, 84GG, L444P, and E326K. Twelve venglustat-treated and 4 placebo-treated patients reported at least 1 treatment-emergent adverse event; most were mild or moderate and resolved without corrective treatment during the study, and the most common were psychiatric, neurological, and gastrointestinal events. No serious AEs or deaths occurred. Two patients on venglustat discontinued due to TEAEs after the primary analysis period (Week 4). Venglustat exposure in plasma and CSF increased in a close to dose proportional manner, and GL-1 levels decreased in a dose-dependent manner over 4 weeks. CSF GL-1 decreased 74.3% (high-dose).