Safety, tolerability and pharmacokinetics of oral venglustat in Parkinson disease patients with a GBA mutation

Mutations in GBA are associated with increased risk of developing Parkinson disease (PD), characterized by younger onset, higher prevalence of cognitive impairment, and more rapid disease progression. Part 1 of the phase 2 MOVES-PD study (NCT02906020) was an up to 36-week randomized, placebo-controlled, double-blind, sequential cohort study of once-daily venglustat at 3 escalating doses. PD patients age 18-80 years with symptoms ≥2 years and Hoehn & Yahr stage ≤2 at baseline who were heterozygous carriers of a GBA mutation were eligible. The primary endpoint was the safety and tolerability of venglustat. Secondary endpoints included plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK). Exploratory endpoints included pharmacodynamics in plasma and CSF. Seventeen patients (13M, 4F) 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. Twelve patients on venglustat and 4 on placebo reported at least 1 treatment-emergent adverse event (TEAE) most were mild or moderate and resolved without corrective treatment during the study. The most common TEAEs were psychiatric, neurological, and gastrointestinal events consistent with common motor/non-motor PD symptoms or known side effects of concurrent PD medications. 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. Plasma and CSF glucosylceramide (GL-1) levels decreased from baseline in a dose-dependent manner over 4 weeks. CSF GL-1 decreased 74.3% (higher dose). The data demonstrate a favorable safety and tolerability profile of venglustat at all doses investigated for up to 36 weeks of treatment. Dose-dependent plasma and CSF exposure and reduction of plasma and CSF GL-1 were observed. Part 2 of MOVES-PD, a 52-week randomized, double-blind, placebo-controlled study, is ongoing. Funding: Sanofi Genzyme.