Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial

Rationale & Objective: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. Study Design: STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9 mL/min/1.73 m². Setting & Participants: Enrollment included 236 and 242 patients in stages 1 and 2, respectively. Interventions: In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8 mg; venglustat, 15 mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15 mg (highest dose identified as safe and well tolerated in stage 1), or placebo. Outcomes: Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2). Results: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early. Limitations: The short follow-up period after the end of treatment and limited generalizability of the findings. Conclusions: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8 mg or 15 mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels. Funding: This study was funded by Sanofi. Trial Registration: Registered at ClinicalTrials.gov with study number NCT03523728.