The following is the summary of “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,” published in the May 2023 issue of the Kidney Disease by Gansevoort et al.

In autosomal dominant polycystic kidney disease (ADPKD), numerous cysts develop in the kidneys, causing the total kidney volume (TKV) to enlarge and eventually result in renal failure. In preclinical models of ADPKD, it was found that the glucosylceramide synthase inhibitor miglustat slowed the growth of cysts and made kidney failure less severe. Adults with ADPKD at high risk of rapid disease progression were enrolled in the STAGED-PKD study, a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study. Eligibility criteria included Mayo Clinic imaging class 1C, 1D, or 1E ADPKD and an estimated glomerular filtration rate (eGFR) between 30 and 89.9 mL/min/1.73 m². 

Patients in the first trial stage were randomly assigned to receive either 8 mg of miglustat, 15 mg of miglustat, or a placebo. Patients in Stage 2 were randomly assigned a 15 mg dose of miglustat (the highest amount safe and well tolerated in Stage 1) or a placebo. The change in TKV over 18 months was the primary end target in Stage 1, while the slope of eGFR over 24 months was the primary endpoint in Stage 2. Secondary endpoints included the 18-month change in eGFR slope, the 2-stage change in TKV rate of change, and the 1- and 2-stage changes in safety/tolerability, discomfort, and fatigue. Treatment with miglustat did not affect the annualized rate of change in TKV over 18 months (stage 1). 

According to a predetermined interim futility study, it resulted in a faster rate of reduction in the slope of eGFR over 24 months (stage 2). This ineffectiveness led to an early study conclusion. The results may only be generalized within the study population due to the short time between treatment completion and follow-up. Even though plasma glucosylceramide levels dropped depending on the dose, therapy with miglustat at 8 or 15 mg did not affect the rate of change in TKV and caused eGFR to drop faster in patients with ADPKD that was getting worse quickly.

Source: sciencedirect.com/science/article/pii/S0272638622010794