Venglustat in GM2 gangliosidoses and related disorders: Results of the AMETHIST randomized controlled and basket trials

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PURPOSE: To evaluate efficacy and safety of venglustat for GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) and cognate diseases. METHODS: The AMETHIST phase 3, randomized, double-blind, placebo-controlled study evaluated oral venglustat (N = 40) vs placebo (N = 19) in adults with late-onset GM2 gangliosidoses. Coprimary endpoints were annual percent change on the 9-Hole Peg Test and percent change in cerebrospinal fluid (CSF) GM2 ganglioside from baseline to week 104. A secondary population of participants with cognate diseases (N = 16) received open-label venglustat in a "basket" trial. RESULTS: CSF GM2 decreased by 47.6% (90% CI: -52.6, -42.6) with venglustat versus 11.3% (90% CI: -18.3, -4.4) with placebo (difference: -36.2 [90% CI: -44.8, -27.7], P < .0001). The annual percent change in 9-Hole Peg Test was 2.49% (90% CI: 0.28, 4.74) with venglustat versus 0.95% (90% CI: -2.16, 4.15) with placebo (difference: 1.54% [90% CI: -2.33, 5.39], P = .74). Decreased CSF GM2 concentrations did not correlate with clinical endpoints. Secondary population participants remained clinically stable. The most common adverse events were fall, headache, and contusion with placebo and fall, and COVID-19 and headache with venglustat. CONCLUSION: In adults with late-onset GM2 gangliosidoses, oral venglustat decreased CSF GM2 concentrations but without clinical improvement in the endpoints assessed. No new safety findings were observed.

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