Historical Control Analysis Demonstrates Greater Long‐Term Reduction in Plasma Globotriaosylceramide (Gb3) by Venglustat Compared With Placebo or Agalsidase Beta in Male Patients With Classic Fabry Disease

Purpose To evaluate the disease biomarker response of venglustat in patients with Fabry disease (FD), utilizing data from a single‐arm phase 2 study of venglustat and a placebo‐controlled phase 3 study of agalsidase beta through historical control and case‐matched analyses. Methods Eleven venglustat‐treated male patients with classic FD in the phase 2 study were matched with placebo‐ or agalsidase beta–treated patients from the phase 3 study based on propensity scores at baseline. Changes from baseline in plasma globotriaosylceramide (GL‐3 or Gb3) concentrations were analyzed at approximately 6–36 months. Results Venglustat treatment resulted in greater significant reductions in plasma GL‐3 concentrations at 6 months from baseline vs. placebo (mean difference −2.56 μg/mL, p < 0.001), and at 24 and 36 months from baseline vs. agalsidase beta (mean difference −1.8 μg/mL, p < 0.05 and −2.35 μg/mL, p < 0.01, respectively). GL‐3 concentrations continued to decline with venglustat for up to 3 years without plateauing. Conclusions Venglustat showed significantly greater reductions in plasma GL‐3 concentrations than placebo after 6 months and agalsidase beta after 24 and 36 months. These findings support the potential of long‐term venglustat treatment to reduce GL‐3 accumulation in patients with classic FD. Further studies are needed to confirm clinical benefit.