Lucerastat, an oral therapy for Fabry disease: results from a pivotal randomized phase 3 study and its open-label extension

In Fabry disease (FD, OMIM #301500), a rare lysosomal storage disorder, the glucosylceramide synthase inhibitor lucerastat acts as substrate reduction therapy. The Phase 3, prospective, double-blind, placebo-controlled, 6-month, randomized clinical trial, MODIFY (NCT03425539), aimed to evaluate the efficacy, safety, and tolerability of lucerastat in adults with FD with moderate-to-severe neuropathic pain. The single-arm, open-label extension (OLE) (NCT03737214) evaluated the longer-term safety and tolerability of lucerastat over 72 months. Lucerastat 1000 mg twice daily (n = 80), compared with placebo (n = 37), failed to affect neuropathic pain at Month-6, with no significant difference between treatment groups (LSM difference -0.42 [95% CI -1.23, 0.40], p = 0.32) (primary endpoint). In contrast, a decrease in baseline plasma Gb3 was observed at Month-6 in lucerastat-treated participants but not placebo-treated participants (LSM difference -873.53 ng/mL [95% CI -1097.53, -649.53], p < 0.0001; NS due to hierarchical testing). In an unplanned OLE Month-18 interim analysis, the eGFR slope (mL/min/1.73m²/year) in 93 participants with pre- and post-randomization (23-month median lucerastat exposure) eGFR data was -3.50 (-5.04, -1.969) and -1.48 (-2.64, -0.33), respectively. Lucerastat was safe and well tolerated. Lucerastat's strong pharmacodynamic effect did not translate into an effect on neuropathic pain. The potential effect of lucerastat on renal function requires further investigation (Trial registration NCT03425539, NCT03737214; 2017-003369-85, 2018-002210-12. The studies were sponsored by Idorsia Pharmaceuticals Ltd).