Canada: Lucerastat, an oral substrate reduction therapy, failed to meet its primary endpoint for neuropathic pain in adults with Fabry disease, but demonstrated encouraging biochemical effects and a possible signal of renal benefit in select patients, according to results from a pivotal Phase 3 trial and its long-term extension, published in Nature Communications.The study was led by Peter Nordbeck from the Department of Internal Medicine I, University Hospital Würzburg, Germany, along with colleagues.Fabry disease is a rare X-linked lysosomal storage disorder characterized by deficient α-galactosidase A activity, resulting in the accumulation of glycosphingolipids, including globotriaosylceramide (Gb3), in multiple organs. Lucerastat works by inhibiting glucosylceramide synthase, thereby reducing the production of glycosphingolipids upstream of their accumulation.The randomized, double-blind, placebo-controlled phase 3 MODIFY trial evaluated the efficacy, safety, and tolerability of lucerastat in adults with Fabry disease experiencing moderate-to-severe neuropathic pain. A total of 117 participants were randomized to receive either lucerastat 1000 mg twice daily or a placebo for six months. The primary endpoint was the change in neuropathic pain severity at Month 6.The trial did not demonstrate a statistically significant improvement in neuropathic pain with lucerastat compared to placebo. Pain scores showed no meaningful difference between the two groups, indicating that the drug’s strong pharmacodynamic activity did not translate into clinical pain relief within the study period. The key findings were as follows:Lucerastat led to a marked reduction in plasma globotriaosylceramide (Gb3) levels at six months, while no comparable reduction was observed in the placebo group, indicating strong target engagement and effective substrate reduction.Although the reduction in plasma Gb3 did not meet formal statistical significance due to the hierarchical testing approach, it demonstrated a clear biological effect of lucerastat.The MODIFY trial was not designed to assess renal outcomes as primary endpoints, and no statistically significant improvements were observed in estimated glomerular filtration rate (eGFR) or urinary albumin-to-creatinine ratio (UACR) in the overall study population.Exploratory post hoc analyses suggested a possible renal benefit of lucerastat among patients with pre-existing kidney impairment at baseline.Data from the open-label extension study, which evaluated long-term exposure to lucerastat for up to 72 months, showed a slower rate of eGFR decline at the 18-month interim analysis compared with the pre-treatment period.The observed attenuation in eGFR decline with extended lucerastat use points to a potential stabilizing effect on kidney function over time.Lucerastat was generally safe and well-tolerated across both the randomized phase 3 trial and the open-label extension, with no unexpected safety signals identified.While lucerastat did not achieve its primary pain-related endpoint, the observed biochemical effects and exploratory renal findings point to a potential role in Fabry disease patients with existing kidney involvement. The authors emphasize that dedicated studies specifically designed to evaluate renal outcomes are needed to clarify lucerastat’s therapeutic value in this population.Reference:Nordbeck, P., Goker-Alpan, O., Bernat, J. A., Germain, D. P., Giraldo, P., Jovanovic, A., Kimonis, V., Nicholls, K., Rockman-Greenberg, C., Schiffmann, R., Thomas, M., Tylki-Szymanska, A., Wallace, E., Welford, R. W., West, M. L., Clozel, M., Frey, A., Trokan, L., Mueller, M. S., . . . Hughes, D. (2026). Lucerastat, an oral therapy for Fabry disease: Results from a pivotal randomized phase 3 study and its open-label extension. Nature Communications. https://doi.org/10.1038/s41467-025-68256-5