Phase 3 MODIFY Shows No Significant Renal Benefit With Lucerastat in Fabry Disease

Exploratory post hoc analyses from the phase 3 MODIFY trial suggested a possible signal among participants with reduced kidney function at baseline, while no statistically significant renal benefit was observed with lucerastat in adults with Fabry disease.1

Although the trial was not designed or powered to assess renal endpoints, lucerastat was associated with numerically higher eGFR changes compared with placebo over 6 months, with interpretation limited by the short duration of the controlled phase.1

“MODIFY is the largest randomized trial performed in Fabry disease to date and included a broad spectrum of participants with Fabry disease, including male and female participants, individuals with classic and nonclassic disease, and participants who were enzyme replacement therapy–naïve or previously treated,” wrote study investigator Derralynn Hughes, professor of experimental hematology at University College London, director of research and innovation at the Royal Free London, and co-clinical director of the North Central London Cancer Alliance, and colleagues.1

Fabry disease is a rare, genetic disorder caused by pathogenic variants in the GLA gene, which encodes the α-galactosidase A enzyme. Deficiency of this enzyme leads to lysosomal accumulation of globotriaosylceramide, which contributes to multisystem involvement, including renal injury characterized by glomerulosclerosis and tubular atrophy. Over time, this process can result in proteinuria, declining kidney function, and progression to end-stage renal disease requiring dialysis or kidney transplantation.1,2

In patients with Fabry disease and renal involvement, major therapeutic goals include stabilizing or slowing eGFR decline and delaying progression from chronic kidney disease to end-stage renal disease.1,,2

Lucerastat is an oral glucosylceramide synthase inhibitor under investigation as a substrate reduction therapy designed to reduce glucosylceramide synthesis and thereby limit downstream globotriaosylceramide accumulation.1

Hughes and colleagues evaluated lucerastat in MODIFY, a 6-month, prospective, double-blind, placebo-controlled, randomized phase 3 clinical trial designed to assess the efficacy, safety, and tolerability of lucerastat monotherapy in adults with Fabry disease. Participants were randomized across 49 sites in 14 countries, including North America, Europe, and Australia.1

The primary objective of MODIFY was to evaluate the effect of lucerastat on neuropathic pain. Prespecified secondary endpoints included assessments of renal function and cardiac parameters. An ongoing open-label extension study is evaluating the long-term safety and tolerability of lucerastat for up to 72 months.1

A total of 118 participants were enrolled, with 117 receiving at least 1 dose of study treatment. Overall, 109 participants completed the 6-month double-blind phase, 107 entered the open-label extension, and 78 remained ongoing at the 18-month interim analysis.1

The least squares mean (LSM) eGFR slope (mL/min/1.73 m² per month) was +0.26 in the lucerastat group compared with +0.08 in the placebo group, corresponding to annualized changes of approximately +3.12 and +0.96 mL/min/1.73 m² per year, respectively. The LSM treatment difference was not statistically significant (LSM difference, 0.19; 95% Confidence Interval [CI], -0.40 to 0.78; P = .5313).1

Changes in the urine albumin-to-creatinine ratio from baseline were not normally distributed. Therefore, investigators analyzed log-transformed data, where LSM exhibited a percentage change difference of +16.2% (95% CI, -23.9 to 77.3; P = .4875), indicating no significant difference between treatment groups, according to investigators.1

In a post hoc analysis stratified by sex, investigators did not observed a difference in mean eGFR change from baseline between treatment groups. A slight increase in eGFR was observed among male participants, while female participants showed no significant change from baseline.1

In an exploratory, post hoc subgroup analysis of participants with impaired renal function at baseline (screening eGFR <90 mL/min/1.73 m²; n = 40), mean eGFR increased by 3.8 mL/min/1.73 m² from baseline to month 6 in the lucerastat group (n = 27), compared with a decrease of 1.6 mL/min/1.73 m² in the placebo group (n = 13). Investigators did not report any notable changes among participants without baseline renal impairment (n = 77).1

“Although the study was not designed to evaluate the impact of lucerastat on renal function because of the short duration of the controlled phase, results from MODIFY and its long-term extension suggest a possible effect on renal outcomes, particularly among patients with greater medical need, such as those with reduced renal function at baseline,” investigators concluded.1

References

1. Nordbeck P, Ozlem Goker-Alpan, Bernat JA, et al. Lucerastat, an oral therapy for Fabry disease: results from a pivotal randomized phase 3 study and its open-label extension. Nature Communications. Published online January 10, 2026. doi:https://doi.org/10.1038/s41467-025-68256-5

2. Sunder-Plassmann G. Renal manifestations of Fabry disease. PubMed. Published 2006. https://www.ncbi.nlm.nih.gov/books/NBK11571/

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