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

Peter Nordbeck; Ozlem Goker-Alpan; John A Bernat; Dominique P Germain; Pilar Giraldo; Ana Jovanovic; Virginia Kimonis; Kathleen Nicholls; Cheryl Rockman-Greenberg; Raphael Schiffmann; Mark Thomas; Anna Tylki-Szymanska; Eric Wallace; Richard W D Welford; Michael L West; Martine Clozel; Aline Frey; Luba Trokan; Markus S Mueller; Markus Vogler; Christoph Wanner; Derralynn Hughes

doi:10.1038/s41467-025-68256-5

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

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

Peter Nordbeck, Ozlem Goker-Alpan, John A Bernat, Dominique P Germain, Pilar Giraldo, Ana Jovanovic, Virginia Kimonis, Kathleen Nicholls, Cheryl Rockman-Greenberg, Raphael Schiffmann, …

Nature communications, Vol.17(1), 1534

2026

DOI: 10.1038/s41467-025-68256-5

PMCID: PMC12891692

PMID: 41519901

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Abstract

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/1.73m /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).

Details

Title: Subtitle: Lucerastat, an oral therapy for Fabry disease: results from a pivotal randomized phase 3 study and its open-label extension
Creators: Peter Nordbeck - Universitätsklinikum Würzburg
Ozlem Goker-Alpan - Lysosomal and Rare Disorders Research and Treatment Center
John A Bernat - University of Iowa
Dominique P Germain - Université Paris-Saclay
Pilar Giraldo - Hospital Quirónsalud Barcelona
Ana Jovanovic - Northern Health and Social Care Trust
Virginia Kimonis - University of California, Irvine
Kathleen Nicholls - The University of Melbourne
Cheryl Rockman-Greenberg - University of Manitoba
Raphael Schiffmann - Baylor Scott & White Health
Mark Thomas - Royal Perth Hospital
Anna Tylki-Szymanska - Children's Memorial Health Institute
Eric Wallace - University of Alabama at Birmingham
Richard W D Welford - Idorsia Pharmaceuticals Ltd (Switzerland)
Michael L West - Dalhousie University
Martine Clozel - Idorsia (Switzerland)
Aline Frey - Idorsia (Switzerland)
Luba Trokan - Idorsia (Switzerland)
Markus S Mueller - Idorsia (Switzerland)
Markus Vogler - Idorsia (Switzerland)
Christoph Wanner - Universitätsklinikum Würzburg
Derralynn Hughes - University College London
Resource Type: Journal article
Publication Details: Nature communications, Vol.17(1), 1534
DOI: 10.1038/s41467-025-68256-5
PMID: 41519901
PMCID: PMC12891692
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: Springer Nature
Grant note: Idorsia Pharmaceuticals Ltd. contributed to study design, data collection, data analysis, and data interpretation and funded the study and medical writing support.
Idorsia Pharmaceuticals Ltd contributed to study design, data collection, data analysis, and data interpretation, and funded the study and medical writing support. All authors were responsible for the decision to submit the manuscript for publication. All authors had full access to all the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. Medical writing support was provided by Anne Sayers and Carlotta Foletti (Idorsia Pharmaceuticals Ltd) and Melanie Gatt (an independent medical writer) in accordance with Good Publications Practice 2022 and was funded by Idorsia Pharmaceuticals Ltd. We thank the patients for their participation and the investigators for their involvement in participant care and contribution to the study.
Language: English
Electronic publication date: 01/10/2026
Date published: 2026
Academic Unit: Stead Family Department of Pediatrics; Medical Genetics and Genomics
Record Identifier: 9985121484302771

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