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/1.73m2/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).
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In addition to Idorsia’s existing clinical trial disclosure activities, the company is committed to implementing the Principles for Responsible Clinical Trial Data Sharing jointly issued by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA). The trial protocol and statistical analysis plan are available with this publication (Supplemental Material Appendix A─D). Source data of results included in this article are provided with this paper. After research completion, data will be shared for replication and verification processes with qualified researchers that request access to trial data by submitting a research proposal to the trial sponsor, Idorsia Pharmaceuticals Ltd. For more information and to submit research proposals, contact clinical-trials-disclosure@idorsia.com.
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Acknowledgements
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.
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P.N.: Contributed to conceptualization, investigation, formal analysis, and writing–review and editing. O.G.-A.: Contributed to investigation and writing–review and editing. J.B.: Contributed to investigation and writing–review and editing. D.P.G.: Contributed to conceptualization, investigation, formal analysis, and writing–review and editing. P.G.: Contributed to investigation and writing–review and editing. A.J.: Contributed to investigation and writing–review and editing. V.K.: Contributed to investigation and writing–review and editing. K.N.: Contributed to investigation and writing–review and editing. C.R.G.: Contributed to investigation and writing–review and editing. R.S.: Contributed to conceptualization, investigation, and writing–review and editing. M.T.: Contributed to investigation and writing–review and editing. A.T.-S.: Contributed to investigation and writing–review and editing. E.W.: Contributed to investigation and writing–review and editing. R.W.: Contributed to conceptualization, investigation, formal analysis, and writing–review and editing. M.W.: Contributed to investigation and writing–review and editing. M.C.: Contributed to conceptualization and writing–review and editing. A.F.: Contributed to conceptualization, investigation, formal analysis, and writing–review and editing. L.T.: Contributed to conceptualization, formal analysis, and writing–review and editing. M.M.: Contributed to conceptualization, formal analysis, and writing–review and editing. M.V.: Contributed to conceptualization, formal analysis, and writing–review and editing. C.W.: Contributed to conceptualization, investigation, formal analysis, and writing–review and editing. D.H.: Contributed to conceptualization, investigation, formal analysis, and writing–review and editing.
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P.N.: Medical writing support for the manuscript as declared in the Acknowledgments; consulting fees from Amicus, Chiesi, Greenovation, Idorsia, Sanofi-Genzyme, Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amicus, Chiesi, Greenovation, Idorsia, Sanofi-Genzyme, Takeda; participation on a data safety monitoring board or advisory board for Amicus, Chiesi, Greenovation, Idorsia, Sanofi-Genzyme, Takeda. O.G.-A.: Medical writing support for the manuscript as declared in the Acknowledgments; grant support from Idorsia, Sanofi, Protalix, Chiesi, Sangamo, 4DMT for clinical research trials; grant support from Sanofi and Takeda for other investigator-initiated studies; has/will receive(d) consulting fees from Sanofi, Chiesi, Takeda, Uniqure; payment or honoraria for speaker bureaus for Sanofi and Takeda; participation on an advisory board on Fabry disease for Chiesi and Sanofi. J.B.: Medical writing support for the manuscript as declared in the Acknowledgments; research support for clinical trial from Idorsia Pharmaceuticals; research support from AVROBIO, BioMarin Pharmaceutical, Chiesi Farmaceutici, Pfizer, Protalix BioTherapeutics, Sangamo Therapeutics, Sanofi, Takeda, Travere Therapeutics; consulting fees from Chiesi USA and Takeda for advisory boards; speaker honorarium from Fabry Support and Information Group. D.P.G.: Medical writing support for the manuscript as declared in the Acknowledgments; consulting fees from Chiesi, Idorsia, Sanofi, and Takeda; support for attending meetings and/or travel from Chiesi, Sanofi, and Takeda. P.G.: Medical writing support for the manuscript as declared in the Acknowledgments. A.J.: Medical writing support for the manuscript as declared in the Acknowledgments; research grants from Takeda and Amicus; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Amicus, Chiesi, Takeda, and Sanofi; support for attending meetings and/or travel from Amicus and Chiesi. V.K.: Medical writing support for the manuscript as declared in the Acknowledgments; payment for expert testimony from Sanofi; participation on a Pompe disease advisory board for Sanofi; PI of trials for Protalix and Idorsia. K.N.: Medical writing support for the manuscript as declared in the Acknowledgments; research/clinical trial funding to institution from Sanofi, Takeda, Amicus and Idorsia; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Takeda, Sanofi and Amicus; participation on a data safety monitoring board or advisory board for Takeda, Sanofi and Amicus. C.R.G.: Medical writing support for the manuscript as declared in the Acknowledgments. R.S.: Medical writing support for the manuscript as declared in the Acknowledgments. M.T.: Medical writing support for the manuscript as declared in the Acknowledgments. A.T.-S.: Medical writing support for the manuscript as declared in the Acknowledgments. E.W.: Medical writing support for the manuscript as declared in the Acknowledgments; grants or contracts from Sanofi, Idorsia, Chiesi, Protalix, Walking Fish Therapeutics, Spark Therapeutics; consulting fees from Sanofi, Amicus, Chiesi, Protalix, Walking Fish Therapeutics, Spark Therapeutics; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Sanofi, Chiesi, and Natera; support for attending meetings and/or travel from Sanofi, Chiesi, and Protalix. R.W.: Medical writing support for the manuscript as declared in the Acknowledgments; employed by Idorsia (the study funder) during the planning and execution of the study; owns stock in Idorsia. M.W.: Medical writing support for the manuscript as declared in the Acknowledgments; contract for research from Chiesi; grants from Takeda, Sanofi and Amicus; IP for Fabry gene therapy and Fabry cardiac biomarkers; consulting fees from Takeda; honoraria for CME presentations from Takeda, Sanofi and Sumitomo; payment for expert testimony from Takeda and Amicus; support for travel expenses from Amicus; participation on advisory boards for Sanofi and Amicus; Chair of the Scientific Committee for the CFDI Registry; Member of the Fabry Outcome Survey Steering Committee for Takeda; Member of the Scientific Committee for the Canadian Symposium on Lysosomal Diseases; Member of the North American Advisory Board for Sanofi; Member of the Scientific Committee for the Fabry Update Meeting. M.C.: Medical writing support for the manuscript as declared in the Acknowledgments; employee of Idorsia Pharmaceuticals Ltd; shareholder of Idorsia Pharmaceuticals Ltd. A.F.: Medical writing support for the manuscript as declared in the Acknowledgments; employee of Idorsia Pharmaceuticals Ltd; shareholder of Idorsia Pharmaceuticals Ltd. L.T.: Medical writing support for the manuscript as declared in the Acknowledgments; employee of Idorsia Pharmaceuticals (Sponsor) at the time of data generation, statistical evaluation, and data interpretation; shareholder of Idorsia Pharmaceuticals Ltd. M.M.: Medical writing support for the manuscript as declared in the Acknowledgments; employee of Idorsia Pharmaceuticals Ltd; owns stock. M.V.: Medical writing support for the manuscript as declared in the Acknowledgments; employee of Idorsia Pharmaceuticals Ltd; shareholder of Idorsia Pharmaceuticals Ltd. C.W.: Medical writing support for the manuscript as declared in the Acknowledgments; grant(s) from Boehringer Ingelheim and Sanofi; consultancy fees from Amgen, Amicus, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Vifor Pharma, Chiesi, Chugai, Fresenius Medical Care, GSK, Idorsia, Eli Lilly, MSD, Novartis, Novo Nordisk, Sanofi. D.H.: Medical writing support for the manuscript as declared in the Acknowledgments; consultancy fees for advisory boards from Idorsia, Amicus, Sanofi, Takeda, Chiesi, Freeline, Sangamo; honoraria for speaking from Idorsia, Amicus, Sanofi, Takeda, Chiesi, Freeline, Sangamo; support for attending meetings and/or travel from Amicus, Sanofi, Freeline, Chiesi.
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Employee of Idorsia Pharmaceuticals Ltd at the time of the study: Richard W. D. Welford, Luba Trokan, Markus S. Mueller, Markus Vogler.
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Nordbeck, P., Goker-Alpan, O., Bernat, J.A. et al. Lucerastat, an oral therapy for Fabry disease: results from a pivotal randomized phase 3 study and its open-label extension. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68256-5
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DOI: https://doi.org/10.1038/s41467-025-68256-5
