Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial

Raphael Schiffmann, Daniel G Bichet, Ana Jovanovic, Derralynn A Hughes, Roberto Giugliani, Ulla Feldt-Rasmussen, Suma P Shankar, Laura Barisoni, Robert B Colvin, J Charles Jennette, Fred Holdbrook, Andrew Mulberg, Jeffrey P Castelli, Nina Skuban, Jay A Barth, Kathleen Nicholls, Raphael Schiffmann, Daniel G Bichet, Ana Jovanovic, Derralynn A Hughes, Roberto Giugliani, Ulla Feldt-Rasmussen, Suma P Shankar, Laura Barisoni, Robert B Colvin, J Charles Jennette, Fred Holdbrook, Andrew Mulberg, Jeffrey P Castelli, Nina Skuban, Jay A Barth, Kathleen Nicholls

Abstract

Background: Fabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations.

Methods: We evaluated minimal clinically important differences (MCID) in diarrhea based on the corresponding domain of the patient-reported Gastrointestinal Symptom Rating Scale (GSRS) in patients with Fabry disease and amenable mutations (N = 50) treated with migalastat 150 mg every other day or placebo during the phase 3 FACETS trial (NCT00925301).

Results: After 6 months, significantly more patients receiving migalastat versus placebo experienced improvement in diarrhea based on a MCID of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031).

Conclusions: Migalastat was associated with a clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations. Reductions in kidney globotriaosylceramide may be a useful surrogate endpoint to predict clinical benefit with migalastat in patients with Fabry disease.

Trial registration: NCT00925301 ; June 19, 2009.

Keywords: Amenable mutation; Diarrhea; Fabry disease; GSRS; Gastrointestinal; Globotriaosylceramide; Lyso-Gb3; Migalastat; Pharmacological chaperone.

Conflict of interest statement

Ethics approval and consent to participate

Written consent to participate in the study was obtained from all patients. The study was approved by the institutional review board or ethics committee at each participating center and was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.

Competing interests

RS has served as a consultant for and received research funding from Protalix Biotherapeutics and Amicus. DGB has received research funding, serves as a consultant, and is on the speaker’s bureau for Amicus and Genzyme, and has received research funding from Shire. AJ has received advisory honoraria and speaker’s fees from Shire, Amicus, Biomarin, and Genzyme. DAH has served as a consultant for and received research funding and honoraria from Amicus, Shire, Genzyme, Protalix, and Actelion. RG has received honoraria from Amicus, Biomarin, Genzyme, and Shire. UFR reports other support from Amicus during the conduct of the study, grant support and speaker’s honoraria from Amicus, Genzyme, and Shire HGT outside the submitted work, and research funding from Novo Nordisk Research Foundation. SPS reports grants and non-financial support from Amicus during the conduct of the study. LB has served as a consultant for Protalix. RBC has served as a consultant for Amicus and has received grants from the National Institutes of Health. JCJ does not have anything to disclose. KN has served as an advisor for Amicus, Shire HGT, and Genzyme, has received research support from Amicus and Shire HGT, and has received travel support from Genzyme. FH, AM, JPC, NS, and JAB are employees of and hold stock in Amicus.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Patients experiencing a minimal clinically important difference in GSRS-D scores after 6 months of treatment. a Improvement of 0.33. b Forest plot showing the effect size of migalastat treatment vs placebo. c Sensitivity analysis: improvement of 0.66

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