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

Raphael SchiffmannEmail author,
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 and
Kathleen Nicholls

Orphanet Journal of Rare Diseases201813:68

https://doi.org/10.1186/s13023-018-0813-7

Received: 29 November 2017

Accepted: 18 April 2018

Published: 27 April 2018

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.