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

• Autor(a) principal: Schiffmann, Raphael
• Data de Publicação: 2018
• Outros Autores: Bichet, Daniel G., Jovanovic, Ana, Hughes, Derralynn A., Giugliani, Roberto, Feldt-Rasmussen, Ulla, Shankar, S. P., Barisoni, Laura, Colvin, Robert B., Jennette, J. Charles, Holdbrook, Fred, Mulberg, Andrew E., Castelli, Jeffrey P., Skuban, Nina, Barth, Jay, Nicholls, Kathleen M.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRGS
• Texto Completo: http://hdl.handle.net/10183/196144
• topic: Doença de Fabry; Diarréia; Amenable mutation; Diarrhea; Fabry disease; Gastrointestinal; Globotriaosylceramide; GSRS; Lyso-Gb3; Migalastat; Pharmacological chaperone

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.