PMID- 29703262 OWN - NLM STAT- MEDLINE DCOM- 20190415 LR - 20190415 IS - 1750-1172 (Electronic) IS - 1750-1172 (Linking) VI - 13 IP - 1 DP - 2018 Apr 27 TI - Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial. PG - 68 LID - 10.1186/s13023-018-0813-7 [doi] LID - 68 AB - 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. FAU - Schiffmann, Raphael AU - Schiffmann R AD - Baylor Scott & White Research Institute, Dallas, TX, USA. raphael.schiffmann@BSWhealth.org. AD - Institute of Metabolic Disease, 3812 Elm Street, Dallas, TX, 75226, USA. raphael.schiffmann@BSWhealth.org. FAU - Bichet, Daniel G AU - Bichet DG AD - Hopital du Sacre-Coeur, University of Montreal, Montreal, Quebec, Canada. FAU - Jovanovic, Ana AU - Jovanovic A AD - Salford Royal Foundation Trust, Manchester, Greater Manchester, UK. FAU - Hughes, Derralynn A AU - Hughes DA AD - NHS Foundation Trust, Royal Free Hospital, London, UK. FAU - Giugliani, Roberto AU - Giugliani R AD - Medical Genetics Service, HCPA/UFRGS, Porto Alegre, Brazil. FAU - Feldt-Rasmussen, Ulla AU - Feldt-Rasmussen U AD - Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. FAU - Shankar, Suma P AU - Shankar SP AD - Emory University School of Medicine, Atlanta, GA, USA. AD - Present Address: UC Davis MIND Institute, Sacramento, CA, USA. FAU - Barisoni, Laura AU - Barisoni L AD - Miller School of Medicine, University of Miami, Miami, FL, USA. FAU - Colvin, Robert B AU - Colvin RB AD - Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. FAU - Jennette, J Charles AU - Jennette JC AD - School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Holdbrook, Fred AU - Holdbrook F AD - Amicus Therapeutics, Inc., Cranbury, NJ, USA. FAU - Mulberg, Andrew AU - Mulberg A AD - Amicus Therapeutics, Inc., Cranbury, NJ, USA. FAU - Castelli, Jeffrey P AU - Castelli JP AD - Amicus Therapeutics, Inc., Cranbury, NJ, USA. FAU - Skuban, Nina AU - Skuban N AD - Amicus Therapeutics, Inc., Cranbury, NJ, USA. FAU - Barth, Jay A AU - Barth JA AD - Amicus Therapeutics, Inc., Cranbury, NJ, USA. FAU - Nicholls, Kathleen AU - Nicholls K AD - Department of Nephrology, Royal Melbourne Hospital, Parkville, VIC, Australia. LA - eng SI - ClinicalTrials.gov/NCT00925301 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20180427 PL - England TA - Orphanet J Rare Dis JT - Orphanet journal of rare diseases JID - 101266602 RN - 0 (Biomarkers) RN - 0 (Trihexosylceramides) RN - 19130-96-2 (1-Deoxynojirimycin) RN - 71965-57-6 (globotriaosylceramide) RN - C4XNY919FW (migalastat) SB - IM MH - 1-Deoxynojirimycin/*analogs & derivatives/therapeutic use MH - Adolescent MH - Adult MH - Aged MH - Biomarkers/metabolism MH - Diarrhea/*drug therapy MH - Fabry Disease/*drug therapy/metabolism MH - Female MH - Humans MH - Kidney/metabolism/pathology MH - Male MH - Middle Aged MH - Mutation/genetics MH - Trihexosylceramides MH - Young Adult PMC - PMC5923014 OTO - NOTNLM OT - Amenable mutation OT - Diarrhea OT - Fabry disease OT - GSRS OT - Gastrointestinal OT - Globotriaosylceramide OT - Lyso-Gb3 OT - Migalastat OT - Pharmacological chaperone COIS- 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. EDAT- 2018/04/29 06:00 MHDA- 2019/04/16 06:00 PMCR- 2018/04/27 CRDT- 2018/04/29 06:00 PHST- 2017/11/29 00:00 [received] PHST- 2018/04/18 00:00 [accepted] PHST- 2018/04/29 06:00 [entrez] PHST- 2018/04/29 06:00 [pubmed] PHST- 2019/04/16 06:00 [medline] PHST- 2018/04/27 00:00 [pmc-release] AID - 10.1186/s13023-018-0813-7 [pii] AID - 813 [pii] AID - 10.1186/s13023-018-0813-7 [doi] PST - epublish SO - Orphanet J Rare Dis. 2018 Apr 27;13(1):68. doi: 10.1186/s13023-018-0813-7.