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

TY - JOUR

T1 - Migalastat improves diarrhea in patients with Fabry disease

T2 - clinical-biomarker correlations from the phase 3 FACETS trial

AU - Schiffmann, Raphael

AU - Bichet, Daniel G

AU - Jovanovic, Ana

AU - Hughes, Derralynn A

AU - Giugliani, Roberto

AU - Feldt-Rasmussen, Ulla

AU - Shankar, Suma P

AU - Barisoni, Laura

AU - Colvin, Robert B

AU - Jennette, J Charles

AU - Holdbrook, Fred

AU - Mulberg, Andrew

AU - Castelli, Jeffrey P

AU - Skuban, Nina

AU - Barth, Jay A

AU - Nicholls, Kathleen

PY - 2018/4/27

Y1 - 2018/4/27

N2 - 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.

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.

KW - 1-Deoxynojirimycin/analogs & derivatives

KW - Adolescent

KW - Adult

KW - Aged

KW - Biomarkers/metabolism

KW - Diarrhea/drug therapy

KW - Fabry Disease/drug therapy

KW - Female

KW - Humans

KW - Kidney/metabolism

KW - Male

KW - Middle Aged

KW - Mutation/genetics

KW - Trihexosylceramides

KW - Young Adult

U2 - 10.1186/s13023-018-0813-7

DO - 10.1186/s13023-018-0813-7

M3 - Journal article

C2 - 29703262

SN - 1750-1172

VL - 13

JO - Orphanet Journal of Rare Diseases

JF - Orphanet Journal of Rare Diseases

M1 - 68

ER -