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 Shankar, Laura Barisoni, Robert B. Colvin, J. Charles Jennette, Fred Holdbrook, Andrew Mulberg, Jeffrey P. Castelli, Nina Skuban, Jay A. Barth, Kathleen Nicholls

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number68
JournalOrphanet Journal of Rare Diseases
Volume13
Issue number1
DOIs
StatePublished - Apr 27 2018

Fingerprint

Fabry Disease
Diarrhea
Biomarkers
Mutation
Placebos
Kidney
migalastat

Keywords

  • Amenable mutation
  • Diarrhea
  • Fabry disease
  • Gastrointestinal
  • Globotriaosylceramide
  • GSRS
  • Lyso-Gb
  • Migalastat
  • Pharmacological chaperone

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Schiffmann, R., Bichet, D. G., Jovanovic, A., Hughes, D. A., Giugliani, R., Feldt-Rasmussen, U., ... Nicholls, K. (2018). Migalastat improves diarrhea in patients with Fabry disease: Clinical-biomarker correlations from the phase 3 FACETS trial. Orphanet Journal of Rare Diseases, 13(1), [68]. https://doi.org/10.1186/s13023-018-0813-7

Migalastat improves diarrhea in patients with Fabry disease : Clinical-biomarker correlations from the phase 3 FACETS trial. / Schiffmann, Raphael; Bichet, Daniel G.; Jovanovic, Ana; Hughes, Derralynn A.; Giugliani, Roberto; Feldt-Rasmussen, Ulla; Shankar, Suma; Barisoni, Laura; Colvin, Robert B.; Jennette, J. Charles; Holdbrook, Fred; Mulberg, Andrew; Castelli, Jeffrey P.; Skuban, Nina; Barth, Jay A.; Nicholls, Kathleen.

In: Orphanet Journal of Rare Diseases, Vol. 13, No. 1, 68, 27.04.2018.

Research output: Contribution to journalArticle

Schiffmann, R, Bichet, DG, Jovanovic, A, Hughes, DA, Giugliani, R, Feldt-Rasmussen, U, Shankar, S, Barisoni, L, Colvin, RB, Jennette, JC, Holdbrook, F, Mulberg, A, Castelli, JP, Skuban, N, Barth, JA & Nicholls, K 2018, 'Migalastat improves diarrhea in patients with Fabry disease: Clinical-biomarker correlations from the phase 3 FACETS trial', Orphanet Journal of Rare Diseases, vol. 13, no. 1, 68. https://doi.org/10.1186/s13023-018-0813-7
Schiffmann, Raphael ; Bichet, Daniel G. ; Jovanovic, Ana ; Hughes, Derralynn A. ; Giugliani, Roberto ; Feldt-Rasmussen, Ulla ; Shankar, Suma ; Barisoni, Laura ; Colvin, Robert B. ; Jennette, J. Charles ; Holdbrook, Fred ; Mulberg, Andrew ; Castelli, Jeffrey P. ; Skuban, Nina ; Barth, Jay A. ; Nicholls, Kathleen. / Migalastat improves diarrhea in patients with Fabry disease : Clinical-biomarker correlations from the phase 3 FACETS trial. In: Orphanet Journal of Rare Diseases. 2018 ; Vol. 13, No. 1.
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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.",
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AU - Bichet, Daniel G.

AU - Jovanovic, Ana

AU - Hughes, Derralynn A.

AU - Giugliani, Roberto

AU - Feldt-Rasmussen, Ulla

AU - Shankar, Suma

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

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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.

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