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

doi:10.1186/s13023-018-0813-7

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

Department of Clinical Medicine

11 Citations (Scopus)

30 Downloads (Pure)

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 language	English
Article number	68
Journal	Orphanet Journal of Rare Diseases
Volume	13
Number of pages	7
ISSN	1750-1172
DOIs	https://doi.org/10.1186/s13023-018-0813-7
Publication status	Published - 27 Apr 2018

Keywords

1-Deoxynojirimycin/analogs & derivatives
Adolescent
Adult
Aged
Biomarkers/metabolism
Diarrhea/drug therapy
Fabry Disease/drug therapy
Female
Humans
Kidney/metabolism
Male
Middle Aged
Mutation/genetics
Trihexosylceramides
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Schiffmann, R., Bichet, D. G., Jovanovic, A., Hughes, D. A., Giugliani, R., Feldt-Rasmussen, U., Shankar, S. P., Barisoni, L., Colvin, R. B., Jennette, J. C., Holdbrook, F., Mulberg, A., Castelli, J. P., Skuban, N., Barth, J. A., & 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, Article 68. https://doi.org/10.1186/s13023-018-0813-7

Schiffmann, R, Bichet, DG, Jovanovic, A, Hughes, DA, Giugliani, R, Feldt-Rasmussen, U, Shankar, SP, 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, 68. https://doi.org/10.1186/s13023-018-0813-7

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

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.",

keywords = "1-Deoxynojirimycin/analogs & derivatives, Adolescent, Adult, Aged, Biomarkers/metabolism, Diarrhea/drug therapy, Fabry Disease/drug therapy, Female, Humans, Kidney/metabolism, Male, Middle Aged, Mutation/genetics, Trihexosylceramides, Young Adult",

author = "Raphael Schiffmann and Bichet, {Daniel G} and Ana Jovanovic and Hughes, {Derralynn A} and Roberto Giugliani and Ulla Feldt-Rasmussen and Shankar, {Suma P} and Laura Barisoni and Colvin, {Robert B} and Jennette, {J Charles} and Fred Holdbrook and Andrew Mulberg and Castelli, {Jeffrey P} and Nina Skuban and Barth, {Jay A} and Kathleen Nicholls",

year = "2018",

month = apr,

day = "27",

doi = "10.1186/s13023-018-0813-7",

language = "English",

volume = "13",

journal = "Orphanet Journal of Rare Diseases",

issn = "1750-1172",

publisher = "BioMed Central",

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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 -

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

Abstract

Keywords

UN SDGs

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