Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jul;60(7):722-731.
doi: 10.1136/jmg-2022-108669. Epub 2022 Dec 21.

Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes

Derralynn A Hughes  1 , Daniel G Bichet  2 , Roberto Giugliani  3 , Robert J Hopkin  4 , Eva Krusinska  5 , Kathleen Nicholls  6 , Iacopo Olivotto  7 , Ulla Feldt-Rasmussen  8 , Norio Sakai  9 , Nina Skuban  5 , Gere Sunder-Plassmann  10 , Roser Torra  11 , William R Wilcox  12
Affiliations

Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes

Derralynn A Hughes et al. J Med Genet. 2023 Jul.

Abstract

Background: Fabry disease is a rare, multisystemic disorder caused by GLA gene variants that lead to alpha galactosidase A deficiency, resulting in accumulation of glycosphingolipids and cellular dysfunction. Fabry-associated clinical events (FACEs) cause significant morbidity and mortality, yet the long-term effect of Fabry therapies on FACE incidence remains unclear.

Methods: This posthoc analysis evaluated incidence of FACEs (as a composite outcome and separately for renal, cardiac and cerebrovascular events) in 97 enzyme replacement therapy (ERT)-naïve and ERT-experienced adults with Fabry disease and amenable GLA variants who were treated with migalastat for up to 8.6 years (median: 5 years) in Phase III clinical trials of migalastat. Associations between baseline characteristics and incidence of FACEs were also evaluated.

Results: During long-term migalastat treatment, 17 patients (17.5%) experienced 22 FACEs and there were no deaths. The incidence rate of FACEs was 48.3 events per 1000 patient-years overall. Numerically higher incidence rates were observed in men versus women, patients aged >40 years versus younger patients, ERT-naïve versus ERT-experienced patients and men with the classic phenotype versus men and women with all other phenotypes. There was no statistically significant difference in time to first FACE when analysed by patient sex, phenotype, prior treatment status or age. Lower baseline estimated glomerular filtration rate (eGFR) was associated with an increased risk of FACEs across patient populations.

Conclusions: The overall incidence of FACEs for patients during long-term treatment with migalastat compared favourably with historic reports involving ERT. Lower baseline eGFR was a significant predictor of FACEs.

Keywords: Cardiovascular Diseases; Cerebrovascular Disorders; Genetics, Medical; Mutation.

PubMed Disclaimer

Conflict of interest statement

Competing interests: DAH reports advisory board participation, consulting fees and honoraria for Takeda, Sanofi, Amicus Therapeutics, Inc., Idorsia, Freeline and Protalix. DGB reports advisory board participation, consulting fees, speakers’ bureau fees and honoraria from Amicus Therapeutics, Inc. and Sanofi/Genzyme. RG reports consulting fees from Abeona, Amicus Therapeutics, Inc., Chiesi, Denali, Inventiva, JCR, Novartis, PTC, Protalix, RegenxBio and Sobi; speakers’ bureau fees from BioMarin, Amicus Therapeutics, Inc., Chiesi, Idorsia, Janssen, Novartis, Pfizer, PTC, Sanofi and Takeda; research funding from Allievex, Avrobio, Azafaros, JCR, Lysogene, Paradigm, PassageBio, RegenxBio, Sanofi, Sigilon, Takeda and Ultragenyx. RJH reports consulting fees from Alexion, Amicus Therapeutics, Inc., Avrobio, Chiesi, Sangamo, Sanofi/Genzyme and Takeda; advisory fees from Alexion, Amicus Therapeutics, Inc. and Sanofi/Genzyme; speakers’ bureau fees from Alexion and Sanofi/Genzyme and grants/research funding from Alexion, Amicus Therapeutics, Inc., Idorsia, Protalix, Sangamo, Sanofi/Genzyme and Takeda. EK reports consulting fees from Amicus Therapeutics, Inc. KN reports advisory board participation for Amicus Therapeutics, Inc., Takeda and Sanofi/Genzyme; consulting fees from Amicus Therapeutics, Inc. and Takeda and research funding from Amicus Therapeutics, Inc., Takeda, Sanofi/Genzyme, Idorsia and Avrobio. IO reports advisory board participation for Amicus Therapeutics, Inc., Bristol Myers Squibb, Bayer, Astra Zeneca and Cytokinetics; contracted research for Amicus Therapeutics, Inc., Menarini International, Shire-Takeda, Bristol Myers Squibb, Boston Scientific and Sanofi/Genzyme and speaker’s bureau fees from Boston Scientific, Bristol Myers Squibb and Sanofi/Genzyme. UF-R reports advisory board participation from Amicus Therapeutics, Inc., Freeline, Sanofi/Genzyme and Takeda; speakers’ fees and travel support from Amicus Therapeutics, Inc., Sanofi/Genzyme and Takeda and research funding from Sanofi/Genzyme and Takeda. NSa reports speakers’ bureau fees from Amicus Therapeutics, Inc., Takeda, JCR and Sanofi and research funding from JCR and Sanofi. NSk was an employee and stockholder in Amicus Therapeutics, Inc. at the time of drafting this manuscript and determining the analysis plan. GS-P reports advisory board participation for Amicus Therapeutics, Inc. and Sanofi, research grants/funding from Amicus Therapeutics, Takeda, Idorsia and Freeline and honoraria from Amicus Therapeutics, Inc. and Sanofi. RT reports advisory board participation, consulting fees and honoraria for Takeda, Sanofi, Amicus Therapeutics, Inc. and Chiesi. WRW reports advisory board participation for Sanofi/Genzyme, Takeda, Chiesi, Alexion/Astra Zeneca and BioMarin; research funding from Amicus Therapeutics, Inc. and Takeda; consulting fees from Amicus Therapeutics, Inc. and Spark; contracted clinical study research from Amicus Therapeutics, Inc., Alexion/Astra Zeneca, BioMarin, Chiesi, Freeline, Orphazyme, Pfizer, Protalix, Sangamo, Sanofi/Genzyme, Takeda and 4D Molecular Therapeutics.

Figures

Figure 1
Figure 1
FACE incidence per 1000 patient-years by ERT status and baseline characteristics while receiving migalastat, (A) overall and (B) by event category. Incidence rates of FACEs while receiving migalastat. (A) For overall FACEs, shown as events per 1000 patient-years for all patients and for ERT-naïve patients* or ERT-experienced patients,† both further analysed by sex and age (≤40 or >40 years) and by phenotype (classic man or other) in ERT-naïve patients or by multiorgan involvement or other in ERT-experienced patients. Circle size correlates with number of events. Overall FACEs included all cardiac, cerebrovascular and renal events (as previously defined) and death due to FACE. (B) For individual renal, cardiac and cerebrovascular events, shown as events per 1000 patient-years, for all patients, sex, age (≤40 years or >40 years) and by ERT status, which were further analysed by phenotype (classic man or other) for ERT-naïve patients* or by men with multiorgan involvement or other in ERT-experienced patients.† Classic men are defined as men with multiorgan involvement (ie, at least two organs of the renal system, cardiac system, central nervous system, peripheral nervous system and gastrointestinal system are affected) and baseline white blood cell α-Gal A<3% of wild type. ‘Other’ patients include non-classic men and all women. *ERT naïve is defined as never having received ERT or not having received ERT for >6 months. †ERT experienced is defined as having initiated ERT>12 months prior to study. ERT, enzyme replacement therapy; FACE, Fabry-associated clinical event.
Figure 2
Figure 2
Kaplan–Meier analysis of time to first composite event by (A) prior treatment status and (B) sex. Time to first composite event by (A) ERT-naïve and ERT-experienced patients and (B) sex, which was further analysed according to ERT status. Composite event included cardiac, cerebrovascular and renal events (as previously defined) and death due to FACE. Number of subjects with events at time 0 is 0. ERT, enzyme replacement therapy.
Figure 3
Figure 3
Influence of baseline variables on the risk of FACE occurrence (time to first FACE) during migalastat treatment. This analysis included only patients with non-missing covariates (n=91). HR for each baseline factor (left side of the graph) is assessed for its influence on time to first FACE during migalastat treatment using Cox regression. HR>1 indicates increased risk of FACE and HR<1 indicates decreased risk of FACE. FACE included renal, cardiac or cerebrovascular events (as previously defined) or death due to FACE. See online supplemental table 3 for associations between baseline variables and the risk of FACEs (composite events). eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; FACE, Fabry-associated clinical event; LVMI, left ventricular mass index.
Figure 4
Figure 4
Graphical abstract.
See this image and copyright information in PMC

References

    1. Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30. 10.1186/1750-1172-5-30 - DOI - PMC - PubMed
    1. Rozenfeld P, Feriozzi S. Contribution of inflammatory pathways to Fabry disease pathogenesis. Mol Genet Metab 2017;122:19–27. 10.1016/j.ymgme.2017.09.004 - DOI - PubMed
    1. Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab 2018;123:416–27. 10.1016/j.ymgme.2018.02.014 - DOI - PubMed
    1. Sugarman M, Choudhury J, Jovanovic A. An atypical p.N215S variant of Fabry disease with end-stage renal failure. Mol Genet Metab Rep 2018;15:43–5. 10.1016/j.ymgmr.2018.01.006 - DOI - PMC - PubMed
    1. Di Stefano V, Mancarella M, Camporeale A, Regalia A, Ferraresi M, Pisaniello M, Cassinerio E, Pieruzzi F, Motta I. Migalastat treatment in a kidney-transplanted patient with Fabry disease and N215S mutation: the first case report. Pharmaceuticals 2021;14. 10.3390/ph14121304 - DOI - PMC - PubMed

Publication types