Molecular Genetics and Metabolism Reports 28 (2021) 100786 Contents lists available at ScienceDirect Molecular Genetics and Metabolism Reports journal homepage: www.elsevier.com/locate/ymgmr Long-term follow-up of renal function in patients treated with migalastat for Fabry disease Daniel G. Bichet a, *, Roser Torra b, Eric Wallace c, Derralynn Hughes d, Roberto Giugliani e, Nina Skuban f, 1, Eva Krusinska f, 2, Ulla Feldt-Rasmussen g, Raphael Schiffmann h, Kathy Nicholls i a Department of Medicine, Hôpital du Sacré-Coeur, University of Montréal, Montreal, Quebec, Canada b Inherited Renal Disorders, Nephrology Department, Fundació Puigvert, REDINREN, IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain c Department of Medicine, University of Alabama, Birmingham, AL, USA d Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, UK e Medical Genetics Service, Department of Genetics, Institute of Biosciences, Institute of Basic Health Sciences, Faculty of Medicine, Faculty of Pharmacy (UFRGS) and, National Institute of Population Medical Genetics (INAGEMP), Porto Alegre, Brazil f Amicus Therapeutics, Inc., Cranbury, NJ, USA g Department of Medical Endocrinology and Metabolism, Rigshospitalet, National University Hospital, Copenhagen University, Copenhagen, Denmark h Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA i Department of Nephrology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia A R T I C L E I N F O A B S T R A C T Keywords: The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)–naive and ERT- Classic phenotype experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 Efficacy clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in Fabry disease patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during Chaperone Migalastat these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated Renal function glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 1.8 mL/min/1.73 m2 and − 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 2.6 mL/min/1.73 m2 and − 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was − 1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: − 0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype. Abbreviations: α-Gal A, α-galactosidase A; Gb3, globotriaosylceramide; eGFRCKD-EPI, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; GLP-HEK, Good Laboratory Practice-validated human embryonic kidney; LVMi, left ventricular mass index; Q1, quartile 1; Q3, quartile 3; RI, renin inhibitor. * Corresponding author at: Hôpital du Sacré-Coeur de Montréal, Research Center, 5400 Blvd Gouin Ouest, Montréal, Québec H4J 1C5, Canada. E-mail address: Daniel.bichet@umontreal.ca (D.G. Bichet). 1 Current affiliation: Innocoll Pharmaceuticals, Newtown Square, PA, USA. 2 Author working as a consultant under the contract of Pharmaland Consulting Group. https://doi.org/10.1016/j.ymgmr.2021.100786 Received 30 July 2021; Accepted 31 July 2021 2214-4269/© 2021 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). D.G. Bichet et al. Molecular Genetics and Metabolism Reports 28 (2021) 100786 1. Introduction profibrotic processes that subsequently lead to glomerular injury [4,5]. Fabry disease is X-linked, and hemizygous males typically experience Fabry disease is a rare, multisystemic disorder caused by pathogenic the most severe manifestations; however, heterozygous females can GLA gene variants that result in functional deficiency of lysosomal develop complications in major organs [1]. Renal manifestations are a enzyme α-galactosidase A (α-Gal A) and accumulation of globo­ significant cause of mortality and morbidity in Fabry disease [6,7], with triaosylceramide (Gb3) throughout the body [1,2]. renal disease being reported as the third most common cause of death In the kidney, glycosphingolipids accumulate in multiple kidney cell after cardiac and cerebrovascular disease based on registry data [7]. types, such as podocytes, endothelial cells, and tubular epithelial cells, Furthermore, decreased renal function and kidney failure have been causing proteinuria and a decline in glomerular filtration rate (GFR) [3]. associated with cardiovascular events and stroke, suggesting that renal Furthermore, the accumulation of Gb3 activates inflammatory and and cardiac manifestations may be interrelated in Fabry disease [8,9]. FACETS ATTRACT Double-blind Migalastat Double-blind Placebo Open-label Migalastat Open-label ERT Baseline 123 mg QOD QOD 123 mg QOD n=19 Baseline n=28 n=22 n=34 (amenable) (amenable) (amenable) (amenable) Open-label Migalastat 123 mg QOD Month 6 n=47 (amenable) Completed treatment Completed treatment Completed treatment Month 12 n=44 n=32 n=16 Month 18 (amenable) (amenable) (amenable) 2 declined extension 1 declined extension 1 declined extension Open-label Migalastat Open-label Migalastat 123 mg QOD 123 mg QOD n=42 n=46 (amenable) (amenable) Completed treatment Completed treatment Month 24 n=41 n=42 Month 30 (amenable) (amenable) 6 declined extension Open-label Migalastat 123 mg QOD AT1001-041 n=68 (amenable)a n=21 entered AT1001-041 n=63 entered n=20 entered AT1001-042 Open-label Migalastat AT1001-042 AT1001-042 123 mg QOD Baseline N=84 (n=83 amenable)b c Variable Completed treatment (up to n=73 48 months)d (amenable) Switched to commercial migalastat n=68 (amenable) Fig. 1. Patient flow in phase 3 studies of migalastat. a The AT1001–041 study also included 12 amenable patients from phase 2 studies. b The AT1001–042 study also enrolled 1 patient from a phase 2 study, for a total of 84 patients, including 1 patient who had a nonamenable GLA variant. c One patient discontinued due to an adverse event, 3 patients met protocol-defined stopping criteria (ie, estimated glomerular filtration rate < 30 mL/min/1.73 m2), 1 patient was lost to follow-up, 4 patients discontinued per physician decision, and 2 patients chose to withdraw. d Duration of the treatment varied among patients. Patients completed the study when they switched to commercial migalastat or had access to migalastat through an alternate source. ERT, enzyme replacement therapy; QOD, every other day. 2 D.G. Bichet et al. Molecular Genetics and Metabolism Reports 28 (2021) 100786 Current treatments for Fabry disease include enzyme replacement glomerular filtration rate using the Chronic Kidney Disease Epidemi­ therapy (ERT) with recombinant human α-Gal A and the oral pharma­ ology Collaboration equation (eGFRCKD-EPI) [19]. eGFRCKD-EPI was cological chaperone migalastat [10–12]. As a small molecule pharma­ determined at baseline and every 6 months through to the completion of cological chaperone, migalastat binds to and stabilizes amenable mutant each study, and annualized changes in eGFRCKD-EPI were calculated. forms of α-Gal A in the endoplasmic reticulum, facilitating trafficking of α-Gal A to lysosomes and restoring endogenous enzyme activity [13,14]. 2.4. Statistical analyses Migalastat 123 mg every other day is approved for the treatment of Fabry disease in adult patients in the United States and in patients aged The annualized rate of change in eGFRCKD-EPI was calculated with ≥16 years in the European Union who have an amenable GLA variant. two methods: by the slope of simple linear regression based on observed In phase 3 clinical trials, migalastat demonstrated efficacy in values and assessment times [15] and by a random coefficient model reducing Gb3 in diverse renal cell types and in stabilizing renal function [20]. The simple linear regression was calculated individually for each [15–17]. ERT-naive patients demonstrated stable renal function for ≤2 patient using their longitudinal data. The random coefficient model years in the double-blind, placebo-controlled study FACETS, as calcu­ comprised a mixed model that included eGFR as the dependent variable lated by simple linear regression [15]. In the open-label, active- and study visit as a main effect, and the rate of eGFR decline was controlled ATTRACT study, ERT-experienced patients who switched to adjusted for the following baseline factors: sex, age, baseline eGFRCKD- migalastat experienced an annualized rate of change in GFR comparable EPI, baseline proteinuria, and time from Fabry diagnosis. Random co­ to that of patients who continued ERT [16]. In ERT-naive patients, the efficients were used for the intercept and visit. The beginning of miga­ mean annualized rate of change from baseline to month 24 was − 0.3 lastat treatment was the baseline and corresponded to month 6 of mL/min/1.73 m2 with migalastat [15]. In ERT-experienced patients, the FACETS for patients in the placebo arm and month 18 of ATTRACT for mean annualized rate of change in estimated glomerular filtration rate patients in the ERT arm. One model was fitted on all data which resulted (eGFR) from baseline to month 18 was − 0.4 mL/min/1.73 m2 after in obtaining a slope for each patient adjusted for the covariates. Then the switching to migalastat and − 1.0 mL/min/1.73 m2 in patients slopes were grouped by sex, baseline eGFRCKD-EPI (>30 to <60, 60–90, continuing ERT [16]. and > 90 mL/min/1.73 m2), baseline urine protein (< 300, 300–1000, Studies are ongoing to evaluate long-term renal outcomes in ERT- and > 1000 mg/24 h). For ERT-naive patients, the slope was also naive and ERT-experienced patients treated with migalastat. Here, a grouped by phenotype (male patients with the classic phenotype vs post hoc analysis was conducted to evaluate long-term changes in renal others). ERT-naive male patients were classified as having the classic function in 78 patients with Fabry disease and amenable GLA variants phenotype if they had residual white blood cell α-Gal A activity of <3% who were treated with migalastat for ≥2 years in the phase 3 FACETS of normal and multiorgan system involvement at baseline, defined as and ATTRACT trials and long-term open-label extension (OLE) studies. involvement of ≥2 of the following organ systems: renal, cardiac, central nervous system, peripheral nervous system, and gastrointestinal tract 2. Materials and methods (Table A.1) [21]. The classification of “Other” included ERT-naive male patients who did not meet the above criteria and all ERT-naive female 2.1. Design patients [21]. ERT-experienced male patients were not evaluated by phenotype because their baseline white blood cell α-Gal A activity may ERT-naive and ERT-experienced patients enrolled in the phase 3 have been confounded by previous ERT. Instead, we analyzed a subset of FACETS (AT1001–011; NCT00925301) or ATTRACT (AT1001–012; ERT-experienced male patients who had multiorgan involvement at NCT01218659) clinical trials received migalastat 123 mg every other baseline. day for ≥2 years; details of these studies have been described previously Descriptive statistics including mean, standard deviation (SD), me­ [15,16]. Patients completing FACETS or ATTRACT were also allowed to dian, range, and percent of total were used for efficacy analyses. enter an additional OLE study of ≤5 years (AT1001–041 [NCT01458119] and/or AT1001–042 [NCT02194985]). 2.5. Ethics We performed a post hoc analysis in which data collected during FACETS, ATTRACT, and the subsequent 5-year OLE studies FACETS, ATTRACT, AT1001–041, and AT1001–042 were designed (AT1001–041 and/or AT1001–042) (Fig. 1) were integrated across and monitored in accordance with the ethical principles of Good Clinical studies. The data cutoff date for the ongoing AT1001–042 study was Practice and the Declaration of Helsinki. Clinical protocols for these March 11, 2020. studies were reviewed and approved by the appropriate Independent Ethics Committee/Institutional Review Board at each study site. All 2.2. Participants patients provided written informed consent prior to initiation of the study. Selection criteria for patients enrolled in the FACETS and ATTRACT studies have been previously published [15,16]. Briefly, patients were 3. Results ERT-naive (FACETS; never received ERT or had not received ERT for ≥6 months) or ERT-experienced (ATTRACT; initiated ERT ≥ 12 months 3.1. Demographics and baseline characteristics of the integrated analysis before study entry); aged 16–74 years; had genetically confirmed Fabry population disease; and had GLA variants that met the amenability criteria. Patients had an eGFR of ≥30 mL/min/1.73 m2 at enrollment, and those taking Demographic characteristics of the 78 patients who had ≥2 years of angiotensin-converting-enzyme inhibitors and/or angiotensin II recep­ migalastat treatment are shown in Table 1. Of these, 36 were ERT-naive tor blockers had to be on a stable dose for ≥4 weeks before the screening (23 females), and 42 were ERT-experienced (24 females). The mean (SD) visit [15,16]. This post hoc analysis included all patients who received age of patients at treatment initiation was 45.1 (10.5) years in the ERT- migalastat for ≥2 years and had migalastat-amenable GLA variants naive group and 50.1 (13.8) years in the ERT-experienced group. The based on results from the good laboratory practice-validated assay using mean (SD) time since Fabry diagnosis was 7.4 (8.0) years in ERT-naive human embryonic kidney 293 cells (GLP-HEK assay) [18]. patients and 12.6 (12.4) years in ERT-experienced patients. Overall, 78% of patients had multiorgan involvement (81% of ERT-naive patients 2.3. Study endpoints and assessments and 76% of ERT-experienced patients). In particular, male patients with the classic phenotype comprised 27.8% of the ERT-naive group and male Serum creatinine values were used to calculate the estimated patients with multiorgan involvement made up 35.7% of the ERT- 3 D.G. Bichet et al. Molecular Genetics and Metabolism Reports 28 (2021) 100786 Table 1 Baseline characteristics. Variable Overall (N = ERT-naive patients ERT-experienced Males (n = 31) Females (n = 78) a patients (n = 42) 47) All (n = 36) Classic phenotype Other (n = 26) (n = 10) Age (years) Mean (SD) 47.8 (12.6) 45.1 (10.5) 45.6 (12.0) 44.9 (10.2) 50.1 (13.8) 48.7 (12.2) 47.2 (12.9) Median (range) 48.0 (18–70) 45.5 (25–68) 45.0 (25–62) 46.0 (27–68) 53.5 (18–70) 48.0 (20–67) 48.0 (18–70) Sex, n (%) Male 19 (24.4) 13 (36.1) 10 (100) 2 (11.5) 18 (42.9) 31 (100) 0 Female 59 (75.6) 23 (63.9) 0 23 (88.5) 24 (57.1) 0 47 (100%) Race, n(%) White 70 (89.7) 34 (94.4) 9 (90.0) 25 (96.2) 36 (85.7) 27 (87.1) 43 (91.5) Asian 5 (6.4) 0 0 0 5 (11.9) 3 (9.7) 2 (4.3) Multiple 1 (1.3) 0 0 0 1 (2.4) 0 1 (2.1) Other 2 (2.6) 2 (5.6) 1 (10.0) 1 (2.8) 0 1 (3.2) 1 (3.2) eGFRCKD-EPI (mL/min/ 1.73 m2) Mean (SD) 90.2 (21.0) 91.4 (22.4) 86.4 (27.5) 93.3 (20.4) 89.2 (19.9) 85.8 (22.1) 93.1 (19.9) Median (range) 90.3 92.0 94.8 (41.4–119.0) 92.0 88.9 (51.4–131.3) 84.0 95.9 (41.4–131.3) (41.4–125.6) (44.6–125.6) (41.4–131.3) (44.6–125.6) eGFRCKD-EPI category, n (%) >30–<60 mL/min/ 5 (6.4) 3 (8.3) 2 (20.0) 1 (3.8) 2 (4.8) 4 (12.9) 1 (2.1) 1.73 m2 60–90 mL/min/1.73 33 (42.3) 14 (38.9) 3 (30.0) 11 (42.3) 19 (45.2) 15 (48.4) 18 (38.3) m2 >90 mL/min/1.73 m2 40 (51.3) 19 (52.8) 5 (50.0) 14 (53.8) 21 (50.0) 12 (38.7) 28 (59.6) Urinary protein, mg/24 h, n (%) <300 mg/24 h 54 (69.2) 22 (61.1) 4(40.0) 18 (69.2) 32 (76.2) 18 (58.1) 36 (76.6) 300–1000 mg/24 h 18 (23.1) 10 (27.8) 4 (40.0) 6 (23.1) 8 (19.0) 9 (29.0) 9 (19.1) >1000 mg/24 h 6 (7.7) 4 (11.1) 2 (20.0) 2 (7.7) 2 (4.8) 4 (12.9) 2 (4.3) Patients taking ACEI/ 32 (41.0) 10 (27.8) 4 (40.0) 6 (23.1) 22 (52.4) 13 (41.9) 19 (40.4) ARB/RI, n (%) Time since diagnosis (years) Mean (SD) 10.2 (10.9) 7.4 (8.0) 6.5 (4.4) 7.8 (9.1) 12.6 (12.4) 7.9 (8.6) 11.8 (11.9) Median (range) 5.5 (1.0, 44.0) 5.0 (1.0, 34.0) 6.0 (1–14) 5.0 (1–34) 6.0 (3.0, 44.0) 5.0 (1.0, 39.0) 6.0 (1.0, 44.0) LVMi (g/m2) Mean (SD) 95.7 (30.3) 99.2 (35.3) 120.5 (24.8) 89.9 (35.5) 92.9 (25.8) 116.4b (35.3) 82.4 (16.3)b Median (range) 88.8 (47.7, 88.8 (61.0, 115.4 (89.6–176.2) 81.2 87.9 (47.7, 165.7) 109.4 (69.9, 77.6 (47.7, 234.4) 234.4) (61.0–234.4) 234.4) 121.8) α-Gal A, alpha galactosidase; ACEI, angiotension-converting enyzme inhibitor; ARB, angiotension II receptor blockers; eGFRCKD-EPI, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; ERT,enzyme replacement therapy; LVMi, left ventricular mass index; RI, renin inhibitor; SD, standard deviation. a ERT-naive male patients who had residual white blood cell α-Gal A activity of <3% of normal and multiorgan system involvement, defined as involvement of ≥2 of the following organ systems: renal, cardiac, central nervous system, peripheral nerves, and gastrointestinal tract [21]. b LVMi data were not available for 2 male patients and 2 female patients. experienced group. The median (range) migalastat treatment duration Table 2 was 7.0 (2.0–8.6) years and 5.1 (2.1–7.2) years for ERT-naive and ERT- Annualized rate of change in eGFRCKD-EPI in ERT-naive and ERT-experienced experienced patients, respectively. patients treated with migalastat for ≥2 years using simple linear regression. ERT-naive patients ERT-experienced patients 3.2. Effects on renal function Overall Male Female Overall Male Female During long-term follow-up, renal function was generally stable in (n = 36) (n = 13) (n = 23) (n = 42) (n = 18) (n = 24) both ERT-naive and ERT-experienced patients and in both male and Mean − 1.6 − 1.8 − 1.4 − 1.6 − 2.6 − 0.8 female patients (Table 2). Using simple linear regression, the mean (SD) (SD) (3.1) (2.7) (3.3) (3.6) (4.8) (2.1) annualized rates of change in eGFRCKD-EPI were − 1.6 (3.1) mL/min/ Median − 1.1 − 1.0 − 1.1 − 1.3 − 1.4 − 1.1 1.73 m2 and − 1.6 (3.6) mL/min/1.73 m2 in ERT-naive and ERT- (Q1, (− 2.4, (− 3.8, (− 1.7, (− 2.2, (− 2.6, (− 2.1, Q3) − 0.6) − 0.8) − 0.6) − 0.5) − 0.7) − 0.4) experienced patients, respectively. eGFRCKD-EPI over time and annual­ ized rate of change in eGFRCKD-EPI in individual patients are shown in eGFRCKD-EPI, estimated glomerular filtration rate using the Chronic Kidney Fig. 2 and Fig. A.1A, respectively. Using the random coefficient model, Disease Epidemiology Collaboration equation; ERT, enzyme replacement ther­ which adjusted for age, sex, baseline renal function, and time since apy; SD, standard deviation; Q1, quartile 1; Q3, quartile 3. Fabry diagnosis, the mean (SD) annualized rates of change in eGFRCKD- 2 2 (Table A.2). EPI were − 0.1 (1.8) mL/min/1.73 m and 0.1 (1.7) mL/min/1.73 m in ERT-naive and ERT-experienced patients, respectively. When patients eGFRCKD-EPI, estimated glomerular filtration rate using the Chronic were analyzed by sex, the mean annualized rates of change in eGFRCKD- Kidney Disease Epidemiology Collaboration equation; ERT, enzyme 2 replacement therapy. EPI were − 0.5 mL/min/1.73 m in (ERT-naive) and − 0.4 mL/min/1.73 m2 in (ERT-experienced) in males, and 0.1 mL/min/1.73 m2 in (ERT- Annualized rates of change from baseline in eGFRCKD-EPI by baseline naive) and 0.5 mL/min/1.73 m2 (ERT-experienced) in females renal function are provided in Table 3 (simple linear regression) and 4 D.G. Bichet et al. Molecular Genetics and Metabolism Reports 28 (2021) 100786 A 150 140 130 120 eGFRCKD-EPI (mL/min/1.73m2) 110 100 90 80 70 60 50 40 30 20 10 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 Time (years) ERT-naïve Males (n = 13) ERT-experienced Males (n = 18) B 150 140 130 120 eGFRCKD-EPI (mL/min/1.73m2) 110 100 90 80 70 60 50 40 30 20 10 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 Time (years) ERT-naïve Females (n = 23) ERT-experienced Females (n = 24) Fig. 2. Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation over time in (A) male and (B) female patients receiving long-term migalastat treatment. 5 D.G. Bichet et al. Molecular Genetics and Metabolism Reports 28 (2021) 100786 Table 3 Annualized rates of change in eGFRCKD-EPI in ERT-naive and ERT-experienced patients treated with migalastat for ≥2 years by baseline renal function using simple linear regression. ERT-naive patients ERT-experienced patients n = 36 n = 42 Baseline eGFRCKD-EPI, mL/min/1.73 m2 >90 60–90 >30–<60 >90 60–90 >30–<60 (n = 19) (n = 14) (n = 3) (n = 21) (n = 19) (n = 2) Mean (SD) − 2.2 (2.9) − 0.81 (2.9) − 1.2 (5.1) − 1.2 (1.5) − 1.6 (5.0) − 4.7 (2.1) Median (Q1, Q3) − 1.0 − 1.1 − 1.2 − 1.3 − 0.9 − 4.7 (− 2.3, − 0.7) (− 2.6, 0.1) (− 6.3, 4.0) (− 2.0, − 0.8) (− 2.2, − 0.2) (− 6.2, − 3.2) Baseline urinary protein, mg/24 h <300 (n = 22) 300–1000 (n = 10) >1000 (n = 4) <300 (n = 32) 300–1000 (n = 8) >1000 (n = 2) Mean (SD) − 2.0 (3.0) − 0.1 (3.1) − 2.9 (2.6) − 0.8 (1.9) − 1.9 (0.8) − 13.3 (10.1) Median (Q1, Q3) − 1.1 (− 2.3, − 0.7) − 0.8 (− 1.7, 0.0) − 2.3 − 1.0 (− 1.7, − 0.3) − 1.7 (− 2.6, − 1.3) − 13.3 (− 5.0, − 0.8) (− 20.5, − 6.2) eGFRCKD-EPI, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; ERT, enzyme replacement therapy; Q1, quartile 1; Q3, quartile 3; SD, standard deviation. Table A.3 (random coefficient model); Fig. A.1B shows individual pa­ plotted against patient age in Fig. A.2. tient data. We analyzed the influence of each covariate included in the analysis and found that baseline eGFR was significant in predicting 4. Discussion further decline in renal function (p < 0.0001), followed by age (p = 0.046). Baseline urine protein was approaching statistical significance This post hoc analysis assessed long-term renal measures associated (p = 0.059). Other covariates were not significant. with migalastat therapy in ERT-naive and ERT-experienced patients Annualized change in eGFRCKD-EPI up to 24 months has been reported with Fabry disease and amenable GLA variants. With either the random for 16 male patients with the classic phenotype in FACETS [21]. Among coefficient model or simple linear regression, ERT-naive and ERT- them, 10 patients had received migalastat for ≥2 years and were experienced patients who received migalastat treatment for ≥2 and ≤ included in the current post hoc analysis. The mean (SD) annualized 8.6 years in the current study had a rate of eGFR decline that was slower rates of change in eGFRCKD-EPI were − 1.7 (3.0) mL/min/1.73 m2 in this than that in untreated historical cohorts [22,23] and similar to the subset of male patients with the classic phenotype and − 1.5 (3.2) mL/ normal rate of decline with age [24]. Renal function was also generally min/1.73 m2 in other patients in FACETS (simple regression) during stable in patients receiving long-term migalastat treatment irrespective long-term follow-up (Table 4). Using the random coefficient model, the of treatment status, sex, or phenotype. mean (SD) annualized rates of change in eGFRCKD-EPI were − 0.5 (2.1) Although linear regression models have often been used to estimate mL/min/1.73 m2 in ERT-naive males with the classic phenotype and 0.0 rates of change in eGFR over time, this statistical method fails to (1.7) mL/min/1.73 m2 in other patients in FACETS, respectively consider the correlation among repeated measurements in the same (Table A.4). Annualized rate of change in eGFRCKD-EPI in male patients patient. A subject-specfic mixed model with random intercepts and with multiorgan involvement versus others have been similarly slopes for each patient may be more suitable to the heterogeneous na­ analyzed for ERT-experienced patients (Table A4 and Table A.4) The ture of Fabry disease and has been used to describe the natural history of genotype, phenotype, and annualized rate of change in eGFRCKD-EPI of Fabry nephropathy [22], which showed that untreated males and fe­ individual patients are presented in Table A.5. Multiorgan involvement males (mean age 41 years at baseline) with a baseline eGFRMDRD of ≥60 for patients is listed in Table A.6. Individual eGFRCKD-EPI slopes are mL/min/1.73 m2 experienced an annual loss in eGFR of − 3.0 mL/min/ 1.73 m2 and − 0.9 mL/min/1.73 m2, respectively; males and females with chronic kidney disease at baseline experienced an annual loss in Table 4 Annualized rates of change in eGFRCKD-EPI in ERT-naive and ERT-experienced eGFR of − 6.8 mL/min/1.73 m2 and − 2.1 mL/min/1.73 m2, respectively patients treated with migalastat for ≥2 years by disease characteristics using [22]. Using a similar model, we found that eGFRCKD-EPI remained stable simple linear regression. during median follow-ups of 7 years and 5 years in ERT-naive and ERT- experienced patients, respectively (mean annualized rate of change was ERT-naive ERT-experienced − 0.1 mL/min/1.73 m2 and 0.1 mL/min/1.73 m2, respectively). Classic Others Multiorgan Others A range of mean eGFR declines has been reported for ERT using phenotypea involvementb different statistical methods [25–28]. In a 5-year follow-up of adult (n = 10) (n = 26) (n = 15) (n = 27) patients treated with agalsidase alfa or agalsidase beta, the mean Mean (SD) − 1.7 (3.0) − 1.5 (3.2) − 2.5 (5.1) − 1.1 (2.3) annualized rates of change in eGFR were approximately − 3 mL/min/ Median − 0.9 (− 4.0, − 1.1 (− 2.3, − 1.3 (− 2.6, − 0.4) − 1.3 (− 2.2, 1.73 m2 in males (mean age 38.9 years, mean baseline eGFR 88.5 mL/ (Q1, Q3) 0.1) − 0.7) − 0.5) min/1.73 m2) and approximately − 0.9 mL/min/1.73 m2 in females α-Gal A, alpha galactosidase; eGFRCKD-EPI, estimated glomerular filtration rate (mean age 46.8 years, mean eGFR 86.6 mL/min/1.73 m2) using a using the Chronic Kidney Disease Epidemiology Collaboration equation; ERT, random coefficient model [25]. In another long-term study of patients enzyme replacement therapy; Q1, quartile 1; Q3, quartile 3; SD, standard (median age 33 years) receiving agalsidase alfa or agalsidase beta for a deviation. median of 7 years, the mean annualized rates of change in eGFR were − a ERT-naive male patients with the classic phenotype had residual white blood 1.8 mL/min/1.73 m2 and − 0.01 mL/min/1.73 m2 in males (mean cell α-Gal A activity of <3% of normal and multiorgan involvement, defined as baseline eGFR 121 mL/min/1.73 m2) and females (mean baseline eGFR involvement of ≥2 of the following organ systems: renal, cardiac, central ner­ 98 mL/min/1.73 m2), respectively, using a linear mixed model [29]. vous system, peripheral nerves, and gastrointestinal tract [21]. b Baseline white blood cell α-Gal A activity in ERT-experienced patients was These rates of eGFR decline during ERT are generally similar to or confounded by ERT and the same classic phenotype definition could not be greater than those reported here for migalastat. applied. Instead, male patients with multiorgan involvement were compared It is known that baseline clinical status plays a critical role in renal with males without multiorgan involvement and females (specified above as outcomes with treatment [25–27]. In long-term studies, ERT did not “others”). stabilize renal function in patients with severe renal involvement (ie, 6 D.G. Bichet et al. Molecular Genetics and Metabolism Reports 28 (2021) 100786 proteinuria >1 g/24 h or eGFR <60 mL/min/1.73 m2, or urinary pro­ There is a growing consensus that treatment should be initiated early tein:creatinine ratio ≥ 1 g/g) [30–32]. In our study, renal outcomes to limit or prevent irreversible organ damage and improve treatment were similar across baseline renal function groups in ERT-naive patients outcomes in patients with Fabry disease [31,37,38]. In this study, we with the random coefficient model that adjusted for baseline factors. defined the classic phenotype as multiorgan system involvement at Unsurprisingly, with the simple linear regression method, larger annu­ baseline, and < 3% enzyme activity for male patients (ERT-naive only). alized rates of change in eGFR were observed in ERT-experienced pa­ We used this phenotypic definition in accordance with the definition tients with low eGFR (> 30 to <60 mL/min/1.73 m2) or high urine used in the FACETS trial [15,21] in order to analyze patients with protein (> 1000 mg/24 h) at baseline in the current study compared clinically advanced Fabry disease at study start. Fabry disease pheno­ with other analyzed subgroups. However, our results are severely types and rates of disease progression are highly variable, even within limited by the small sample sizes of these 2 patient subgroups (n = 2 families with the same variant [39]. A binary definition of “classic” each). Results were also distorted by one patient with an eGFR decline of versus “other” does not capture the true complexity of Fabry disease. We >20 mL/min/1.73 m2; however, it is likely that this patient had irre­ posit that Fabry disease is a continuum, dependent upon many factors, versible nephropathy prior to migalastat initiation. as evidenced by the including genetic, epigenetic, environmental, and lifestyle, and that large decline in renal function that also occurred during ERT treatment. such binary classifications should be considered as only one factor in Long-term data are especially important when assessing annualized terms of guiding treatment decisions. Biopsy studies suggest that change in eGFR. A recent Delphi consensus has recommended at least 2 podocyte injury occurs in early childhood, progresses with increasing years of data for reliable eGFR analyses [33], and the current analysis age, and may act as an early marker for renal damage in Fabry disease provides data on patients who were treated with migalastat for at least 2 [40–42]. Therefore, treatment before substantial renal damage occurs is years (median exposure 5.9 years). Published real-world evidence can imperative because renal function may not be restored when podocyte also be helpful in guiding treatment decisions. A recent 24-month real- loss and damage to glomeruli have occurred [43,44]. There is also evi­ world cohort publication from Lenders et al. in Germany provided dence of a strong correlation between proteinuria and renal disease further evidence of LVMi reduction in migalastat-treated patients with progression in patients with Fabry disease [45]. Therefore, stabilizing or Fabry disease (primary outcome), especially in those with left ven­ slowing the decline in renal function requires strategies that control tricualr hypertrophy at baseline [34]. That publication also examined proteinuria (ie, angiotensin-converting-enzyme inhibitors and/or annualized eGFR slopes over 24 months and found antihypertensive angiotensin II receptor blockers) [46].Furthermore, inflammatory pro­ medication use was associated with greater annualized eGFR decline cesses in podocytes have been linked to Fabry nephropathy, suggesting over time, and the authors posited that either this may have been inflammatory pathways could potentially be therapeutic targets in Fabry causative of the larger decline in eGFR, or that these patients were more disease [4]. Further studies are needed to investigate the impact of severely affected at baseline. When excluding the patients on inhibitors current therapies, including migalastat, on these pathophysiological of angiotensin-converting enzyme, angiotensin II receptor 1, or aldo­ processes in renal tissues and optimal time for treatment initiation. sterone, eGFR was found to be stable over 24 months in migalastat- Limitations of this study that should be considered when interpreting treated patients (mean change over 24 months: − 3.0 ± 10.9 mL/min/ the results include its post hoc design, small sample sizes in some sub­ 1.73 m2; p = 0.4346). These findings support the thinking that patient groups, and the lack of statistical comparisons with untreated or ERT- management decisions should be made holistically, and that treatment treated historical cohorts. Assessment of renal function using eGFR before irreversible damage has occurred may be beneficial. may also be a limitation, given that eGFR has been associated with The current study also extends findings from a previous analysis of pseudo-hyperfiltration in some patients with Fabry disease [36]. In male patients with the classic phenotype in the FACETS study [21], addition, the heterogeneity of statistical methods used to estimate eGFR which reported a mean annualized rate of change in eGFRCKD-EPI of − 0.3 slopes in the literature limited direct comparisons. mL/min/1.73 m2 over 2 years. The current study shows that renal In summary, the results of this post hoc analysis suggest that patients function remained stable in ERT-naive male patients with the classic with Fabry disease and amenable GLA variants had stable renal function phenotype for ≤8.6 years (median exposure: 6.6 years), supporting long- during long-term migalastat treatment (≤8.6 years) irrespective of term efficacy in this patient population. In comparison, male patients treatment status, sex or phenotype. Early treatment should be encour­ with the classic phenotype (mean age 31 years, median baseline eGFR aged to stabilize or slow the decline in renal function in patients with ~120 mL/min/1.73 m2) who received agalsidase beta for 54 months Fabry disease. had an eGFR decline of − 2.2 mL/min/1.73 m2, as estimated by a random coefficient model [21,30]. The current study also included male Data availability statement patients with the classic phenotype who had relatively high eGFR values at baseline (mean [SD]: 88.5 [22.5] mL/min/1.73 m2). Interestingly, All relevant data, including deidentified participant data, are con­ one patient with the classic phenotype in our study had a GLA variant tained in this manuscript and its supplemental materials. associated with the late-onset phenotype (p.I253T) according to the International Fabry Disease Genotype-Phenotype Database, which con­ Author contributions solidates data in the literature as well as available biochemical data to set a reasonable expectation of phenotypic severity [35], This supports D.G.B., R.T., D.H., R.G., N.S., U.F.R. and K.N. contributed to the thinking that that genotype-phenotype correlation is complex and conceptualization; D.H., N.S., U.F.R. and K.N., participated in data that environmental factors and genetic modifiers may be at work. This curation; R.T., D.H., R.G., N.S., U.F.R. and K.N. participated in investi­ observation highlights the importance of evaluating each patient holis­ gation; R.T., R.G., N.S., E.K., U.F.R. and K.N. contributed to methodol­ tically, and of making individualized treatment decisions that account ogy; D.G.B. and D.H. participated in supervision; R.T. and D.H. for the multiple organ systems affected by Fabry disease. It also high­ contributed to validation; R.T. and E.W. contributed to visualization; N. lights the fact that the GLP-HEK amenability assay should be used only S. and E.K. analyzed and interpreted the data; R.T. participated in to determine a patient's eligibility for treatment with migalastat and that writing the original draft; D.G.B., R.T., E.W., D.H., R.G., N.S., E.K., U.F. the assay is not prognostic of clinical outcomes or disease course. R., R.S. and K.N. participated in reviewing and editing the article. Finally, some patients with the same variant had different severity of disease at study baseline, possibly related to entering the study at Funding different stages during the progressive disease course [1], which high­ lights the importance of multisystemic monitoring and early treatment This study was funded by Amicus Therapeutics, Inc. initiation when managing this disease. 7 D.G. Bichet et al. Molecular Genetics and Metabolism Reports 28 (2021) 100786 Declaration of Competing Interest [13] G.H. Yam, C. Zuber, J. Roth, A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder, FASEB J. 19 (2005) 12–18. [14] S. Ishii, H.H. Chang, K. Kawasaki, K. Yasuda, H.L. Wu, S.C. Garman, et al., Mutant D.G.B. served as a consultant and speaker for and received grants alpha-galactosidase a enzymes identified in Fabry disease patients with residual from Amicus, Sanofi Genzyme and Otsuka; and served as a board enzyme activity: biochemical characterization and restoration of normal member for Amicus. intracellular processing by 1-deoxygalactonojirimycin, Biochem. J. 406 (2007) 285–295. E.W. received grants and consulting fees from Sanofi Genzyme and [15] D.P. Germain, D.A. Hughes, K. Nicholls, D.G. Bichet, R. Giugliani, W.R. Wilcox, et received research and travel support from Protalix and Idorsia. al., Treatment of Fabry's disease with the pharmacologic chaperone migalastat, D.H. received consultant fees from Amicus, Sanofi Genzyme, Shire- N. Engl. J. Med. 375 (2016) 545–555. [16] D.A. Hughes, K. Nicholls, S.P. Shankar, G. Sunder-Plassmann, D. Koeller, K. Nedd, Takeda, Protalix, Idorisia, and Freeline Therapeutics; and served as a et al., Oral pharmacological chaperone migalastat compared with enzyme speaker for Amicus, Shire-Takeda, and Sanofi Genzyme. replacement therapy in Fabry disease: 18-month results from the randomised phase R.G. was a paid consultant for JCR Pharmaceuticals, REGENXBIO, III ATTRACT study, J. Med. Genet. 54 (2017) 288–296. [17] M. Mauer, A. Sokolovskiy, J.A. Barth, J.P. Castelli, H.N. Williams, E.R. Benjamin, et and Sigilon; received grants from BioMarin, Novartis, Shire-Takeda, and al., Reduction of podocyte globotriaosylceramide content in adult male patients Ultragenyx; was a paid speaker for Amicus, BioMarin, Chiesi, Janssen, with Fabry disease with amenable GLA mutations following 6 months of migalastat PTC Therapeutics, Sanofi Genzyme, Shire-Takeda, and Ultragenyx; and treatment, J. Med. Genet. 54 (2017) 781–786. [18] E.R. Benjamin, M.C. Della Valle, X. Wu, E. Katz, F. Pruthi, S. Bond, et al., The served as a board member for Amicus, Abeona, Sobi, Sanofi Genzyme, validation of pharmacogenetics for the identification of Fabry patients to be treated and Shire-Takeda. with migalastat, Genet. Med. 19 (2017) 430–438. N.S. was an employee of Amicus at the time of this study. [19] A.S. Levey, L.A. Stevens, C.H. Schmid, Y.L. Zhang, A.F. Castro III, H.I. Feldman, et al., A new equation to estimate glomerular filtration rate, Ann. Intern. Med. 150 E.K. served as a paid consultant for Amicus. (2009) 604–612. U.F.R. served as a board member and paid consultant for Amicus, [20] L.M. Sullivan, K.A. Dukes, E. Losina, Tutorial in biostatistics. An introduction to Sanofi Genzyme, and Shire-Takeda, and received an unrestricted hierarchical linear modelling, Stat. Med. 18 (1999) 855–888. research grant from Sanofi Genzyme. [21] D.P. Germain, K. Nicholls, R. Giugliani, D.G. Bichet, D.A. Hughes, L.M. Barisoni, et al., Efficacy of the pharmacologic chaperone migalastat in a subset of male patients K.N. has served on advisory boards for Amicus Therapeutics, Sanofi with the classic phenotype of Fabry disease and migalastat-amenable variants: data Genzyme, and Shire; has served as a speaker for Amicus Therapeutics; from the phase 3 randomized, multicenter, double-blind clinical trial and extension and has received research funding from Sanofi Genzyme and Shire. study, Genet. Med. 21 (2019) 1987–1997. [22] R. Schiffmann, D.G. Warnock, M. Banikazemi, J. Bultas, G.E. Linthorst, R.T. and R.S have no conflicts to declare. S. Packman, et al., Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy, Nephrol. Acknowledgments Dial. Transplant. 24 (2009) 2102–2111. [23] M. Branton, R. Schiffmann, J.B. Kopp, Natural history and treatment of renal involvement in Fabry disease, J. Am. Soc. 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