Cardio- Renal Outcomes With Long- Term Agalsidase Alfa Enzyme Replacement Therapy: A 10- Year Fabry Outcome Survey (FOS) Analysis

Abstract

Purpose: Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed.

Patients and methods: FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10.

Results: Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9-67.3) for females (n=62), 34.4 (18.0-66.8) for males (n=90). With eGFR ≥60 mL/min/1.73 m2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; -0.55 [-1.12, +0.01]) and slightly declined in males (n=79; -1.99 [-2.45, -1.54]). With impaired kidney function (eGFR <60 mL/min/1.73 m2) at baseline, mean (95% CI) eGFR/year was stable in females (n=10; -0.14 [-1.43, +1.15]) and slightly declined in males (n=11; -2.79 [-4.01, -1.56]) over 10 years. Median (range) age (years) of the evaluable treated cardiac cohort at treatment start was 46.7 (3.7-67.3) for females (n=34), 28.2 (4.0-54.2) for males (n=35). With left ventricular hypertrophy (LVH; LVMI >48 g/m2.7 in females, >50 g/m2.7 in males) at baseline, mean (95% CI) LVMI/year slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in females (n=16; +0.52 [-0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years.

Conclusion: Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney function and/or normal LVMI at baseline remained largely stable; those with decreased kidney function or LVH at baseline experienced modest declines in renal function and/or increases in LVMI.

Keywords: Fabry disease; agalsidase alfa; cardio-renal outcomes; enzyme replacement therapy.

Conflict of interest statement

Uma Ramaswami has received travel and research grants and honoraria for lectures and advisory boards from Amicus, Chiesi, Genzyme, and Shire (now a member of the Takeda group of companies). She is also a member of the steering committee (SC) of FOS, a registry of Fabry disease sponsored by Shire/Takeda, and has received honoraria for compensation of the time spent on SC meetings. Michael Beck has received consulting fees from Genzyme and Shire. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Derralynn Hughes has received travel and research grants and honoraria for speaking and advisory boards from Amicus, Genzyme, Protalix, and Shire. She also reports personal fees from Takeda, Sanofi, and Amicus, outside the submitted work. She is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Christoph Kampmann has received consulting fees from Amicus, BioMarin, Gore, and Shire and honoraria for lectures and travel and research grants from BioMarin, Shire, and Gore. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Jaco Botha is an employee of Takeda and a Takeda stock owner. Guillem Pintos-Morell has received consulting fees, honoraria for lectures, and travel grants from Alexion, Amicus, BioMarin, and Shire, during the conduct of the study. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Michael West has received consulting fees from GlaxoSmithKline, AvroBio and Shire; has performed contract research for Alexion, Genzyme, Idorsia and Shire; has received speaker honoraria from Excelsior, Genzyme, Shire, and Sumitomo; honoraria for serving on a data and safety monitoring board for Amicus; and honoraria for advisory boards from Actelion, Genzyme, and Shire. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Dau-Ming Niu has received travel and research grants and speaker honoraria from Genzyme and Shire. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Kathy Nicholls reports grants from Melbourne Health, during the conduct of the study and has received research support from Amicus, Genzyme, and Shire, outside the submitted work. She is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Roberto Giugliani has received consulting fees, fees for non-CME/CE services, investigator fees, and support for travel expenses to attend scientific meetings from Actelion, Amicus, Armagen, BioMarin, GC Pharma, Inventiva, JCR Pharmaceuticals, Lysogene, RegenxBio, Sanofi-Genzyme, Shire, Sobi and Ultragenyx. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. The authors report no other conflicts of interest in this work.

© 2019 Ramaswami et al.

Figures

Figure 1

Flow diagram of participants included in the evaluable treated renal cohort and the evaluable treated cardiac cohort. Abbreviations: eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; FOS, Fabry Outcome Survey; LVMI, left ventricular mass index.

Figure 2

Mean (95% CI) eGFR MDRD (mL/min/1.73 m2) over a 10-year duration of enzyme replacement therapy for female and male populations in the evaluable treated renal cohort*. *Data shown are cross-sectional values. Abbreviations: eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease.

Figure 3

Individual profiles and average slope estimates for eGFR over time for the evaluable renal cohort (n=152) for the: (A) female population, baseline eGFR ≥60 mL/min/1.73 m2; (B) female population, baseline eGFR <60 mL/min/1.73 m2; (C) male population, baseline eGFR ≥60 mL/min/1.73 m2; (D) male population, baseline eGFR <60 mL/min/1.73 m2. Full interaction model: [age] × [sex] × [baseline] category. Abbreviations: eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; SEM, standard error of the mean.

Figure 4

Mean (95% CI) LVMI (g/m2.7) over a 10-year duration of enzyme replacement therapy for female and male populations in the evaluable treated cardiac cohort*. *Data shown are cross-sectional values. Abbreviations: LVMI, left ventricular mass index.

Figure 5

Individual profiles and average slope estimates for LVMI over time for the evaluable cardiac cohort (n=69) for the (A) female population, LVH at baseline; (B) female population, no LVH at baseline; (C) male population, LVH at baseline; (D) male population, no LVH at baseline. Abbreviations: LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; SEM, standard error of the mean.

Figure 6

Individual profiles and average slope estimates for left ventricular PWTD over time for the evaluable cardiac cohort (n=69) for the (A) female population, baseline eGFR ≥60 mL/min/1.73 m2; (B) female population, baseline eGFR <60 mL/min/1.73 m2; (C) male population, baseline eGFR ≥60 mL/min/1.73 m2; (D) male population, baseline eGFR <60 mL/min/1.73 m2. Abbreviations: eGFR, estimated glomerular filtration rate; PWTD, left ventricular posterior wall thickness in diastole; SEM, standard error of the mean.

Figure 7

Mean (95% CI) LVMI (g/m2.7) over a 10-year duration of enzyme replacement therapy for female and male patients with baseline eGFR >90 mL/min/1.73 m2 and urinary protein <0.5 g/day in the evaluable treated cardiac cohort. Abbreviations: eGFR, estimated glomerular filtration rate; LVMI, left ventricular mass index.