Analysis of Renal and Cardiac Outcomes in Male Participants in the Fabry Outcome Survey Starting Agalsidase Alfa Enzyme Replacement Therapy Before and After 18 Years of Age

Abstract

Purpose

To determine the impact of initiating enzyme replacement therapy (ERT) with agalsidase alfa early in the course of Fabry disease, we evaluated renal and cardiac outcomes for ≤10 years after ERT initiation in males from the Fabry Outcome Survey (FOS).

Patients and Methods

Male patients from FOS were stratified into three cohorts by age at ERT initiation: ≤18 years (cohort 1), >18 and ≤30 years (cohort 2), and >30 years (cohort 3). Analysis included age at symptom onset, diagnosis, and ERT initiation; ERT duration; FOS-Mainz Severity Score Index (FOS-MSSI); estimated glomerular filtration rate (eGFR); proteinuria level; and left ventricular mass indexed to height (LVMI). Mixed-effect models estimated renal and cardiac outcomes during follow-up between and within cohorts.

Findings

The analysis included 560 male patients: 151 (27.0%) in cohort 1, 155 (27.7%) in cohort 2, and 254 (45.4%) in cohort 3. Mean±SD duration of ERT for cohorts 1, 2, and 3 was 6.3±4.3, 8.6±4.9, and 7.9±4.9 years, respectively. Mean±SD baseline FOS-MSSI scores increased with age from 9.8±7.2 in cohort 1 to 24.7±11.4 in cohort 3. Cohort 3 showed the lowest baseline mean±SD value for eGFR (87.1±29.0 mL/min/1.73m²) and highest baseline mean±SD values for proteinuria (801.9±952.6 mg/day) and LVMI (56.7±16.0 g/m^2.7) among the three cohorts. Evaluation of mean annual rates of change in eGFR, proteinuria, and LVMI revealed no significant differences in any parameter for cohort 1. For cohort 2, proteinuria and LVMI remained stable, whereas eGFR significantly deteriorated annually (–1.12 mL/min/1.73m²; P<0.001). Cohort 3 demonstrated significant annual deteriorations in eGFR (–2.60 mL/min/1.73m²; P<0.001), proteinuria (+34.10 mg/day; P<0.001), and LVMI (+0.59 g/m^2.7; P=0.001).

Implications

Renal and/or cardiac disease progression appears attenuated in patients starting ERT in childhood or early adulthood versus patients starting ERT in later adulthood. These findings support early ERT initiation in Fabry disease. ClinicalTrials.gov identifier: NCT03289065.

Keywords:

• agalsidase alfa
• Fabry disease
• enzyme replacement therapy
• Fabry Outcome Survey
• estimated glomerular filtration rate
• left ventricular hypertrophy

Acknowledgments

Dr Uma Ramaswami is the senior author of this study. The authors would like to thank Jaco Botha (Shire International GmbH, a Takeda company) for his contribution to the initial statistical analyses, which was supported by Shire, a Takeda company. Under the direction of the authors, Latoya M. Mitchell, PhD, CMPP, and Tina Rose, MSc, both of Excel Medical Affairs, provided writing assistance for this manuscript. Editorial assistance in the form of formatting, proofreading, copy editing, and fact-checking also was provided by Excel Medical Affairs. Shire International GmbH, a Takeda company, provided funding to Excel Medical Affairs for support in writing and editing this manuscript.

Abbreviations

ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; CI, confidence interval; eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; FOS, Fabry Outcome Survey; FOS-MSSI, Fabry Outcome Survey-Mainz Severity Score Index; LVH, left ventricular hypertrophy; LVMI, left ventricular mass indexed to height; Q, quartile.

Data Sharing Statement

The datasets, including redacted study protocol, redacted statistical analysis plan, and individual participants' data behind the results reported in this article, will be available three months after the submission of a request to https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers by researchers who provide a methodologically sound proposal, after de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.

Ethics Approval and Consent Statement

FOS was approved by the ethics institutional review boards of participating centers (Supplemental File). Further, this registry was compliant with relevant global and local regulations and best practices. Good Pharmacoepidemiological Practice, Good Research for Comparative Effectiveness principles, and the relevant principles of the International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines (ICH E6) were followed as appropriate for an observational registry and consistent with the Declaration of Helsinki. All participants or their caregivers gave written informed consent.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

Dr Parini reports personal fees and clinical trial participation from Shire, a Takeda company, and personal fees from BioMarin, Chiesi, Sanofi Genzyme, and Ultragenyx, outside the submitted work. Dr Pintos-Morrell reports personal fees from Alexion, Amicus, BioMarin, Kyowa-Kirin, Sanofi Genzyme, and Shire, a Takeda company, outside the submitted work. Dr Hennermann reports grants and personal fees from Shire, a Takeda company, and personal fees from Amicus, outside the submitted work. Dr Karabul reports grants and personal fees from Shire, a Takeda company, grants and personal fees from Sanofi Genzyme, and personal fees from BioMarin, outside the submitted work. Ms Kalampoki is an employee of and reports stock ownership from Shire, a Takeda company, during the conduct of the study. Dr Gurevich was an employee of Shire, a Takeda company, during the conduct of the study. Dr Ramaswami reports personal fees and clinical trial participation from Amicus, clinical trial participation from Protalix; grants, personal fees, and clinical trial participation from Sanofi Genzyme; grants, personal fees, and clinical trial participation from Shire, a Takeda company; and personal fees from Actelion, Idorsi, and Chiesi, outside the submitted work. The authors report no other conflicts of interest in this work.