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

Rossella Parini,1,2 Guillem Pintos-Morell,3 Julia B Hennermann,4 Ting-Rong Hsu,5 Nesrin Karabul,6 Vasiliki Kalampoki,7 Andrey Gurevich,7 Uma Ramaswami8 On behalf of the FOS Study Group1Rare Metabolic Diseases Unit, MBBM Foundation, San Gerardo Hospital, Reference Centre for Hereditary Metabolic Disorders (MetabERN), Monza, Italy; 2TIGET Institute, IRCCS San Raffaele Hospital, Milan, Italy; 3Division of Rare Diseases, Reference Centre for Hereditary Metabolic Disorders (MetabERN), University Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain; 4Villa Metabolica, Department of Pediatric and Adolescent Medicine, University Medical Center, Mainz, Germany; 5Department of Pediatrics, Taipei Veterans General Hospital and Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; 6Department of Neuropaediatric and Inborn Metabolic Disorders (Metabolicum Ruhr), University Children’s Hospital and Centre for Rare Diseases, Ruhr University Bochum, Bochum, Germany; 7Shire, a Takeda company, Zurich, Switzerland; 8Royal Free London NHS Foundation Trust, London, UKCorrespondence: Rossella PariniRare Metabolic Diseases Unit, MBBM Foundation, San Gerardo Hospital, Via Pergolesi 33, Monza 20900, ItalyEmail Rossella.parini@unimib.itPurpose: 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/m2.7) 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/m2.7; 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