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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.
Drug Des Devel Ther. 2020; 14:2149-2158.DD

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/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.

Authors+Show Affiliations

Rare Metabolic Diseases Unit, MBBM Foundation, San Gerardo Hospital, Reference Centre for Hereditary Metabolic Disorders (MetabERN), Monza, Italy. TIGET Institute, IRCCS San Raffaele Hospital, Milan, Italy.Division of Rare Diseases, Reference Centre for Hereditary Metabolic Disorders (MetabERN), University Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain.Villa Metabolica, Department of Pediatric and Adolescent Medicine, University Medical Center, Mainz, Germany.Department of Pediatrics, Taipei Veterans General Hospital and Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.Department of Neuropaediatric and Inborn Metabolic Disorders (Metabolicum Ruhr), University Children's Hospital and Centre for Rare Diseases, Ruhr University Bochum, Bochum, Germany.Shire, a Takeda company, Zurich, Switzerland.Shire, a Takeda company, Zurich, Switzerland.Royal Free London NHS Foundation Trust, London, UK.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32581513

Citation

Parini, Rossella, et al. "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." Drug Design, Development and Therapy, vol. 14, 2020, pp. 2149-2158.
Parini R, Pintos-Morell G, Hennermann JB, et al. 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. Drug Des Devel Ther. 2020;14:2149-2158.
Parini, R., Pintos-Morell, G., Hennermann, J. B., Hsu, T. R., Karabul, N., Kalampoki, V., Gurevich, A., & Ramaswami, U. (2020). 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. Drug Design, Development and Therapy, 14, 2149-2158. https://doi.org/10.2147/DDDT.S249433
Parini R, et al. 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. Drug Des Devel Ther. 2020;14:2149-2158. PubMed PMID: 32581513.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Parini,Rossella, AU - Pintos-Morell,Guillem, AU - Hennermann,Julia B, AU - Hsu,Ting-Rong, AU - Karabul,Nesrin, AU - Kalampoki,Vasiliki, AU - Gurevich,Andrey, AU - Ramaswami,Uma, AU - ,, Y1 - 2020/06/03/ PY - 2020/02/12/received PY - 2020/04/28/accepted PY - 2020/6/26/entrez PY - 2020/6/26/pubmed PY - 2021/3/31/medline KW - Fabry Outcome Survey KW - Fabry disease KW - agalsidase alfa KW - enzyme replacement therapy KW - estimated glomerular filtration rate KW - left ventricular hypertrophy SP - 2149 EP - 2158 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 14 N2 - 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/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. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/32581513/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_ L2 - https://dx.doi.org/10.2147/DDDT.S249433 DB - PRIME DP - Unbound Medicine ER -