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Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial

Schiffmann, R; Goker-Alpan, O; Holida, M; Giraldo, P; Barisoni, L; Colvin, RB; Jennette, CJ; ... Hughes, D; + view all (2019) Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial. Journal of Inherited Metabolic Disease , 42 (3) pp. 534-544. 10.1002/jimd.12080. Green open access

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Abstract

Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM Pegunigalsidase alfa, a novel PEGylated, covalently crosslinked form of α-galactosidase A developed as enzyme replacement therapy (ERT) for Fabry disease (FD), was designed to increase plasma half-life and reduce immunogenicity, thereby enhancing efficacy compared with available products. Symptomatic adults with FD participated in this open-label, 3-month dose-ranging study, followed by a 9-month extension. Three cohorts were enrolled in a stepwise manner, each receiving increased doses of pegunigalsidase alfa: 0.2, 1.0, 2.0 mg/kg, via intravenous infusion every other week. Pharmacokinetic analysis occurred on Day 1 and Months 3, 6, and 12. Kidney biopsies at baseline and Month 6 assessed peritubular capillary globotriaosylceramide (Gb3) content. Renal function, cardiac parameters, and other clinical endpoints were assessed throughout. Treatment-emergent adverse events (AEs) and presence of immunoglobulin G (IgG) antidrug antibodies (ADAs) were assessed. Sixteen patients completed 1 year's treatment. Mean terminal plasma half-life (each cohort) ranged from 53 to 121 hours. All 11 male and 1 of 7 female patients presented with classic FD phenotype, in whom renal peritubular capillary Gb3 inclusions were reduced by 84%. Mean estimated glomerular filtration rate was 111 mL/min/1.73 m 2 at baseline, remaining stable throughout treatment. Three patients developed treatment-induced IgG ADAs; following 1 year's treatment, all became ADA-negative. Nearly all treatment-emergent AEs were mild or moderate. One patient withdrew from the study following a serious related AE. Pegunigalsidase alfa may represent an advance in ERT for FD, based on its unique pharmacokinetics and apparent low immunogenicity.

Type: Article
Title: Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/jimd.12080
Publisher version: http://doi.org/10.1002/jimd.12080
Language: English
Additional information: Copyright © 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: antidrug antibodies, enzyme replacement therapy, Fabry disease, immunogenicity, pegunigalsidase alfa, pharmacokinetics
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/10072975
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