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.
Preview |
Text
Schiffmann_et_al-2019-Journal_of_Inherited_Metabolic_Disease.pdf - Published Version Download (1MB) | Preview |
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 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: | https://discovery.ucl.ac.uk/id/eprint/10072975 |
Archive Staff Only
 |
View Item |
