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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

2019; Springer Science+Business Media; Volume: 42; Issue: 3 Linguagem: Inglês

10.1002/jimd.12080

1573-2665

Raphael Schiffmann, Özlem Göker-Alpan, Myrl Holida, Pilar Giraldo, Laura Barisoni, Robert B. Colvin, Charles J. Jennette, Gustavo Maegawa, Simeon A. Boyadjiev, Derlis Gonzalez, Kathy Nicholls, Ahmad Tuffaha, Mohamed G. Atta, Bonita Rup, Martha R. Charney, Alona Paz, Mali Szlaifer, Sari Alon, Einat Brill‐Almon, Raul Chertkoff, Derralynn Hughes,

Carbohydrate Chemistry and Synthesis

Abstract 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.