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. Issue 3 (8th April 2019)

• Record Type: Journal Article
• Authors: Schiffmann, Raphael; Goker‐Alpan, Ozlem; Holida, Myrl; Giraldo, Pilar; Barisoni, Laura; Colvin, Robert B.; Jennette, Charles J.; Maegawa, Gustavo; Boyadjiev, Simeon A.; Gonzalez, Derlis; Nicholls, Kathy; Tuffaha, Ahmad; Atta, Mohamed G.; Rup, Bonita; Charney, Martha R.; Paz, Alona; Szlaifer, Mali; Alon, Sari; Brill‐Almon, Einat; Chertkoff, Raul; Hughes, Derralynn
• Is Part Of: Journal of inherited metabolic disease. Volume 42:Issue 3(2019)
• Page Start: 534
• Page End: 544
• Publication Date: 2019-04-08
• Subjects: antidrug antibodies -- enzyme replacement therapy -- Fabry disease -- immunogenicity -- pegunigalsidase alfa -- pharmacokinetics; Metabolism, Inborn errors of -- Periodicals; Metabolism -- Disorders -- Periodicals; 616.39042
• DOI: 10.1002/jimd.12080
• Languages: English
• ISSNs: 0141-8955

Abstract

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.