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Clinical Trial
. 2019 May;42(3):534-544.
doi: 10.1002/jimd.12080. Epub 2019 Apr 8.

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

Raphael Schiffmann  1 , Ozlem Goker-Alpan  2 , Myrl Holida  3 , Pilar Giraldo  4 , Laura Barisoni  5 , Robert B Colvin  6 , Charles J Jennette  7 , Gustavo Maegawa  8 , Simeon A Boyadjiev  9 , Derlis Gonzalez  10 , Kathy Nicholls  11 , Ahmad Tuffaha  12 , Mohamed G Atta  13 , Bonita Rup  14 , Martha R Charney  15 , Alona Paz  16 , Mali Szlaifer  16 , Sari Alon  16 , Einat Brill-Almon  16 , Raul Chertkoff  16 , Derralynn Hughes  17
Affiliations
Clinical Trial

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

Raphael Schiffmann et al. J Inherit Metab Dis. 2019 May.

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 m2 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.

Keywords: Fabry disease; antidrug antibodies; enzyme replacement therapy; immunogenicity; pegunigalsidase alfa; pharmacokinetics.

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