TY - JOUR
T1 - Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics
T2 - A 1-year Phase 1/2 clinical trial
AU - Schiffmann, Raphael
AU - Goker-Alpan, Ozlem
AU - Holida, Myrl
AU - Giraldo, Pilar
AU - Barisoni, Laura
AU - Colvin, Robert B.
AU - Jennette, Charles J.
AU - Maegawa, Gustavo
AU - Boyadjiev, Simeon A.
AU - Gonzalez, Derlis
AU - Nicholls, Kathy
AU - Tuffaha, Ahmad
AU - Atta, Mohamed G.
AU - Rup, Bonita
AU - Charney, Martha R.
AU - Paz, Alona
AU - Szlaifer, Mali
AU - Alon, Sari
AU - Brill-Almon, Einat
AU - Chertkoff, Raul
AU - Hughes, Derralynn
N1 - Funding Information:
information Protalix Biotherapeutics provided the funding for this study.The investigators would like to thank the patients and their families for their participation in this study. The authors received professional medical writing and editing assistance that were provided by Edward Weselcouch, PhD, and Barbara Schwedel, ELS, of PharmaWrite, LLC (Princeton, NJ, USA), and were funded by Protalix Biotherapeutics. Protalix Biotherapeutics provided the funding for this study. In addition, it was responsible for the design of the study with input from the investigators, monitoring of the study, and collection and analysis of the results. All authors had full access to the data, participated fully in drafting and revising the manuscript, and approved the decision to submit for publication.
Funding Information:
R.S. reports grant funds, and consultancy and research funds, from Amicus Therapeutics, and consultancy and research funds from Sanofi Genzyme, all outside the submitted work. O.G.-A. reports, along with participation in the current Protalix-sponsored study, grant funds from and use of a product manufactured by Protalix during the conduct of the study; and outside the submitted work, membership on company advisory boards/similar committees for Genzyme, Protalix, and Shire; receiving consulting fees or other remuneration, including speaker fees, from Actelion, Genzyme, Pfizer, and Shire; receiving research support from Alexion, Amicus, Genzyme, Pfizer, Protalix, and Shire; assisting in the design of and/or participating in clinical studies using products manufactured by Genzyme, Protalix, and Shire; and current or recent participation in clinical trials sponsored by Genzyme, Protalix, and Shire. M.H. reports institutional research funding and associated travel reimbursement for scientific meeting presentation from Protalix during the conduct of the study; and outside the submitted work, personal fees and institutional funding for rare disease registry data entry and data presentation from Sanofi-Genzyme. R.B.C. reviewed pathology of trial-coded samples for Protalix during the conduct of the study. K.N. reports nonfinancial support provided by Protalix during the current study; and outside the submitted work, grant funds from Shire Genetic Therapies, and personal fees and nonfinancial support from Shire Genetic Therapies, Genzyme Sanofi, and Amicus Therapeutics. B.R. reports receiving personal fees from Protalix Biotherapeutics during the conduct of the study; and outside the submitted work, personal fees from multiple companies in the biopharmaceutical industry. M.R.C. reports receiving a consulting fee from Protalix Biotherapeutics during the conduct of the study for performing pharmacokinetic calculations. M.S. reports grant funds from the National Authority for Technology and Innovation (Israel) during the conduct of the study; and outside the submitted work, employment by Protalix. S.A., E.B.-A., and R.C. report grant funds from the National Authority for Technology and Innovation (Israel) during the conduct of the study; and outside the submitted work, employment by Protalix and pending Patent PCT/IL2018/050018 (licensee CHIESI Farmaceutici S.p.A.) with royalties. D.H. reports institutional grant funds to complete the study and travel support (to conference presentations and advisory boards) from Protalix Therapeutics during the conduct of the study; and outside the submitted work, grant funds and personal fees (speaker fees, advisory boards, institutional research) from Shire, Genzyme Sanofi, and Amicus. P.G., L.B., J.C.J., G.M., S.A.B., D.G., A.T., M.G.A., and A.P. declare that they have no conflict of interest.
Publisher Copyright:
© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Fabry disease
KW - antidrug antibodies
KW - enzyme replacement therapy
KW - immunogenicity
KW - pegunigalsidase alfa
KW - pharmacokinetics
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U2 - 10.1002/jimd.12080
DO - 10.1002/jimd.12080
M3 - Article
C2 - 30834538
AN - SCOPUS:85064010726
VL - 42
SP - 534
EP - 544
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
SN - 0141-8955
IS - 3
ER -