PMID- 30834538 OWN - NLM STAT- MEDLINE DCOM- 20200625 LR - 20220409 IS - 1573-2665 (Electronic) IS - 0141-8955 (Linking) VI - 42 IP - 3 DP - 2019 May TI - 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. PG - 534-544 LID - 10.1002/jimd.12080 [doi] AB - Pegunigalsidase alfa, a novel PEGylated, covalently crosslinked form of alpha-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. CI - (c) 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. FAU - Schiffmann, Raphael AU - Schiffmann R AD - Institute of Metabolic Disease, 3812 Elm Street, Dallas, TX 75226. FAU - Goker-Alpan, Ozlem AU - Goker-Alpan O AD - Lysosomal Disorders Research and Treatment Unit, O&O Alpan LLC, Fairfax, Virginia. FAU - Holida, Myrl AU - Holida M AD - Medical Genetics-Lysosomal Storage Disorders, University of Iowa, Iowa City, Iowa. FAU - Giraldo, Pilar AU - Giraldo P AD - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Hospital de Dia Quiron, Zaragoza, Spain. FAU - Barisoni, Laura AU - Barisoni L AD - Department of Pathology, University of Miami, Miami, Florida. FAU - Colvin, Robert B AU - Colvin RB AD - Department of Pathology Boston, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. FAU - Jennette, Charles J AU - Jennette CJ AD - Department of Pathology, University of North Carolina, Chapel Hill, North Carolina. FAU - Maegawa, Gustavo AU - Maegawa G AD - Department of Pediatrics/Genetics & Metabolism, University of Florida, Gainesville, Florida. FAU - Boyadjiev, Simeon A AU - Boyadjiev SA AD - Department of Pediatrics, Section of Genetics, MIND Institute, UC Davis Medical Center, Sacramento, California. FAU - Gonzalez, Derlis AU - Gonzalez D AD - Department of Haematology, Instituto Privado de Hematologia e Investigacion Clinica, Asuncion, Paraguay. FAU - Nicholls, Kathy AU - Nicholls K AD - Nephrology Department, The Royal Melbourne Hospital, Melbourne, Victoria, Australia. FAU - Tuffaha, Ahmad AU - Tuffaha A AD - Division of Nephrology & Hypertension, University of Kansas Medical Center, Kansas City, Kansas. FAU - Atta, Mohamed G AU - Atta MG AD - Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland. FAU - Rup, Bonita AU - Rup B AD - Bioanalysis, Immunogenicity, Regulatory at Bonnie Rup Consulting LLC, Bonnie Rup Consulting LLC, Reading, Massachusetts. FAU - Charney, Martha R AU - Charney MR AD - Pharmacokinetics Consultant, Pharmacokinetics, Pharmacokinetics Consultant, Toronto, Ontario, Canada. FAU - Paz, Alona AU - Paz A AD - Department of Product Development, Protalix Biotherapeutics, Carmiel, Israel. FAU - Szlaifer, Mali AU - Szlaifer M AD - Department of Product Development, Protalix Biotherapeutics, Carmiel, Israel. FAU - Alon, Sari AU - Alon S AD - Department of Product Development, Protalix Biotherapeutics, Carmiel, Israel. FAU - Brill-Almon, Einat AU - Brill-Almon E AD - Department of Product Development, Protalix Biotherapeutics, Carmiel, Israel. FAU - Chertkoff, Raul AU - Chertkoff R AD - Department of Product Development, Protalix Biotherapeutics, Carmiel, Israel. FAU - Hughes, Derralynn AU - Hughes D AD - Department of Haematology, LSDU, Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, London, UK. LA - eng PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20190408 PL - United States TA - J Inherit Metab Dis JT - Journal of inherited metabolic disease JID - 7910918 RN - 0 (Trihexosylceramides) RN - 71965-57-6 (globotriaosylceramide) RN - EC 3.2.1.22 (alpha-Galactosidase) SB - IM MH - Adolescent MH - Adult MH - *Enzyme Replacement Therapy MH - Fabry Disease/*drug therapy MH - Female MH - Glomerular Filtration Rate MH - Heart/physiopathology MH - Humans MH - Internationality MH - Kidney/physiopathology MH - Male MH - Middle Aged MH - Treatment Outcome MH - Trihexosylceramides/*metabolism MH - Young Adult MH - alpha-Galactosidase/*administration & dosage/*pharmacokinetics OTO - NOTNLM OT - Fabry disease OT - antidrug antibodies OT - enzyme replacement therapy OT - immunogenicity OT - pegunigalsidase alfa OT - pharmacokinetics EDAT- 2019/03/06 06:00 MHDA- 2020/06/26 06:00 CRDT- 2019/03/06 06:00 PHST- 2018/07/23 00:00 [received] PHST- 2019/02/27 00:00 [accepted] PHST- 2019/03/06 06:00 [pubmed] PHST- 2020/06/26 06:00 [medline] PHST- 2019/03/06 06:00 [entrez] AID - 10.1002/jimd.12080 [doi] PST - ppublish SO - J Inherit Metab Dis. 2019 May;42(3):534-544. doi: 10.1002/jimd.12080. Epub 2019 Apr 8.