BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.

Academisch Medisch Centrum Universiteit van Amsterdam Amsterdam The Netherlands

Baylor University Medical Center at Dallas Dallas Texas USA

Centro de Investigación Biomédica en Red de Enfermedades Raras Zaragoza Spain

Chiesi Farmaceutici SpA Parma Italy

DataSights Haifa Israel

Department of Clinical Science University of Bergen Bergen Norway

Department of Diabetes Endocrinology and Metabolism Queen Elizabeth Hospital Birmingham Birmingham UK

Department of Endocrinology and Clinical Nutrition University Hospital Zurich and University of Zurich Zurich Switzerland

Department of Human Genetics Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA

Department of Human Genetics Emory University School of Medicine Atlanta Georgia USA

Department of Internal Medicine General Hospital Slovenj Gradec Slovenj Gradec Slovenia

Department of Internal Medicine School of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Medicine Division of Nephrology The University of Alabama at Birmingham Birmingham Alabama USA

Department of Pediatrics Division of Medical Genetics University of Utah Health Salt Lake City Utah USA

Department of Pediatrics Haukeland University Hospital Bergen Norway

Department of Pediatrics Medical College of Wisconsin Milwaukee Wisconsin USA

Department of Pediatrics University of California Irvine Irvine California USA

Department of Pediatrics University of California San Diego La Jolla California USA

Department of Pediatrics University of Iowa Hospitals and Clinics Iowa City Iowa USA

Department of Pediatrics UPMC Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA

Department of Public Health Universita degli Studi di Napoli Federico 2 Napoli Italy

Division of Medical Genetics University of Versailles Garches France

Division of Medicine Turku University Hospital Turku Finland

Infusion Associates Grand Rapids Michigan USA

Institute of Genomic Medicine and Rare Disorders Semmelweis University Clinical Center Budapest Hungary

Lysosmal Disorders Unit Department of Medicine Cambridge University Hospitals NHS Foundation Trust Cambridge UK

Lysosomal and Rare Disorders Research and Treatment Center Inc Fairfax Virginia USA

Lysosomal Storage Disorders Unit Royal Free London NHS Foundation Trust and University College London London UK

Mark Holland Metabolic Unit Northern Care Alliance NHS Foundation Trust Greater Manchester UK

Massachusetts General Hospital for Children Boston Massachusetts USA

Phoenix Children's Hospital Phoenix Arizona USA

Product Development Protalix Biotherapeutics Carmiel Israel

Protalix Biotherapeutics Carmiel Israel

Unidad de Investigación Traslacional Hospital Universitario Miguel Servet Instituto de Investigación Sanitaria Aragón Zaragoza Spain

University of Sunderland Sunderland UK

doi: 10.1136/jmg-2023-109818 PubMed

doi: 10.1136/jmg-2024-109876 PubMed

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A phase III, open-label clinical trial evaluating pegunigalsidase alfa administered every 4 weeks in adults with Fabry disease previously treated with other enzyme replacement therapies

Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study

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ClinicalTrials.gov
NCT02795676