Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials

• Published in: EBioMedicine Vol. 37; pp. 366 - 373
• Main Authors: Gupta, Soumi, Lau, Kelly, Harding, Cary O., Shepherd, Gillian, Boyer, Ryan, Atkinson, John P., Knight, Vijaya, Olbertz, Joy, Larimore, Kevin, Gu, Zhonghu, Li, Mingjin, Rosen, Orli, Zoog, Stephen J., Weng, Haoling H., Schweighardt, Becky
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2018; Elsevier
• Subjects: Adult; Antibodies - blood; Antibodies - immunology; Antidrug antibody; Antigen-Antibody Complex - blood; Antigen-Antibody Complex - immunology; Circulating immune complex; Complement C3 - immunology; Complement C3 - metabolism; Complement C4 - immunology; Complement C4 - metabolism; Drug Hypersensitivity - blood; Drug Hypersensitivity - immunology; Enzyme replacement therapy; Female; Humans; Hypersensitivity; Male; Phenylalanine; Phenylalanine - blood; Phenylalanine - immunology; Phenylalanine Ammonia-Lyase - administration & dosage; Phenylalanine Ammonia-Lyase - adverse effects; Phenylketonurias - blood; Phenylketonurias - drug therapy; Phenylketonurias - immunology; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Research paper; Circulating immune complex; Phenylalanine; Enzyme replacement therapy; Antidrug antibody; Hypersensitivity
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2018.10.038

This study assessed the immunogenicity of pegvaliase (recombinant Anabaena variabilis phenylalanine [Phe] ammonia lyase [PAL] conjugated with polyethylene glycol [PEG]) treatment in adults with phenylketonuria (PKU) and its impact on safety and efficacy. Immunogenicity was assessed during induction, upward titration, and maintenance dosing regimens in adults with PKU (n = 261). Total antidrug antibodies (ADA), neutralizing antibodies, immunoglobulin (Ig) M and IgG antibodies against PAL and PEG, IgG and IgM circulating immune complex (CIC) levels, complement components 3 and 4 (C3/C4), plasma Phe, and safety were assessed at baseline and throughout the study. Pegvaliase-specific IgE levels were measured in patients after hypersensitivity adverse events (HAE). All patients developed ADA against PAL, peaking by 6 months and then stabilizing. Most developed transient antibody responses against PEG, peaking by 3 months, then returning to baseline by 9 months. Binding of ADA to pegvaliase led to CIC formation and complement activation, which were highest during early treatment. Blood Phe decreased over time as CIC levels and complement activation declined and pegvaliase dosage increased. HAEs were most frequent during early treatment and declined over time. No patient with acute systemic hypersensitivity events tested positive for pegvaliase-specific IgE near the time of the event. Laboratory evidence was consistent with immune complex-mediated type III hypersensitivity. No evidence of pegvaliase-associated IC-mediated end organ damage was noted. Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. BioMarin Pharmaceutical Inc.