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

Soumi Gupta, Kelly Lau, Cary Harding, Gillian Shepherd, Ryan Boyer, John P. Atkinson, Vijaya Knight, Joy Olbertz, Kevin Larimore, Zhonghu Gu, Mingjin Li, Orli Rosen, Stephen J. Zoog, Haoling H. Weng, Becky Schweighardt

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: 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. Methods: 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). Findings: 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. Interpretation: Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. Fund: BioMarin Pharmaceutical Inc.

Original languageEnglish (US)
JournalEBioMedicine
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Phase III Clinical Trials
Phenylketonurias
Antigen-Antibody Complex
Ammonia-Lyases
Phenylalanine
Safety
Antibodies
Complement Activation
Immunoglobulin E
Antibody Formation
Immunoglobulin M
Hypersensitivity
Anabaena variabilis
Immunoglobulin G
Immune Complex Diseases
Phenylalanine Ammonia-Lyase
Complement C4
Blood
Complement C3
Chemical activation

Keywords

  • Antidrug antibody
  • Circulating immune complex
  • Enzyme replacement therapy
  • Hypersensitivity
  • Phenylalanine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials. / Gupta, Soumi; Lau, Kelly; Harding, Cary; 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.

In: EBioMedicine, 01.01.2018.

Research output: Contribution to journalArticle

Gupta, S, Lau, K, Harding, C, Shepherd, G, Boyer, R, Atkinson, JP, Knight, V, Olbertz, J, Larimore, K, Gu, Z, Li, M, Rosen, O, Zoog, SJ, Weng, HH & Schweighardt, B 2018, 'Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials', EBioMedicine. https://doi.org/10.1016/j.ebiom.2018.10.038
Gupta, Soumi ; Lau, Kelly ; Harding, Cary ; 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. / Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials. In: EBioMedicine. 2018.
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AU - Gupta, Soumi

AU - Lau, Kelly

AU - Harding, Cary

AU - Shepherd, Gillian

AU - Boyer, Ryan

AU - Atkinson, John P.

AU - Knight, Vijaya

AU - Olbertz, Joy

AU - Larimore, Kevin

AU - Gu, Zhonghu

AU - Li, Mingjin

AU - Rosen, Orli

AU - Zoog, Stephen J.

AU - Weng, Haoling H.

AU - Schweighardt, Becky

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N2 - Background: 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. Methods: 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). Findings: 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. Interpretation: Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. Fund: BioMarin Pharmaceutical Inc.

AB - Background: 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. Methods: 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). Findings: 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. Interpretation: Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. Fund: BioMarin Pharmaceutical Inc.

KW - Antidrug antibody

KW - Circulating immune complex

KW - Enzyme replacement therapy

KW - Hypersensitivity

KW - Phenylalanine

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