Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study

Nicola Longo, Roberto Zori, Melissa P Wasserstein, Jerry Vockley, Barbara K Burton, Celeste Decker, Mingjin Li, Kelly Lau, Joy Jiang, Kevin Larimore, Janet A Thomas, Nicola Longo, Roberto Zori, Melissa P Wasserstein, Jerry Vockley, Barbara K Burton, Celeste Decker, Mingjin Li, Kelly Lau, Joy Jiang, Kevin Larimore, Janet A Thomas

Abstract

Background: Deficiency of phenylalanine hydroxylase causes phenylketonuria (PKU) with elevated phenylalanine (Phe) levels and associated neuropsychiatric and neurocognitive symptoms. Pegvaliase (PEGylated phenylalanine ammonia lyase) is an investigational agent to lower plasma Phe in adults with PKU. This study aimed to characterize the long-term efficacy, safety, and immunogenicity of pegvaliase in adults with PKU.

Methods: PAL-003 is an ongoing, open-label, long-term extension study of the pegvaliase dose-finding parent phase 2 studies. Participants continued the dose of pegvaliase from one of three parent studies, with dose adjustments to achieve a plasma Phe concentration between 60 and 600 μmol/L.

Results: Mean (standard deviation [SD]) plasma Phe at treatment-naïve baseline for 80 participants in the parent studies was 1302.4 (351.5) μmol/L. In the 68 participants who entered the extension study, plasma Phe decreased 58.9 (39)% from baseline, to 541.6 (515.5) μmol/L at Week 48 of treatment. Plasma Phe concentrations ≤120 μmol/L, ≤360 μmol/L, and ≤ 600 μmol/L were achieved by 78.7, 80.0, and 82.5% of participants, respectively. Mean (SD) protein intake at baseline was 69.4 (40.4) g/day (similar to the recommended intake for the unaffected population) and remained stable throughout the study. All participants experienced adverse events (AEs), which were limited to mild or moderate severity in most (88.8%); the most common AEs were injection-site reaction (72.5%), injection-site erythema (67.5%), headache (67.5%), and arthralgia (65.0%). The AE rate decreased from 58.3 events per person-year in the parent studies to 18.6 events per person-year in the extension study.

Conclusions: Pegvaliase treatment in adults with PKU produced meaningful and persistent reductions in mean plasma Phe concentration with a manageable safety profile for most subjects that continued with long-term treatment.

Trial registration: ClinicalTrials.gov , NCT00924703. Registered June 18, 2009, https://ichgcp.net/clinical-trials-registry/NCT00924703.

Keywords: PKU; Pegvaliase; Phenylketonuria; Recombinant Anabaena variabilis PEGylated phenylalanine ammonia lyase.

Conflict of interest statement

Ethics approval and consent to participate

All individuals consented to participate in the study, which was conducted in accordance with the Declaration of Helsinki of 1975, as revised in 2008.

Consent for publication

Not applicable.

Competing interests

JV, BKB, RZ, JAT, MPW, and NL are investigators of BioMarin Pharmaceutical Inc. clinical trials, and RZ, JAT, and NL are on the steering committee for the pegvaliase clinical program. NL reports grants (Aeglea, BioMarin, Genzyme, Horizon, Lumos Pharma, Protalix, Retrophin, Shire, Stealth Therapeutics, Ultragenix), consultant fees (Aeglea, BioMarin, Censa Pharmaceuticals, Dimension Therapeutics, Genzyme, Hemoshear, Horizon, Lumos Pharma, Moderna, Mitobridge, Pfizer, Retrophin, Stealth Therapeutics), participation in clinical trials (Aeglea, BioMarin, Genzyme, Horizon, Protalix, Retrophin, Shire, Stealth Therapeutics, Ultragenix), and travel fees (BioMarin, Cello Health Sciences, Lumos Pharma, SigmaTau/AlphaSigma). JV has received research support (BioMarin). BKB has participated in advisory boards (BioMarin, ReGenXBio), received research support (Shire), received consulting fees (Alexion, Shire, BioMarin), and participated as trial investigator (BioMarin, Shire, Ultragenyx, Alexion Armagen, Cytonet). JAT has participated in advisory boards and received research support (BioMarin). CD, ML, KL, JJ, and KL are BioMarin Pharmaceutical Inc. employees and stockholders.

Publisher’s Note

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Figures

Fig. 1
Fig. 1
Plasma Phe concentration, pegvaliase dose, and protein intake over time. Protein intake includes medical food and natural protein intake and was calculated as the daily average of intake over 3 days prior to the assessment point. Data are presented as mean (SE). All phase 2 data are included. Sample size reflects participants with data available at study timepoint; study is ongoing. Abbreviations: Phe phenylalanine, SE standard error
Fig. 2
Fig. 2
Frequency of hypersensitivity events and incidence of antibody positivity over time. Antibody positivity is calculated as the number of participants testing positive divided by the total number of participants at each study visit. All phase 2 data are included. Sample size reflects participants with data available at study timepoint; study is ongoing. Abbreviations: IgG immunoglobulin G, IgM immunoglobulin M, PAL phenylalanine ammonia lyase, PEG polyethylene glycol, NAb neutralizing antibody

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