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A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria.

ABSTRACT: Objective:To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations, pegvaliase injection. Data Sources:Searches of MEDLINE (1946-September 1, 2018) were conducted using the terms pegvaliase and phenylalanine ammonia lyase (PAL). Additional data were obtained from the prescribing information, the product dossier obtained from the manufacturer, and Clinicaltrials.gov. Study Selection and Data Extraction:All English language articles related to pharmacology, pharmacokinetics, efficacy, or safety of the combination therapy in human subjects were reviewed. Data Synthesis:Pegvaliase is a pegylated PAL enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. Blood phenylalanine levels were reduced by approximately 50% to 70% in patients receiving therapeutic doses of pegvaliase. However, most patients experienced adverse events. Conclusions and Relevance:The mainstay of therapy in phenylketonuria (PKU) has historically consisted of dietary restriction of phenylalanine. Pegvaliase injection is the first Food and Drug Administration (FDA)-approved enzyme substitution therapy for patients with PKU. The therapy may be a viable option for patients with documented blood phenylalanine >600?µmol/L who have failed existing management strategies.

SUBMITTER: Hydery T

PROVIDER: S-EPMC6589953 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria.

Hydery Tasmina T Coppenrath Valerie Azzopardi VA

Drug target insights 20190621

<h4>Objective</h4>To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations, pegvaliase injection.<h4>Data sources</h4>Searches of MEDLINE (1946-September 1, 2018) were conducted using the terms pegvaliase and phenylalanine ammonia lyase (PAL). Additional data were obtained from the prescribing information, the product dossier obtained from the manufacturer, and Clinicaltrials ...[more]

PMID: 31258325

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Project description:ObjectiveTo present a case series that illustrates real-world use of pegvaliase based on the initial experiences of US healthcare providers.MethodsSixteen healthcare providers from 14 centers across the US with substantial clinical experience in treating patients with phenylketonuria (PKU) with pegvaliase in the two-plus years since FDA approval (May 2018) provided cases that exemplified important lessons from their initial experiences treating patients with pegvaliase. Key lessons from each case and takeaway points were discussed in both live and virtual meetings.ResultsFifteen cases of adults with PKU (eight males, seven females), representing a spectrum of age (18 to 53 years), previous PKU care, comorbidities, and socioeconomic situations were reviewed and discussed. Full extended case reports are included in the Supplement. The cases showed that treating patients with a daily injectable can be challenging due to a patient's financial problems, treatment challenges, and neuropsychological and psychiatric comorbidities, which can be identified before starting pegvaliase, but do not prohibit successful treatment. The authors agreed that patient education on adverse events (AEs), time to efficacy, dietary changes, and food preparation is an ongoing process that should start prior to initiating pegvaliase treatment. Treatment goals and planned dietary changes once efficacy is reached should be defined prior to treatment initiation and re-evaluated throughout the course of therapy. Each patient's titration schedule and dietary adjustments are unique, depending on occurrence of AEs and individual goals of treatment. Despite the AE profile of pegvaliase, all but two patients remained motivated to continue treatment and achieved efficacy (except one patient in whom titration was still ongoing). AEs occurring early in the treatment pathway may require prolongation of the titration phase and/or concomitant medication use, but do not seem indicative of future tolerability or eventual efficacy. Close follow-up of patients during titration and maintenance to help with dietary changes is important.ConclusionThis case series provides real-world experience on the use of pegvaliase. Until data from registries and independent research become available, the data presented herein can support appropriate management of patients receiving pegvaliase in clinical practice.

Project description:BackgroundDeficiency 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.MethodsPAL-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.ResultsMean (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.ConclusionsPegvaliase 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 registrationClinicalTrials.gov , NCT00924703. Registered June 18, 2009, https://clinicaltrials.gov/ct2/show/NCT00924703.

Dataset Information

A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria.

Publications

A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria.

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