Abstract

PurposePhenylketonuria (PKU) is a rare metabolic disorder that requires life-long management to reduce phenylalanine (Phe) concentrations within the recommended range. The availability of pegvaliase (PALYNZIQ™, an enzyme that can metabolize Phe) as a new therapy necessitates the provision of guidance for its use. MethodsA Steering Committee comprising 17 health-care professionals with experience in using pegvaliase through the clinical development program drafted guidance statements during a series of face-to-face meetings. A modified Delphi methodology was used to demonstrate consensus among a wider group of health-care professionals with experience in using pegvaliase. ResultsGuidance statements were developed for four categories: (1) treatment goals and considerations prior to initiating therapy, (2) dosing considerations, (3) considerations for dietary management, and (4) best approaches to optimize medical management. A total of 34 guidance statements were included in the modified Delphi voting and consensus was reached on all after two rounds of voting. ConclusionHere we describe evidence- and consensus-based recommendations for the use of pegvaliase in adults with PKU. The manuscript was evaluated against the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument and is intended for use by health-care professionals who will prescribe pegvaliase and those who will treat patients receiving pegvaliase.

Highlights

  • IntroductionPhenylketonuria (PKU, OMIM 261600) is a rare genetic disorder caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene, which results in elevated phenylalanine (Phe) concentrations in the blood and brain.[1,2,3] The concentration of blood Phe in healthy individuals is ~60 (±30) μmol/L, but in individuals with PKU who have not restricted their Phe intake, can be ≥1200 μmol/L.4 Elevated blood Phe concentrations are associated with impairment of executive function, behavioral and psychiatric problems, including depression and anxiety, and have a negative impact on patient quality of life (QoL), mood, and attention span.[2,5,6,7,8,9] Even on treatment, deficits in executive functioning, motor ability, and behavior can occur.[7,10,11,12] lowering of Phe levels is associated with improved neurological performance.[13]

  • Guidance statements were developed for four categories: (1) treatment goals and considerations prior to initiating therapy, (2) dosing considerations, (3) considerations for dietary management, and (4) best approaches to optimize medical management

  • Here we describe evidence- and consensus-based recommendations for the use of pegvaliase in adults with PKU

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Summary

Introduction

Phenylketonuria (PKU, OMIM 261600) is a rare genetic disorder caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene, which results in elevated phenylalanine (Phe) concentrations in the blood and brain.[1,2,3] The concentration of blood Phe in healthy individuals is ~60 (±30) μmol/L, but in individuals with PKU who have not restricted their Phe intake, can be ≥1200 μmol/L.4 Elevated blood Phe concentrations are associated with impairment of executive function, behavioral and psychiatric problems, including depression and anxiety, and have a negative impact on patient quality of life (QoL), mood, and attention span.[2,5,6,7,8,9] Even on treatment, deficits in executive functioning, motor ability, and behavior can occur.[7,10,11,12] lowering of Phe levels is associated with improved neurological performance.[13]. More frequent monitoring can be considered during dose titration, diet/dose adjustment, and episodes of hypophenylalaninemia (Phe concentration of

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