# Pegvaliase Treatment for Adolescents With Phenylketonuria: A Multi‐Site Study

## TL;DR

This study shows that pegvaliase, a treatment for PKU, effectively lowers phenylalanine levels in adolescents and is more sustainable when started earlier.

## Contribution

The study evaluates pegvaliase in adolescents with PKU, a population previously excluded from clinical trials.

## Key findings

- Pegvaliase reduced phenylalanine levels by 44% in adolescents with PKU.
- Discontinuation rates were higher in older adolescents (12th graders and college students) compared to younger ones.
- Adolescents achieved target phenylalanine levels once treatment efficacy was reached.

## Abstract

Phenylketonuria (PKU) is an inherited metabolic disorder causing elevated phenylalanine (Phe) levels and neurocognitive impairment if left untreated. While dietary therapy remains the treatment standard, adherence declines during adolescence. Pegvaliase, an injectable enzyme therapy approved for adults > 18 years in the United States, lowers Phe levels while allowing dietary flexibility. This study examines pegvaliase use in adolescents, focusing on efficacy, discontinuation patterns, and predictors of success. We conducted a retrospective chart review from four metabolic centers with 53 individuals with PKU (age 14–22 years) who initiated pegvaliase through March 2025. Data included demographics, treatment response, side effects, and discontinuation reasons. Mean pretreatment Phe was 716 μmol/L, which decreased by 44% post‐treatment initiation. Sixty‐four percent of individuals achieved efficacy with a mean Phe of 231 μmol/L (60% decrease) after 14 months at mean dose of 37.4 mg/day. Common side effects included injection site reactions in 77%, joint pain in 64%, rash in 45%, headaches in 26%, fatigue in 19%, fever and/or chills in 13%, GI symptoms in 13%, and anaphylaxis in 9%. Discontinuation occurred in 24.5% of this cohort, with rates significantly higher in 12th graders (40%) and college students (32%) versus 9th–11th graders (5.5%). Pegvaliase may lower Phe levels in adolescents, reaching target blood Phe goals (≤ 360 μmol/L) once efficacy is achieved. Treatment showed better sustainability when initiated earlier in adolescence. The higher discontinuation during transitional years (12th grade/college) suggests treatment challenges increase during these periods. Earlier initiation, when family support is typically stronger, may improve outcomes. These findings support reconsidering current age restrictions for pegvaliase therapy.

Adolescents with PKU on pegvaliase achieved a significant reduction in blood Phe, demonstrating the efficacy of pegvaliase in this population overall.Average pegvaliase dosing and side effect profiles were similar in this adolescent cohort compared to adults in clinical trials, whereas time to efficacy was slightly longer in this adolescent cohort.Younger adolescents showed lower discontinuation rates on pegvaliase possibly due to a stronger support system or decreased stressors that accompany later adolescent transition years.

Adolescents with PKU on pegvaliase achieved a significant reduction in blood Phe, demonstrating the efficacy of pegvaliase in this population overall.

Average pegvaliase dosing and side effect profiles were similar in this adolescent cohort compared to adults in clinical trials, whereas time to efficacy was slightly longer in this adolescent cohort.

Younger adolescents showed lower discontinuation rates on pegvaliase possibly due to a stronger support system or decreased stressors that accompany later adolescent transition years.