SAFETY OF SEPIAPTERIN AND PEGVALIASE FOR THE TREATMENT OF PHENYLKETONURIA (PKU): A SIMULATED TREATMENT COMPARISON (STC)
Author(s)
Fiona O'Sullivan, PhD1, Juan Pablo Diaz-Martinez, PhD (c)1, Ida Schwartz, Sr., MD2, Karissa M. Johnston, BSc, MSc, PhD1, Ioannis Tomazos, MBA, PhD3;
1Broadstreet HEOR, Vancouver, BC, Canada, 2Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, 3PTC Therapeutics, Executive Director, Head of GHEOR, Warren, NJ, USA
1Broadstreet HEOR, Vancouver, BC, Canada, 2Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, 3PTC Therapeutics, Executive Director, Head of GHEOR, Warren, NJ, USA
OBJECTIVES: PKU causes elevated blood phenylalanine (Phe) leading to neurological damage and cognitive disability. Approved therapies for reducing blood-Phe levels include sepiapterin, a once-daily, oral treatment, and pegvaliase, a subcutaneous injection requiring dose titration at initiation. The safety profiles differ between these therapies; the two most common adverse events (AEs) with sepiapterin are diarrhea (7.7%) and headache (6.5%), vs arthralgia (75.9%) and injection site reactions (63.6%) with pegvaliase. As comparative safety data is lacking, this simulated treatment comparison (STC) explored safety (by risk of AEs, without accounting for seriousness) of sepiapterin relative to pegvaliase among patients with PKU.
METHODS: Safety data from sepiapterin and pegvaliase clinical trials were identified in a literature review conducted in December 2024. Heterogeneity in trial characteristics and study designs precluded anchored indirect treatment comparisons. Pairwise STCs fitted patient-level trial data using predictive equations, adjusting for baseline characteristics (age, sex, Phe levels, body mass index) to determine treatment outcomes. Risk (rate ratio, 95% confidence interval) of AEs occurring with sepiapterin vs pegvaliase was compared.
RESULTS: Pairwise STCs used APHENITY (sepiapterin) vs PRISM (pegvaliase), and vs PAL (pegvaliase) trials. In the APHENITY/PRISM comparison, sepiapterin had significantly lower overall AE risk compared to pegvaliase (0.40, 0.23-0.69), and significantly lower risk of nausea (0.21, 0.05-0.91) and upper respiratory tract infection (0.18, 0.04-0.79). Similar results were seen with the APHENITY/PAL comparison.
CONCLUSIONS: In this analysis, sepiapterin exhibited a significantly more favorable safety profile than pegvaliase. Immune reactions are prominent in pegvaliase-treated patients. As such, it has been graded a black box warning and is available only under a restricted program (Risk Evaluation and Mitigation Strategy). All patients treated with pegvaliase are prescribed with auto-injectable epinephrine. Study findings represent the best available AE analysis given data limitations and methodological challenges in the evidence base; other safety-related factors including route of administration should be considered.
METHODS: Safety data from sepiapterin and pegvaliase clinical trials were identified in a literature review conducted in December 2024. Heterogeneity in trial characteristics and study designs precluded anchored indirect treatment comparisons. Pairwise STCs fitted patient-level trial data using predictive equations, adjusting for baseline characteristics (age, sex, Phe levels, body mass index) to determine treatment outcomes. Risk (rate ratio, 95% confidence interval) of AEs occurring with sepiapterin vs pegvaliase was compared.
RESULTS: Pairwise STCs used APHENITY (sepiapterin) vs PRISM (pegvaliase), and vs PAL (pegvaliase) trials. In the APHENITY/PRISM comparison, sepiapterin had significantly lower overall AE risk compared to pegvaliase (0.40, 0.23-0.69), and significantly lower risk of nausea (0.21, 0.05-0.91) and upper respiratory tract infection (0.18, 0.04-0.79). Similar results were seen with the APHENITY/PAL comparison.
CONCLUSIONS: In this analysis, sepiapterin exhibited a significantly more favorable safety profile than pegvaliase. Immune reactions are prominent in pegvaliase-treated patients. As such, it has been graded a black box warning and is available only under a restricted program (Risk Evaluation and Mitigation Strategy). All patients treated with pegvaliase are prescribed with auto-injectable epinephrine. Study findings represent the best available AE analysis given data limitations and methodological challenges in the evidence base; other safety-related factors including route of administration should be considered.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
CO150
Topic
Clinical Outcomes
Topic Subcategory
Clinical Outcomes Assessment, Comparative Effectiveness or Efficacy
Disease
SDC: Diabetes/Endocrine/Metabolic Disorders (including obesity), SDC: Rare & Orphan Diseases