Modeling Intelligence Quotient (IQ) Changes Relative to Blood Phe Levels in Individuals With Phenylketonuria (PKU) Treated With Sepiapterin and Sapropterin Dihydrochloride
Author(s)
Rongrong Zhang, MSc1, Karissa M. Johnston, PhD2, Samantha L. Radford, MSc2, Ioannis Tomazos, MBA, PhD3.
1PTC Therapeutics, Askim, Sweden, 2Broadstreet HEOR, Vancouver, BC, Canada, 3Executive Director, Head of GHEOR, PTC Therapeutics, Warren, NJ, USA.
1PTC Therapeutics, Askim, Sweden, 2Broadstreet HEOR, Vancouver, BC, Canada, 3Executive Director, Head of GHEOR, PTC Therapeutics, Warren, NJ, USA.
OBJECTIVES: There is a well-established association between blood phenylalanine (Phe) levels and cognitive outcomes in individuals with PKU. Treatment with sepiapterin, a therapy currently in development for PKU, and sapropterin dihydrochloride, has lowered blood Phe levels; thus, these are expected to mitigate the adverse cognitive impact of PKU. This study aims to quantitatively synthesize existing data to characterize the overall relationship between PKU treatment, blood Phe levels, and IQ.
METHODS: Model inputs for the sepiapterin versus sapropterin Phe-level comparison were adopted from controlled clinical trials and an indirect treatment comparison (ITC) that quantitatively estimated the relative treatment effect between the two treatments. A model was developed assuming baseline characteristics from the sepiapterin pivotal MD-003 trial, and estimated treatment-specific changes to blood Phe, and resulting impact on IQ. The lifetime (>12 months between measures) relationships between blood Phe and IQ were adopted from a published meta-analysis, which used 85-points as a threshold for low IQ and presented results separately for age ≤6 and >6 years.
RESULTS: Based on the ITC, for an initial baseline blood Phe of 649 µmol/L (from MD-003), blood Phe after treatment was estimated to be 266.40 µmol/L for sepiapterin and 487.61 µmol/L for sapropterin. The resulting probability of low IQ for individuals ≤6 years was 13.4% for sepiapterin and 23.4% for sapropterin, representing a 74.6% higher risk for sapropterin versus sepiapterin. For patients >6 years, the risk of low IQ was 10.1% for sepiapterin and 15.9% for sapropterin, a 57% higher risk for sapropterin versus sepiapterin.
CONCLUSIONS: This model demonstrated that, compared to sapropterin, sepiapterin provided a greater reduction in blood Phe levels and consequently a lower probability of low IQ. These findings support the clinical relevance of effectively controlling blood Phe levels in PKU and highlight the value of sepiapterin in addressing the adverse cognitive outcomes that patients experience.
METHODS: Model inputs for the sepiapterin versus sapropterin Phe-level comparison were adopted from controlled clinical trials and an indirect treatment comparison (ITC) that quantitatively estimated the relative treatment effect between the two treatments. A model was developed assuming baseline characteristics from the sepiapterin pivotal MD-003 trial, and estimated treatment-specific changes to blood Phe, and resulting impact on IQ. The lifetime (>12 months between measures) relationships between blood Phe and IQ were adopted from a published meta-analysis, which used 85-points as a threshold for low IQ and presented results separately for age ≤6 and >6 years.
RESULTS: Based on the ITC, for an initial baseline blood Phe of 649 µmol/L (from MD-003), blood Phe after treatment was estimated to be 266.40 µmol/L for sepiapterin and 487.61 µmol/L for sapropterin. The resulting probability of low IQ for individuals ≤6 years was 13.4% for sepiapterin and 23.4% for sapropterin, representing a 74.6% higher risk for sapropterin versus sepiapterin. For patients >6 years, the risk of low IQ was 10.1% for sepiapterin and 15.9% for sapropterin, a 57% higher risk for sapropterin versus sepiapterin.
CONCLUSIONS: This model demonstrated that, compared to sapropterin, sepiapterin provided a greater reduction in blood Phe levels and consequently a lower probability of low IQ. These findings support the clinical relevance of effectively controlling blood Phe levels in PKU and highlight the value of sepiapterin in addressing the adverse cognitive outcomes that patients experience.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
CO165
Topic
Clinical Outcomes
Topic Subcategory
Clinical Outcomes Assessment, Comparative Effectiveness or Efficacy, Relating Intermediate to Long-term Outcomes
Disease
Rare & Orphan Diseases