The FDA has accepted for filing PTC Therapeutics' New Drug Application (NDA) for sepiapterin, a promising treatment for both pediatric and adult patients with phenylketonuria (PKU). This acceptance marks a significant step toward providing a new therapeutic option for individuals managing this rare inherited metabolic disorder. The FDA has set a target regulatory action date of July 29, 2025, for the review of sepiapterin.
Clinical Trial Data and Efficacy
The NDA is based on data from the Phase 3 APHENITY trial, which demonstrated statistically significant and clinically meaningful results. The trial revealed a 63% mean reduction in phenylalanine (Phe) levels in the overall treated population and a 69% reduction in subjects with classical PKU. Notably, 84% of subjects achieved Phe control in accordance with treatment guidelines (<360 µmol/L), and 22% experienced normalization of Phe levels.
Matthew B. Klein, M.D., CEO of PTC Therapeutics, stated, "The FDA filing acceptance for sepiapterin is a critical milestone toward bringing this potential important therapy to children and adults living with PKU in the United States. The clinical trial data, including the evidence of enabling diet liberalization, support that sepiapterin can provide significant benefit to PKU patients, helping to meet the persistent, significant unmet need in this community."
Sepiapterin's Mechanism of Action
Sepiapterin, formerly known as PTC923, is an oral formulation of synthetic sepiapterin. It features a dual mechanism of action designed to enhance the activity of the phenylalanine hydroxylase (PAH) enzyme. First, it acts as a precursor, rapidly converting into tetrahydrobiopterin (BH4), a crucial cofactor for PAH. Second, it functions as a pharmacological chaperone, correcting PAH misfolding to improve enzyme function. This dual approach effectively reduces blood phenylalanine levels.
Impact on Diet and Lifestyle
A significant finding from the Phe tolerance sub-study indicates that approximately 60% of subjects could achieve protein intake above the age-adjusted recommended daily allowance while maintaining Phe levels below 360 μmol/L. This suggests that sepiapterin could enable patients to relax their stringent diets while still maintaining control of Phe levels, potentially improving their quality of life.
Catherine Warren, Executive Director of the National PKU Alliance, emphasized the importance of new treatments, stating, "Our families have been anxiously waiting for new treatments that provide an opportunity to lessen their dependence on costly and burdensome diets. We are excited by today's news, as it brings us one step closer to providing another option for people of all ages with PKU to manage their condition."
Phenylketonuria: An Unmet Need
PKU is a rare, inherited metabolic disease affecting approximately 58,000 people worldwide. It results from a defect in the gene responsible for producing the enzyme needed to break down phenylalanine. Untreated, phenylalanine can accumulate to harmful levels, leading to severe disabilities, including intellectual disability and seizures. Current management often involves restrictive diets, highlighting the need for additional therapeutic options.
