PKU and sepiapterin data with Suzanne Hollander, MS, RD, LDN

Phenylketonuria (PKU), a rare genetic disorder that affects the body’s ability to metabolize phenylalanine (Phe), can cause severe neurocognitive and emotional complications without strict treatment.¹

“Without treatment, individuals with PKU would have very high blood Phe levels, and high blood Phe levels are a toxin to the brain, so that results in neurocognitive deficits and mood disorders," said Suzanne Hollander, MS, RD, LDN, senior clinical nutrition specialist at Boston Children’s Hospital, in the above video interview with Contemporary Pediatrics.

PKU is typically diagnosed shortly after birth through newborn screening, and treatment begins immediately. The goal is to keep blood Phe levels under 360 micromoles per liter, according to Hollander.

“The current standard treatment that we use for PKU is a phenylalanine-restricted diet,” she said. “We pair that with a phenylalanine-restricted medical formula that provides a lot of the nutrients that would otherwise be deficient in the protein-restricted diet alone. The diet is both logistically challenging and clinically challenging. Sepiapterin is an exciting novel treatment. It works to lower levels of phenylalanine in the blood, which can improve clinical outcomes and also allow for individuals to eat more natural protein in their diet. Getting to expand their diet really can alleviate the treatment burden that goes along with PKU," added Hollander.

Sepiapterin enhances the function of the enzyme that converts phenylalanine to tyrosine, lowering Phe levels and potentially enabling greater diet liberalization.

“Overall, participants in the trial were able to lower their Phe levels, and 84% of individuals reached the target range of less than 360,” said Hollander, highlighting findings from the Phase 3 APHENITY trial. “That’s really meaningful, because historically, those individuals often do not respond to the current oral phenylalanine-lowering therapy that’s on the market.”

These data were supported by recent findings presented at the 2025 ACMG Annual Clinical Genetics Meeting and shared by PTC Therapeutics, showing that over 70% of trial participants had a genotype consistent with classical PKU and still responded to treatment.

“From a dietary standpoint, the study was really exciting because we did a Phe tolerance assessment,” said Hollander. “For individuals who had their Phe level lowered with the medication to less than 360, they were able to participate in a portion of the study where we systematically monitored their Phe levels and then increased their dietary or natural protein.” Overall, participants saw a 126% increase in natural protein intake and a 50% reduction in their use of medical formula, a meaningful outcome given the burden the formula places on children and families.¹

"Seventy-three percent of the patients doubled their phenylalanine intake, and 34% tripled it. So on an individual basis, people were really able to liberalize their diet quite a bit," Hollander stated in the interview. "Additionally, those who came into the study on the current Phe lowering medication, BH4, they were able to increase their Phe intake, 52% of them doubled their Phe intake beyond what they had tolerated on BH4 therapy alone."

The phase 3 APHENITY trial results were recently published in The Lancet, and the FDA has assigned a Prescription Drug User Fee Act date of July 29, 2025, to review sepiapterin for potential approval. If approved, the treatment could represent a significant step forward in both metabolic control and quality of life for individuals with PKU.^1,2

References:

1. PTC Therapeutics Presents New Sepiapterin Data from Ongoing Studies. PTC Therapeutics. Press release. March 20, 2025. Accessed May 6, 2025.https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-presents-new-sepiapterin-data-ongoing-studies

2. PTC Therapeutics Announces FDA Target Regulatory Action Date for Sepiapterin and Lancet Publication of Phase 3 Trial Results. Press release. October 14, 2025. Accessed May 6, 2025. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-target-regulatory-action-date