FDA approves sepiapterin to treat phenylketonuria in adult, pediatric patients

On July 28, 2025, the FDA approved PTC Therapeutics' sepiapterin (Sephience) to treat adult and pediatric patients with phenylketonuria (PKU), including all age groups and the full spectrum of disease subtypes, according to a press release from PTC. Additionally, the approval includes broad labeling to treat hyperphenylalaninemia (HPA) in patients 1 month or older with sepiapterin-responsive PKU.^1,2

WATCH: Experts react to the FDA approval of sepiapterin to treat PKU

"We are excited to have reached this important milestone for those affected by PKU," Matthew B. Klein, MD, CEO of PTC, said a press release. "The broad labeling reflects the potential of [sepiapterin] to meet the significant unmet need of patients [with] PKU. The [sepiapterin] clinical data, along with our expertise in launching rare disease therapies, positions [sepiapterin] to become the future standard of care. Our experienced customer-facing teams are ready to bring this therapy to children and adults with PKU in the United States as quickly as possible."

“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," Suzanne Hollander, MS, RD, LDN, a metabolic dietitian at Boston Children’s Hospital previously told Contemporary Pediatrics.³

PKU is typically diagnosed shortly after birth through newborn screening, and treatment begins immediately. The goal is to keep blood Phe levels under 360 µmol/L.

In March, PTC announced new data from the phase 3 APHENITY trial, which ultimately led to approval from the FDA.¹ According to the company, key findings included the following⁴:

• Over 97% of participants in the Phe tolerance protocol of the APHENITY open-label extension study demonstrate the ability to liberalize their diet while on sepiapterin treatment, with a mean increase in protein intake of 126%.
• A total of 66% of participants in the Phe tolerance substudy reached or exceeded the age-adjusted recommended daily allowance of protein intake for an individual without PKU while maintaining control of blood Phe levels.
• Genetic variant analysis of participants in the APHENITY study demonstrates that over 70% had a genotype-phenotype value consistent with classical PKU.

"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 [μmol/L], 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."³

WATCH: PKU and the pediatrician with Suzanne Hollander, MS, RD, LDN

"The approval marks an exciting milestone for the PKU community," Catherine Warren, executive director of National PKU Alliance, said a statement. "This progress brings renewed hope, and we are eager to see the positive impact this new treatment option will have on advancing care and potentially improving quality of life for individuals of all ages and PKU subtypes who respond to this therapy."¹

Sepiapterin is to be used in conjunction with a Phe-restricted diet, with the aim of liberalization to allow for an increase in protein.

"[Sepiapterin and a Phe-restricted diet will go] hand in hand. The approach has always centered on diet, with pharmacologic management as an adjunct to hopefully help liberalize diet," Timothy Tramontana, MD, medical and biochemical geneticist at Cleveland Clinic Foundation, told Contemporary Pediatrics. "That approach has helped a number of people through the use of sapropterin and now with sepiapterin. The hope is to expand the number of patients who may be able to liberalize their diet and increase their protein intake. That is our goal for most of our patients: to help them live a more normal life in terms of intake. It may never be 100% protein unrestricted, but the hope is to liberalize it enough to allow increased intake," said Tramontana.

References

1. PTC Therapeutics announces FDA approval of Sephience (sepiapterin) for the treatment of children and adults living with phenylketonuria (PKU). Press release. PTC Therapeutics. July 28, 2025. Accessed July 28, 2025. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-approval-sephiencetm-sepiapterin
2. PTC Therapeutics announces FDA target regulatory action date for sepiapterin and Lancet publication of phase 3 trial results. Press release. PTC Therapeutics. October 14, 2024. Accessed July 25, 2025. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-target-regulatory-action-date
3. Fitch J. PKU and sepiapterin data with Suzanne Hollander, MS, RD, LDN. Contemporary Pediatrics. May 7, 2025. Accessed July 25, 2025. https://www.contemporarypediatrics.com/view/pku-and-sepiapterin-data-with-suzanne-hollander-ms-rd-ldn
4. PTC Therapeutics presents new sepiapterin data from ongoing studies. Press release. PTC Therapeutics. March 20, 2025. Accessed July 25, 2025. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-presents-new-sepiapterin-data-ongoing-studies