The FDA has approved Sephience (sepiapterin) for treating phenylketonuria (PKU) in patients as young as one month. Developed by PTC Therapeutics, Sephience is intended for individuals with sepiapterin-responsive PKU and is approved as an addition to a phenylalanine-restricted diet.
The approval includes broad labeling for all PKU subtypes and follows a similar authorization from the European Commission earlier this year.
Around 58,000 people worldwide have PKU. In the US, PKU affects about 1 in 13,500 to 19,000 newborns.
PKU is a rare genetic metabolic disorder caused by a deficiency in phenylalanine hydroxylase (PAH), the enzyme that breaks down phenylalanine, an amino acid found in most protein-rich foods. Without treatment, phenylalanine accumulates in the blood and can cause cognitive impairment, seizures and behavioral issues.
Most babies appear healthy at birth, but symptoms may emerge within the first weeks of life if untreated. Newborn screening allows for early diagnosis, and lifelong dietary management is crucial. Easing treatment later in life — or during pregnancy — can lead to serious complications.
Sephience is a synthetic version of a naturally occurring precursor to tetrahydrobiopterin (BH4), a co-factor that aids PAH in metabolizing phenylalanine. By replenishing BH4, sepiapterin helps enhance the remaining PAH activity and reduces toxic phenylalanine levels in those who respond to the treatment. This oral therapy is used together with a phenylalanine-restricted diet and is customized based on individual responses.
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The FDA’s approval was based on the Phase III APHENITY trial and its long-term extension, which involved individuals with sepiapterin-responsive PKU. This randomized, placebo-controlled study met its primary endpoint by significantly reducing blood phenylalanine levels compared to placebo. Long-term results supported the durability of the effect, confirming its use as a maintenance therapy.
Patients take Sephience orally under the guidance of clinicians experienced in managing PKU. Regular blood monitoring is essential, particularly for pediatric patients, to ensure phenylalanine levels remain within a safe range.
The most common side effects reported include diarrhea, headache, abdominal pain and low phenylalanine levels. The label also mentions a risk of bleeding events and advises caution for patients taking levodopa, as they may experience neurological symptoms.
PTC Therapeutics indicated that Sephience’s broad label covers patients across all PKU subtypes. The company plans to launch the treatment in the US and has submitted it for review in other countries, including Japan and Brazil.
Current therapies for PKU include BioMarin’s sapropterin dihydrochloride (Kuvan), which provides a synthetic form of BH4 to help lower phenylalanine levels in individuals with some PAH activity. BioMarin also developed pegvaliase (Palynziq), an injectable enzyme therapy approved for adults with uncontrolled phenylalanine levels. The company recently shared positive Phase III results in adolescents and plans to submit them for regulatory review later this year.
Unlike sapropterin, sepiapterin serves as a precursor to BH4, offering an alternative way to support PAH activity in responsive patients.
Researchers are investigating various strategies beyond dietary control, including enzyme substitution, BH4 analogs, amino acid supplements and gene therapies. Other experimental methods, such as amino acid transport inhibitors and tRNA-based treatments, are also being explored.
More than 25 therapies are in development, alongside digital tools like Aptatek’s in-home phenylalanine monitor and Cycle’s AI-based diet app that support daily disease management.
Recent forecasts suggest that the global PKU treatment market could nearly double by 2034, signaling steady progress in therapeutic and monitoring solutions.
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