Sepiapterin, a new oral drug for phenylketonuria, cut blood phenylalanine by 63%

The Food and Drug Administration approved sepiapterin, a new oral treatment for phenylketonuria. The approval was recorded in the agency's Drugs@FDA database on 28 July 2025 under new drug application 219666, held by PTC Therapeutics [s2]. The product, brand name Sephience, is supplied as an oral powder [s2].

Phenylketonuria is an inherited condition in which phenylalanine (Phe), an amino acid, accumulates to neurotoxic levels [s1]. Management has long rested on a highly restrictive low-protein diet, sometimes alongside the drug sapropterin. Sepiapterin is a synthetic compound that the body converts to tetrahydrobiopterin, the cofactor the enzyme phenylalanine hydroxylase needs to clear Phe. The distinction APHENITY's investigators drew is that the trial recruited across the severity spectrum — people whose blood Phe was 360 μmol/L or higher — rather than only the milder end where cofactor therapies have historically worked best [s1].

What the pivotal trial tested

The approval rests on APHENITY, a phase 3, randomised, double-blind, placebo-controlled trial conducted at 34 clinics, hospitals and university sites in 13 countries [s1]. People of all ages with a clinical diagnosis of phenylketonuria were eligible if their blood Phe concentration was 360 μmol/L or higher at entry; those with primary tetrahydrobiopterin deficiency due to variants in GCH1, PTS, QDPR, SPR or PCBD1 were excluded [s1].

The trial ran in two parts. Part 1 was a 14-day open-label test of whether a participant's blood Phe responded to sepiapterin [s1]. In part 2, responders were randomly assigned 1:1 to six weeks of sepiapterin — a forced dose escalation of 20, 40 and 60 mg/kg per day across consecutive two-week periods — or placebo [s1]. The primary endpoint was the mean change from baseline in blood Phe after six weeks, assessed in the participants who had shown at least a 30% reduction in part 1 [s1].

What it found

APHENITY ran between 30 September 2021 and 3 April 2023 [s1]. Of 187 people assessed, 157 were enrolled [s1]. In part 1, 114 (73%) of the 156 participants assessed were classed as sepiapterin-responsive, defined as at least a 15% reduction in blood Phe from baseline [s1]. Part 2's primary analysis set comprised 98 participants, 49 assigned to placebo and 49 to sepiapterin [s1].

The reduction was large. After six weeks, blood Phe fell by 63% (SD 20) with sepiapterin against a 1% change with placebo — a least-squares mean difference of −395.9 μmol/L (SE 33.8; p<0.0001) [s1].

On safety, treatment-emergent adverse events were reported in 33 (59%) of 56 participants who received sepiapterin and 18 (33%) of 54 who received placebo [s1]. Most were mild gastrointestinal events — 11 (20%) with sepiapterin and 10 (19%) with placebo — that resolved quickly [s1]. There were no deaths and no serious or severe adverse events [s1]. The gap between the two arms, 59% versus 33%, is the kind of difference a short trial can detect but cannot fully characterise: it says more people reported some event on the drug than on placebo, not that those events were dangerous, and the trial's own summary is that sepiapterin was well tolerated [s1].

How to read it

Two cautions sit alongside the headline number. First, the 63% reduction was measured only in participants who had already demonstrated a response in part 1 — the trial enriched its population for people likely to benefit, which is standard for a drug of this class but means the figure does not describe every patient with phenylketonuria [s1]. Of those assessed in part 1, 73% were responders, so a substantial minority were not [s1].

Second, the endpoint is a blood marker over six weeks, not a clinical outcome over years [s1]. Lowering phenylalanine is the mechanism through which harm in phenylketonuria is thought to be prevented, and lower blood Phe is the accepted treatment target, but the trial measured the chemistry, not cognition, mood or quality of life, and it did so over a short window [s1]. The trial was funded by the manufacturer, PTC Therapeutics [s1].

What to watch

The practical questions are which patients the labelling covers across the severity spectrum, how sepiapterin changes the dietary protein restriction that defines daily life with phenylketonuria, and whether the short-term biochemical effect holds over the long term. The trial was conducted under two regulators' registries — EudraCT 2021-000474-29 and ClinicalTrials.gov NCT05099640 — and its own authors describe sepiapterin as a promising therapy rather than a proven long-term one [s1]. Longer follow-up and real-world use will tell whether the reduction seen in APHENITY's responders translates into the clinical gains that matter [s1].

This article describes research and regulatory news and is not medical advice. Decisions about phenylketonuria treatment are for patients, families and their treating clinicians.