Minor wording changes in Section 3 to make it clearer how to take the medicine and change to the Date of revision to April 2026

Minor wording changes to Section 4.2 to make meanings clearer.

Addition of study 301 to Section 5.1 as follows:-

Study 4 (PTC923-PKU-301) was a Phase 3, 2-part, open-label, randomised, active-controlled crossover study of sepiapterin versus sapropterin in participants with PKU aged ≥2 years.​

In Part 1 of the study, participants underwent a 14-day open-label treatment with sepiapterin 60 mg/kg/day  to assess their responsiveness, defined by a ≥20% reduction in blood Phe levels from baseline. Of 82 participants, 67 (81.7%) were responsive, achieving a mean Phe reduction of 415.5  μmol/L (59.1% decrease from baseline). Of these, 62 participants qualified for Part 2, where they were randomiseds into two sequences: sapropterin-sepiapterin (n=30) or sepiapterin-sapropterin (n=32), each treatment separated by a 14-day washout. The primary efficacy endpoint for Part 2 was the mean change in blood Phe levels from baseline to Weeks 3 and 4. The primary analysis showed a statistically significant treatment difference favouring 60 mg/kg/day sepiapterin over 20 mg/kg/day sapropterin (p<0.0001) in participants who demonstrated a ≥30% Phe reduction in Part 1. Sepiapterin treatment led to a rapid and sustained decrease in Phe levels. By Day 28 of treatment, the LS mean change in blood Phe levels from baseline to Weeks 3 and 4 was -437.0 μmol/L with sepiapterin and --256.6 μmol/L with sapropterin, for an LS mean treatment difference of -180.4 μmol/L (p<0.0001). In BH4-responsive participants, the mean absolute Phe concentration decreased from 775.9 to 323.7 µmol/L with sepiapterin, versus 854.1 to 552 µmol/L with sapropterin dihydrochloride (LS  mean difference:: -214 µmol/L [95% CI: -274.1, -153.9]; p<0.0001). In patients who were receiving BH4 at study entry, the mean absolute Phe concentration decreased from 842.6 to 370.9  µmol/L with sepiapterin, versus a decrease from 910.8 to 629.0 µmol/L with sapropterin dihydrochloride (LS mean difference: -248.5 µmol/L [95% CI: -320.5, -176.5]; p<0.0001). Sepiapterin demonstrated a statistically significantly greater reduction in the primary endpoint versus sapropterin in the overall population; enabling a greater proportion of patients to achieve target blood Phe levels.

Update to Section 10 to revise the text on 04.2026

Variation to extend the shelf-life of Sephience in the EU from 24 to 36 months was approved on August 28, 2025

Summary of Product Characteristics for new product Sephience (Sepiapterin).

New patient information leaflet for new product.