Efficacy and safety of sepiapterin versus sapropterin in patients with phenylketonuria: Results from the Phase 3, randomized, crossover, open-label, active-controlled AMPLIPHY trial
Giżewska, Maria Inwood, Anita Tyčová, Renáta Vijay, Suresh Fjellbirkeland, Olivia van Spronsen, Francjan Venegas-Moreno, Eva Maria Guilder, Laura Burlina, Alberto Peters, Heidi
Giżewska, Maria
Inwood, Anita
Tyčová, Renáta
Vijay, Suresh
Fjellbirkeland, Olivia
van Spronsen, Francjan
Venegas-Moreno, Eva Maria
Guilder, Laura
Burlina, Alberto
Peters, Heidi
Abstract
AIM: AMPLIPHY is the first Phase 3 study comparing sepiapterin versus sapropterin in children and adults with phenylketonuria (PKU).
METHODS: AMPLIPHY was an international, Phase 3, two-part, open-label study in participants with PKU aged ≥2 years. Participants responsive to sepiapterin (60 mg/kg/day) in Part 1 (≥20% reduction in blood phenylalanine [Phe]) entered Part 2, a crossover treatment period, and were randomized 1:1 to alternative treatment sequences of sepiapterin (60 mg/kg/day, licensed dosage) and sapropterin (20 mg/kg/day, maximum licensed dosage) for 4 weeks each, with a 14-day washout between treatments. The primary endpoint was mean change in blood Phe from baseline to Weeks 3-4 of each treatment period (Part 2).
RESULTS: Of 82 participants enrolled, 67 (81.7%) and 62 (75.6%) had reductions in blood Phe ≥20% and ≥30%, respectively, in Part 1. Sixty-two participants were randomized in Part 2 (mean [SD] age, 15.8 [10.8] years). In the primary analysis set (≥30% reduction in blood Phe in Part 1, n = 58), mean (SD) baseline blood Phe before sepiapterin and sapropterin treatment was 725.8 (302.1) and 790.4 (370.0) μmol/L, respectively. Least-squares mean (SE) reduction in blood Phe from baseline was -437.0 (28.0) and -256.6 (28.2) μmol/L, respectively, representing a least-squares mean difference of -180.4 μmol/L (95% CI: -229.5, -131.4; p < 0.0001) and a relative 70% greater reduction with sepiapterin versus sapropterin. Both treatments were well tolerated, with safety profiles consistent with previous reports.
CONCLUSIONS: Sepiapterin was superior to the highest approved dose of sapropterin in lowering blood Phe. No new safety signals were observed. The trial was registered in the UK Clinical Study Registry, ISRCTN, on January 29, 2024 (ID number, ISRCTN79102999; https://www.isrctn.com/ISRCTN79102999).
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Date
2026-01-28
Type
Article
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Citation
Giżewska M, Inwood A, Tyčová R, Vijay S, Fjellbirkeland O, van Spronsen F, Venegas-Moreno EM, Guilder L, Burlina A, Peters H, Potter M, Grošelj U, Chakrapani A, Bélanger-Quintana A, Maillot F, Rutsch F, Arnoux JB, Tchan M, Ingalls K, Zhao Z, Hughes C, Smith N, Muntau AC. Efficacy and safety of sepiapterin versus sapropterin in patients with phenylketonuria: Results from the Phase 3, randomized, crossover, open-label, active-controlled AMPLIPHY trial. Metabolism. 2026 May;178:156513. doi: 10.1016/j.metabol.2026.156513. Epub 2026 Jan 28.