PTC923 (sepiapterin) lowers elevated blood phenylalanine in subjects with phenylketonuria: a phase 2 randomized, multi-center, three-period crossover, open-label, active controlled, all-comers study

Background & aim: PTC923 (formerly CNSA-001), an oral formulation of sepiapterin, a natural precursor of intracellular tetrahydrobiopterin (BH4), has been shown in humans to induce larger increases in circulating BH4 vs. sapropterin dihydrochloride. Sapropterin reduces blood phenylalanine (Phe) by >= 20-30% in a minority of subjects with PKU. This was a Phase 2 randomized, multicenter, three-period crossover, open-label, active controlled, all-comers [regardless of phenylalanine hydroxylase (PAH) variants] comparison of PTC923 60 mg/kg, PTC923 20 mg/kg and sapropterin 20 mg/kg in 24 adults with phenylketonuria (PKU) and hyperphenylalaninemia. Methods: Eligible subjects were adult men or women (18-60 y) with PKU. Subjects enrolled received 7 days of once-daily oral treatment with PTC923 20 mg/kg/day, PTC923 60 mg/kg/day and sapropterin dihydrochloride 20 mg/kg/day each in a random order. Treatments were separated by a 7-day washout. Subjects maintained their usual pre-study diet, including consumption of amino acid mixtures. Blood Phe was measured on Day 1 (predose baseline), Day 3, Day 5, and Day 7 of each treatment period. Results: Least squares mean changes (SE) from baseline in blood Phe were: -206.4 (41.8) mu mol/L for PTC923 60 mg/kg (p < 0.0001); -146.9 (41.8) mu mol/L for PTC923 20 mg/kg (p = 0.0010); and - 91.5 (41.7) mu mol/L for sapropterin (p = 0.0339). Effects of PTC923 60 mg/kg on blood Phe vs. sapropterin were significantly larger (p = 0.0098) and faster in onset with a significantly larger mean reduction in blood Phe at day 3 of treatment, p = 0.0135 (20 mg/kg) and p = 0.0007 (60 mg/kg). Only PTC923 60 mg/kg reduced blood Phe in classical PKU subjects (n = 11, p = 0.0287). The mean blood Phe reduction (PTC923 60 mg/kg) in a cofactor responder analysis (n = 8; baseline Phe >= 300 mu mol/L and blood Phe reduction >= 30%) was -463.3 mu mol/L (SE 51.5) from baseline. Adverse events were mostly mild to moderate, transient, and similar across treatment groups with no serious adverse events or discontinuations. Conclusions: The substantially significantly better effect of PTC923 60 mg/kg on blood Phe reduction vs. sapropterin supports further clinical development of PTC923 for PKU; ANZCTR number, ACTRN12618001031257. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).