RESUMO
Sepiapterin is an orally administered drug in development for the treatment of phenylketonuria, an inborn error of metabolism characterized by the deficiency of the phenylalanine-metabolizing enzyme phenylalanine hydroxylase. This study characterized the pharmacokinetics, safety, and tolerability of 2 clinical sepiapterin formulations (Phase 1/2, Phase 3) and the effects of food on the pharmacokinetics of the Phase 3 formulation in healthy participants. In Part A, 18 participants were randomized to one of 2 treatment sequences, each with 4 dosing periods comprising a single dose (20 or 60 mg/kg) of the Phase 1/2 or the Phase 3 formulation with a low-fat diet. In Part B, 14 participants were randomized to one of 2 sequences, each comprising 4 dosing periods of a single dose (20 or 60 mg/kg) of the Phase 3 formulation under fed (high-fat) or fasted conditions. Following oral administration, sepiapterin was quickly absorbed and rapidly and extensively converted to tetrahydrobiopterin (BH4). BH4 was the major circulating active moiety. Under low-fat conditions, the Phase 3 formulation was bioequivalent to the Phase 1/2 formulation at 20 mg/kg, while slightly lower BH4 exposure (approximately 0.81×) for the Phase 3 formulation was observed at 60 mg/kg. BH4 exposure increased to approximately 1.7× under the low-fat condition and approximately 2.8× under the high-fat condition at a dose of either 20 or 60 mg/kg for the Phase 3 formulation, compared with the fasted condition. Both sepiapterin formulations were well tolerated, with no serious or severe adverse events reported. All treatment-emergent adverse events were mild or moderate in severity.
Assuntos
Disponibilidade Biológica , Biopterinas , Biopterinas/análogos & derivados , Estudos Cross-Over , Interações Alimento-Droga , Voluntários Saudáveis , Pterinas , Humanos , Masculino , Adulto , Administração Oral , Feminino , Pterinas/administração & dosagem , Pterinas/farmacocinética , Pterinas/efeitos adversos , Adulto Jovem , Biopterinas/administração & dosagem , Biopterinas/farmacocinética , Biopterinas/efeitos adversos , Pessoa de Meia-Idade , Fenilcetonúrias/tratamento farmacológico , Equivalência Terapêutica , Jejum , AdolescenteRESUMO
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 60â¯mg/kg, PTC923 20â¯mg/kg and sapropterin 20â¯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 7â¯days of once-daily oral treatment with PTC923 20â¯mg/kg/day, PTC923 60â¯mg/kg/day and sapropterin dihydrochloride 20â¯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) µmol/L for PTC923 60â¯mg/kg (pâ¯<â¯0.0001); -146.9 (41.8) µmol/L for PTC923 20â¯mg/kg (pâ¯=â¯0.0010); andâ¯-â¯91.5 (41.7) µmol/L for sapropterin (pâ¯=â¯0.0339). Effects of PTC923 60â¯mg/kg on blood Phe vs. sapropterin were significantly larger (pâ¯=â¯0.0098) and faster in onset with a significantly larger mean reduction in blood Phe at day 3 of treatment, pâ¯=â¯0.0135 (20â¯mg/kg) and pâ¯=â¯0.0007 (60â¯mg/kg). Only PTC923 60â¯mg/kg reduced blood Phe in classical PKU subjects (nâ¯=â¯11, pâ¯=â¯0.0287). The mean blood Phe reduction (PTC923 60â¯mg/kg) in a cofactor responder analysis (nâ¯=â¯8; baseline Phe ≥300⯵mol/L and blood Phe reduction ≥30%) was -463.3⯵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 60â¯mg/kg on blood Phe reduction vs. sapropterin supports further clinical development of PTC923 for PKU; ANZCTR number, ACTRN12618001031257.
Assuntos
Fenilalanina/sangue , Fenilcetonúrias/tratamento farmacológico , Pterinas/uso terapêutico , Adolescente , Adulto , Biopterinas/análogos & derivados , Biopterinas/líquido cefalorraquidiano , Estudos Cross-Over , Feminino , Humanos , Masculino , Fenilalanina/administração & dosagem , Fenilcetonúrias/sangue , Pterinas/efeitos adversos , Adulto JovemAssuntos
Compostos Organofosforados/uso terapêutico , Pterinas/uso terapêutico , Animais , Estudos Clínicos como Assunto , Humanos , Estimativa de Kaplan-Meier , Erros Inatos do Metabolismo dos Metais/mortalidade , Molibdoferredoxina/efeitos dos fármacos , Compostos Organofosforados/efeitos adversos , Compostos Organofosforados/farmacologia , Pterinas/efeitos adversos , Pterinas/farmacologia , Estados Unidos , United States Food and Drug AdministrationRESUMO
Fosdenopterin (NulibryTM) is a synthetic cyclic pyranopterin monophosphate that is being developed by Origin Biosciences (a subsidiary of BridgeBio Pharma) for the treatment of molybdenum cofactor deficiency (MoCD) type A. Fosdenopterin was recently approved by the US FDA for use in reducing the risk of mortality in paediatric and adult patients with MoCD type A. This article summarizes the milestones in the development of fosdenopterin leading to this first approval.