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Background: Sepiapterin is a natural precursor of tetrahydrobiopterin (BH4), a key cofactor for phenylalanine hydroxylase. It is being developed for the treatment of patients with phenylketonuria. In this study, the ethnic differences in pharmacokinetics and safety of sepiapterin in Japanese and non-Japanese participants and food effects were evaluated. Methods: Healthy participants (n = 60) received a single oral dose of sepiapterin at either 20, 40, or 60 mg/kg with a low-fat diet. The Japanese participants received two doses at 40 mg/kg, either under fasted conditions or with a low-fat diet with a 3-day washout period in between. Results: Sepiapterin was well tolerated in all participants, with no serious adverse events. Sepiapterin was quickly absorbed (Tmax 1.4–4.5 h) and rapidly and extensively converted to BH4 (Tmax ~4 h). Exposures to sepiapterin were <1% of BH4. BH4 exposures were essentially dose-independent between 20 and 60 mg/kg. A low-fat diet increased BH4 exposures in Japanese participants by 1.7-fold compared with fasted conditions. Conclusions: BH4 exposures (Cmax and AUC0–last) in Japanese participants were 10–30% higher than in non-Japanese participants, which is deemed not clinically relevant; no dose adjustment is warranted. The slightly higher BH4 exposures in Japanese participants are likely due to the higher frequency of ABCG2 c.421C>A mutation in the Japanese population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A comprehensive genetic map of the mouse is presented. The five-year project produced a map containing 7,377 genetic markers that are comprised of 6,580 simple sequence length polymorphisms integrated with 797 restriction fragment length polymorphisms in mouse genes. About 0.2 centimorgans or 400 kilobases is the average spacing between genetic markers. The map concludes the first phase of the Human Genome Project, which involves the creation of genetic maps of man and of the mouse.