Pathogenic variants in the gene encoding 6-pyruvoyl-tetrahydropterin synthase cause primary BH4 deficiency (PBD), leading to hyperphenylalaninemia and reduced monoamine neurotransmitter synthesis. This phase 1/2 study in eight patients with PBD found that sepiapterin increased blood BH4 and rapidly normalized blood phenylalanine levels, with no dose-limiting toxicity or dose-related adverse events.