1 BACKGROUND

Molybdenum cofactor deficiency (MoCD) type A is a very rare, fatal, autosomal recessive disease with an estimated U.S. prevalence of approximately 50 patients, primarily under 10 years of age. It is caused by pathogenic variants in the MOCS1 gene that lead to deficiency of cyclic pyranopterin monophosphate (cPMP), an intermediate in the biosynthetic pathway of molybdenum cofactor (MoCo), an essential cofactor of certain enzymes.^{1, 2} cPMP deficiency causes accumulation of toxic metabolites including sulfites, taurine, thiosulfate, and S-sulfocysteine (SSC).³ Patients experience intractable seizures, failure to thrive, feeding difficulties, axial hypotonia, limb hypertonia, and significantly delayed neurocognitive and motor skills.^{2, 3} Most patients die in the first years of life with a median survival of 36 months.^{2, 3} Treatment thus far has focused on managing symptoms.

Fosdenopterin is a chemically synthesized form of endogenous cPMP. It treats MoCD type A by replacing the deficient cPMP substrate and permitting the biosynthesis of MoCo, enabling activation of MoCo-dependent enzymes and the reduction of accumulated sulfites. Fosdenopterin is administered as an intravenous infusion once daily based on body weight.

中文翻译：

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监管新闻： Nulibry (fosdenopterin) 获批可降低 A 型钼辅因子缺乏症患者的死亡风险：FDA 批准摘要

1 背景

A 型钼辅因子缺乏症 (MoCD) 是一种非常罕见的致命常染色体隐性遗传疾病，据估计美国约有 50 名患者患病，主要是 10 岁以下患者。它是由MOCS1基因的致病性变异引起的，导致缺乏环状吡喃蝶呤单磷酸 (cPMP)，它是钼辅因子 (MoCo) 生物合成途径中的一种中间体，钼辅因子 (MoCo) 是某些酶的必需辅因子。^{1, 2} cPMP 缺乏会导致有毒代谢物的积累，包括亚硫酸盐、牛磺酸、硫代硫酸盐和 S-磺基半胱氨酸 (SSC)。³患者经历顽固性癫痫发作、发育迟缓、喂养困难、轴向张力减退、肢体张力亢进，以及显着延迟的神经认知和运动技能。^2、3大多数患者在出生后头几年死亡，中位生存期为 36 个月。^{2, 3}迄今为止的治疗主要集中在控制症状上。

磷蝶呤是一种化学合成的内源性 cPMP。它通过替换缺乏的 cPMP 底物并允许 MoCo 的生物合成来治疗 A 型 MoCD，从而激活 MoCo 依赖性酶并减少积累的亚硫酸盐。磷蝶呤根据体重每天一次静脉输注给药。