2026-06-26 | Molecular Genetic and Biochemical Characterization of Hyperphenylalaninemia Based on Expanded Neonatal Screening Data from 2023 to 2024 in the Russian Federation.
Since January 2023, the Russian Federation has implemented expanded neonatal screening for 36 hereditary disorders, which has changed the diagnostic algorithm for hyperphenylalaninemia/phenylketonuria (HPA/PKU) by introducing tandem mass spectrometry (MS/MS) on the second day of life, followed by confirmatory biochemical and molecular testing in newborns at risk. We analyzed 1247 newborns aged 5-15 days with elevated phenylalanine levels (≥120 µmol/L) and a phenylalanine to tyrosine ratio of at least 1 detected during the first stage of screening using MS/MS. At the reference center, newborns underwent repeat biochemical testing and stepwise molecular analysis of HPA-associated genes. Two pathogenic variants in HPA-associated genes were identified in 538 newborns, including 534 newborns with biallelic pathogenic variants in PAH and 4 with BH4-deficient forms (PTS, QDPR). The incidence of molecularly confirmed HPA was 1:4518 newborns (95% CI: 1:4152-1:4925). The PAH variant spectrum was dominated by p.Arg408Trp (c.1222C>T) (33.4%). Genotype-based analysis indicated that 73 newborns (13.7%) were likely responsive to cofactor therapy, whereas 222 (41.6%) were potentially responsive. These findings define the molecular epidemiology of HPA in Russia and support early genetic stratification for diagnosis and treatment.
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2026-05-13 | Sepiapterin: From sapropterin to next-generation therapy.
Sepiapterin is a naturally occurring pteridine and BH4 precursor that links classic pterin chemistry to tetrahydrobiopterin biology. Tetrahydrobiopterin (BH4; sapropterin) is an essential redox-active cofactor for phenylalanine hydroxylase (PAH), the aromatic amino acid hydroxylases, and nitric oxide synthases, whereas 7,8-dihydrobiopterin (BH2) reflects pterin redox balance and can antagonize BH4-dependent nitric oxide signaling. This review integrates historical and chemical perspectives with current biochemical and clinical understanding of BH4 homeostasis, including de novo synthesis, recycling/oxidation, and the sepiapterin salvage pathway. Sepiapterin is taken up by cells through equilibrative nucleoside transport mechanisms and is intracellularly converted through sepiapterin reductase and dihydrofolate reductase to expand BH4 pools. In healthy volunteers, oral sepiapterin produced marked systemic BH4 exposure with minimal parent-drug exposure (geometric mean Cmax 640 ng/mL for BH4 versus 1.74 ng/mL for sepiapterin after 60 mg/kg) and increased cerebrospinal fluid BH4 after 7 days of 60 mg/kg/day dosing. In phenylketonuria (PKU), the Phase 3 APHENITY trial showed a placebo-adjusted least-squares mean blood phenylalanine reduction of 395.9 μmol/L at Week 6 among sepiapterin-responsive participants, and the Phase 3 AMPLIPHY trial showed greater lowering with sepiapterin 60 mg/kg/day than with sapropterin 20 mg/kg/day (least-squares mean difference 180.4 μmol/L; 95% CI 131.4-229.5; p < 0.0001). Together, these data position sepiapterin as a next-step therapy beyond sapropterin, while underscoring the importance of biomarker studies that quantify BH4, BH2, and the BH4/BH2 ratio in plasma and cerebrospinal fluid.
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2026-04-17 | Ethnic Bridging of Sepiapterin in Chinese and Korean Populations Based on Predictions From Genetic Polymorphism of Breast Cancer Resistance Protein.
Ethnic differences are crucial when considering the efficacy, safety, and dose of pharmaceuticals across diverse populations. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline E5 addresses the acceptability of extrapolating foreign clinical data taking ethnic factors into consideration. Sepiapterin has recently been approved for the treatment of hyperphenylalaninemia (HPA) in patients with phenylketonuria (PKU) in Europe, the USA, and multiple additional countries worldwide. To date, no clinical trials have been conducted in the Chinese or Korean populations. An ethnic sensitivity analysis identified that the breast cancer resistance protein (BCRP) c.421C>A variant was the primary factor leading to ethnic differences in BH4 exposures. A correlation was established and validated between the frequency of BCRP c.421C>A variant in ethnic groups and the relative Cmax and AUC0-24h of sepiapterin major active metabolite 5,6,7,8-tetrahydrobiopterin (BH4). Based on this correlation, it was predicted that compared to White, the mean BH4 Cmax and AUC0-24h were 1.16-fold and 1.23-fold higher, respectively, in Chinese subjects, and 1.12-fold and 1.17-fold higher, respectively, in Korean subjects. These findings, including the clinically insignificant differences in PK exposures, the comprehensive evidence of sepiapterin's efficacy and safety, the recognition of PKU as a rare disease and designation of sepiapterin as an orphan drug for treatment of PKU in EU, the USA, Japan, South Korea, and several other countries, and the urgent unmet medical need, collectively support that conducting an ethnic bridging study in Chinese and Korean populations is not warranted.
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