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.