MON-238 GenSciP152, a Highly Potent Stabilizer of PAH R408W, for Treatment of Classical Phenylketonuria

Abstract Disclosure: K. Zhang: None. K. Geng: None. Y. Xia: None. B. Lu: None. F. Yang: None. Phenylketonuria (PKU) is an autosomal recessive disease mainly caused by mutation of phenylalanine hydroxylase (PAH), the rate-limiting enzyme in the metabolism of phenylalanine (Phe). The abnormal accumulation of Phe couldcause intellectual disability, cognitive and motor deficits. The PKU prevalence was highest in European and certain Middle Eastern populations (Italy (1:4,000), Ireland (1:4,545), Iran and Jordan (both1:5,000)). More than 3000 PAH variants were identified so far and the most prevalent variants was p.Arg408Trp (R408W), with an allele frequency (AF) = 22.2% in the whole world and 63.7% throughout Europe. The distribution of patients with R408W on at least one allele (compound heterozygotes and homozygotes) is over 80% in many European countries and 32.9% in USA. Often associated with a classical PKU phenotype, patients harboring PAH R408W don’t respond well to current treatments. It has been reported that the R408W mutation destabilizes PAH protein, making it subject to degradation. Thus restoring the mutant protein function becomes a potential option for this type of PKU. Here we report the identification and pharmacological characterization of a “best in class” potential PAH R408W stabilizer GenSciP152. In vitro, GenSciP152 stabilized the PAH R408W protein, leading to an increased in both protein expression and enzyme activity. In vivo, in a mouse PAH R408W/R408W mutation model, GenSciP152 significantly induced over 70% Phe reduction in plasma comparing to untreated animals. GenSciP152 exhibits a favorable ADME profile in rodents, dogs and NHPs, as well as a great safety window in toxicology studies. The compound is under active IND-enabling studies and expected to enter clinic study in early 2026. Presentation: Monday, July 14, 2025