MON-240 GSC002874, a highly potent inhibitor of SLC6A19, for treatment of phenylketonuria

Abstract Disclosure: P. Tu: None. C. Zhang: None. Y. Xia: None. B. Lu: None. F. Yang: None. Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine, which can result in neurotoxicity. For the classic PKU cohort accounting for over 60 percent of cases, the only approved drug is pegvaliase; however, it is associated with inconvenient dosing and side effects. The epithelial neutral amino acid transporter B0AT1, encoded by gene SLC6A19, is a broad spectrum neutral amino acid transporter for the absorption of neutral amino acids including phenylalanine in the intestine and their reabsorption in the kidney. Actually a knock out of SLC6A19 in a mouse model of PKU induced an elevated neutral amino acids in urine and significantly reduced elevated phenylalanine levels in the plasma, suggesting that SLC6A19 inhibition may help to alleviate PKU symptoms. Here we report the identification and pharmacological characterization of a “best in class” potential SLC6A19 inhibitor GSC002874 for treatment of PKU.In vitro, GSC002874 inhibited SLC6A19 activity with high potency through FLIPR membrane potential assay using CHO cell expressing human SLC6A19 and TMEM27. In vivo, in a cynomolgus macaques model (animals were orally challenged with L-Phenylalanine to mimic clinical hyperphenylalaninemia), GSC002874 significantly decreased plasma phenylalanine concentration by ∼70%. In an PAH pR408W PKU mouse model with its mouse SLC6A19 replaced by human orthologue, GSC002874 significant decreased phenylalanine level in plasma at lower dosage that of JNT-517. GSC002874 exhibits a favorable ADME profile in rodents, dogs and NHPs, as well as an excellent profile in safety panels. GSC002874 also displayed good safety window in 14-day toxicology study in rats. GSC002874 is under active IND-enabling studies and expected to enter clinic in early 2026. Presentation: Monday, July 14, 2025