A Randomized, Open-Label, Phase 2a Study to Assess the Safety, Pharmacodynamics, and Pharmacokinetics of YAQ007 Versus Rifaximin in Cirrhosis

Background & Aims: Ammonia is central in the pathogenesis of hepaticencephalopathy (HE), but there are no approved treatments targeting ammonia. LOrnithinePhenylacetate (YAQ007) is a novel drug, which effectively reduces ammoniawhen administered intravenously. This exploratory Phase 2a study evaluated theshort-term pharmacodynamics, pharmacokinetics, and safety of oral YAQ007 inpatients with cirrhosis and a history of overt HE.Approach & Results: In this randomized, open-label, multicenter study, 48-cirrhosispatients (28 male, mean of 57.2 years, Child-Pugh of 8 and MELD score of 10) wererandomized (1:1:1:1) to one of three YAQ007 dosing regimens (2 g three times daily;4 g twice daily; 4 g three times daily) or rifaximin (550 mg twice daily) for 5 days underinpatient conditions. A decrease of ammonia at day-5 was observed in group C(p=0.009) and group B (p=0.002). After multivariable adjustment, treatment Group Bvs Group D, bilirubin, INR and sodium (p<0.05) remained significant factors forabsolute ammonia reduction. Urinary phenylacetylglutamine excretion increased onday 5 compared to day 1 across all YAQ007 dose groups (p<0.001). Exposure–response relationships were variable, and a clear dose–response relationship was notdemonstrated. Overall, 20 (55.6%) patients who received YAQ007 and 5 (41.7%) whoreceived rifaximin had at least 1 treatment-emergent adverse events, with mainly mildgastrointestinal and neurological symptoms.Conclusions: In this Phase 2a study, oral YAQ007 demonstrated short-termammonia-lowering activity at doses ≥4 g BID. Given the exploratory design, thesefindings are hypothesis-generating and support further clinical evaluation.