A randomized, open-label, phase 2a study to assess the safety, pharmacodynamics, and pharmacokinetics of YAQ007 versus rifaximin in cirrhosis

BACKGROUND AND AIMS: Ammonia is central in the pathogenesis of HE, but there are no approved treatments targeting ammonia. L -Ornithine Phenylacetate (YAQ007) is a novel drug that effectively reduces ammonia when administered intravenously. This exploratory phase 2a study evaluated the short-term pharmacodynamics, pharmacokinetics, and safety of oral YAQ007 in patients with cirrhosis and a history of overt HE. APPROACH AND RESULTS: In this randomized, open-label, multicenter study, 48 cirrhosis patients (28 male, mean of 57.2 y, Child-Pugh of 8, and MELD score of 10) were randomized (1:1:1:1) to 1 of 3 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 under inpatient 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 B versus group D, bilirubin, INR, and sodium ( p <0.05) remained significant factors for absolute ammonia reduction. Urinary phenylacetylglutamine excretion increased on day 5 compared with day 1 across all YAQ007 dose groups ( p <0.001). Exposure-response relationships were variable, and a clear dose-response relationship was not demonstrated. Overall, 20 (55.6%) patients who received YAQ007 and 5 (41.7%) who received rifaximin had at least 1 treatment-emergent adverse event, with mainly mild gastrointestinal and neurological symptoms. CONCLUSIONS: In this phase 2a study, oral YAQ007 demonstrated short-term ammonia-lowering activity at doses ≥4 g BID. Given the exploratory design, these findings are hypothesis-generating and support further clinical evaluation.