Hepatic improvement within 27 days of avenciguat treatment in Child-Pugh A cirrhosis detected by an oral cholate challenge test

• Published in: Liver transplantation Vol. 30; no. 10; pp. 982 - 990
• Main Authors: Lawitz, Eric J., Ertle, Judith, Schoelch, Corinna, Gashaw, Isabella, McRae, Michael P., Helmke, Steve M., Everson, Gregory T.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.10.2024
• Subjects: Administration, Oral; Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypertension, Portal - diagnosis; Hypertension, Portal - drug therapy; Hypertension, Portal - etiology; Liver - drug effects; Liver Cirrhosis - blood; Liver Cirrhosis - complications; Liver Cirrhosis - diagnosis; Liver Cirrhosis - drug therapy; Liver Function Tests - methods; Liver Function Tests - statistics & numerical data; Male; Middle Aged; Severity of Illness Index; Soluble Guanylyl Cyclase - metabolism; Time Factors; Treatment Outcome
• ISSN: 1527-6465; 1527-6473; 1527-6473
• DOI: 10.1097/LVT.0000000000000420

New methods for measuring hepatic improvement in clinical trials and the clinic are needed. One new method, HepQuant SHUNT, detected dose-dependent improvements in hepatic function and portal physiology in the phase 1b study (NCT03842761) of avenciguat, an activator of soluble guanylyl cyclase that is being developed for the treatment of portal hypertension. Herein, we examined whether HepQuant Duo, an easy-to-administer test version, could similarly detect the effects of avenciguat. Twenty-three patients with Child-Pugh A cirrhosis and liver stiffness >15 kPa received either a placebo (n = 5) or a maximum twice-daily avenciguat dose of 1, 2, or 3 mg (n = 6 per group) for 28 days. The DuO test was performed at baseline and on days 11 and 27 in each subject. The test involved administering 40 mg of d4-cholate orally, measuring d4-cholate concentrations in serum at 20 and 60 minutes, and calculating portal hepatic filtration rate, disease severity index, portal-systemic shunting (SHUNT%), and hepatic reserve (HR%). Avenciguat demonstrated dose-dependent improvement in all test parameters. Changes from baseline in SHUNT% after 27 days' treatment were 0.1 ± 9.0% for placebo, 1.7 ± 5.5% for 1 mg twice-daily, −3.2 ± 2.7% for 2 mg twice-daily, and −6.1 ± 5.0% for 3 mg twice-daily (paired t test for change from baseline p = 0.98, 0.48, 0.04, and 0.03, respectively). The changes detected by HepQuant DuO were similar to those previously observed and reported for HepQuant SHUNT. The results support further study of avenciguat in treating portal hypertension and spotlight the utility of HepQuant DuO in the development of drug therapy for liver disease. HepQuant DuO facilitates the use of function testing to measure hepatic improvement in clinical trials and the clinic.