Interim report for a phase II, multi-centre, dose-escalating study of LB80380/ANA380 in hepatitis B patients with lamivudine-resistant YMDD mutant HBV

Abstract

Background: LB80380 (also termed ANA380) is a novel ant/viral agent that is converted after administration to LB80317, a novel guanosine phosphonate nucleotide analogue that exhibits potent activity against HBV, including in vitro activity against HBV variants resistant to lanfivudine. Objectives: This study investigates the safety and ant/viral activity of escalating doses of LB80380 in HBeAg+ patients with lamivudine-resistant HBM Patients and Methods: 40 patients were enrolled into 3 cohorts. Staggered cohorts received LB80380 in escalating doses of 30rag (n= 13), 60mg (n= 13) or 90mg (n = 14) once daily for 12 weeks. Eligible patients were required to be positive for HBeAg with HBV DNA )lxl06 copies/ml, documented to have lamivudine resistance encoded in M204I/V alone or with L180M, and on continuous lamivudine therapy prior to the study. LB80380 was co-administered with continued lamivudine (100rag) for the first 4 weeks, and LB80380 was given alone for the remaining 8 weeks. Patients were switched to adefovir dipivoxil upon discontinuation of LB80380, and monitored for an additional 24 weeks. Results: We report here 12-week results for patients for whom data are available. No serious adverse events were observed during treatment. Four weeks after initiation of treatment with LB80380, plasma HBV vital DNA was reduced approximately 2.1, 2.5 and 2.9 logm units in the 30rng, 60rng and 90rng dose groups, respectively. HBV viral DNA continued to decline during the LB80380 monotherapy phase following discontinuation of lamivudine. At week 12, plasma HBV viral DNA was reduced approximately 2.8 and 3.2 log10 units in the 30mg and 60mg dose groups, respectively. The 90 rng cohort appeared to reduce HBV DNA more than 30 and 60mg cohorts during the first 4 weeks. Conclusions: Administration of 30 mg and 60mg of LBS0380/ANA380 for 12 weeks was safe, well tolerated, and associated with a significant reduction of plasma HBV DNA in patients with lamiwtdine-resistant HBV.