Phase I/II double-blind, randomized, placebo-controlled study of the novel anti-HBV agent LB80380/ANA380 in patients with chronic HBV infection

Abstract

BACKGROUND: LB80380/ANA380 is an orally available drug that is converted after dosing to LB80331 and subsequently to LB80317, a novel guanosine phosphonate nucleotide analogue that exhibits activity against HBV in vitro, including HBV variants resistant to lamivudine. The compound has a favourable toxicity profile in vitro, including low potential for renal toxicity. Animal toxicology studies confirmed the favourable tolerability of LB80380/ANA380, and studies in woodchucks showed reductions in serum viral titre greater than six log after four weeks of dosing. Phase I studies in healthy volunteers demonstrated good safety, tolerability, and pharmacokinetics consistent with once daily dosing. We report the final study results of a Phase 1/11 study designed to assess the safety, pharmacokinetics, and antiviral activity of LB803801 ANA380 in HBeAg positive, HBV DNA positive patients. Study Design: This study was a double-blind, randomised, placebo-controlled, multiple ascending dose evaluation of LB80380/ ANA380 dosed once daily for 28 days at 30mg, 60mg, 120mg, and 240 mg. Cohorts of seven patients were randomised (6:l active: placebo) at each dose level, and safety was established at each dose prior to dose escalation. Patients were followed for 12 weeks after completing the dosing phase. RESULTS: The median age and male: female ratio was 27.5 years and 208 respectively. Serum HBV levels at screening ranged from lx107 to 5x109. LB80380 was well tolerated, with no serious or moderate adverse events attributed to treatment. Systemic exposure to LB80331 and LB80317 was proportional to LB803801 ANA380 dose. HBV DNA reductions were observed during treatment in all patients receiving LB80380/ANA380, and returned to pre-treatment levels during follow-up. Median log serum HBV reductions on day 28 of treatment were 3 to 4 log. CONCLUSIONS: Treatment with LB803801ANA380 for 28 days at doses up to 240mg was well tolerated and safe in this study population. Substantial anti-HBV effects were observed at all doses of LB803801ANA380. These results encourage additional investigation for longer duration and in other study populations.