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LB80380, new HBV Drug
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Reported by Jules Levin
"Phase I/II Double-Blind, randomized, placebo-Controlled Trial of a Novel Agent LB80380/ANA380 in patients with Chronic HBV Infection"
Man-fung Yuen reported these results in an oral hepatitis B session at AASLD (Oct 29-Nov 2, 2004). Yuen provided this background----Desirable properties for HBV drugs: potent activity against HBV including resistant strains; high barrier to viral resistance; minimum side effect profile; minimum side effect/toxicity; long half-life to allow at least once daily dosing. LB80380/ANA380, an ester prodrug of phosphonate nucleoside analogue of guanosine monophosphate, has potent activity against HBV. The drug is designed to overcame problems of currently approved HBV drugs such as resistance to lamivudine and concerns of renal toxicity of adefovir dipivoxil.
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 I/II study designed to assess the safety, pharmacokinetics, and antiviral activity of LB80380/ANA380 in HBeAg positive, HBV DNA positive patients.
PRECLINICAL DATA
In vitro antiviral activity against wild-type & YMDD mutants
| EC50 (uM) | Adefovir | LB80317 | | Wild-type | 1.3 | 0.5 | | rtM204I | 2.5 | 1.0 | | rtM204V | 1.5 | 5.4 | | rtL180M/M204I | 1.2 | 1.5 | | rtL180M/M204V | 2.0 | 2.0 |
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 (6:1 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.
The median age and male: female ratio was 27.5 years and 20:8 respectively. Serum HBV levels at screening ranged from 1x107 to 5x109 (Amplicor HBV Monitor Assay), serum HBV DNA 8.1 to 9.1 log copies/ml. ALT <5 x ULN, serum ALT 25-80 IU/mL. All patients were ethnic asian. All HBsAg & HBeAg positive.
LB80380 was well tolerated, with no serious or moderate adverse events attributed to treatment. Systemic exposure to LB80331 and LB80317 was proportional to LB80380/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. HBV DNA rebounded immediately after drug was stopped. Yuen provided reported 4-week & 52-week HBV DNA reductions for other HBV drugs: lamivudine -2.3 log (52-week: -3 to 4 log); adefovir -2 log (wk 52: -3.5 log); entecavir (0.5 mg): -2.8-3 log (52 wk: -4 to 5 log, studies at this AASLD show 5-7 log median HBV DNA reductions); LdT (400-600 mg): -3.8 log; LB80380 (60-240 mg): -3.4 log.
Side effects included: infection, nasopharyngitis,influenza, urinary tract infection, headache, dizziness, GI, nausea, abdominal pain upper. Most of these adverse events occurred in the high dose 240 mg and several occurred at the 120 mg dose.
Yuen concluded that treatment with LB80380/ANA380 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 LB80380/ANA380. These results encourage additional investigation for longer duration and in other study populations.
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