新药跟踪: ACH-126,443 对拉米抗药变异株病毒的作用

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(谢谢大家能够帮助大家翻译) Potent Anti-HBV Activity of ACH-126,443 Correlated with 14-DAY Pharmacokinetics and Safety Study: Predictions for Activity Against Epivir-HBV-Resistant Mutant Strains The development of novel agents with good safety and favorable resistance profiles are needed for use in combination regimens for the treatment of chronic hepatitis B. ACH-126,443 (ß-L-Fd4C) is an L-nucleoside analog with 10-30 fold greater potency against Hepatitis B virus (HBV) than Epivir (lamivudine;3TC) or Hepsera (adefovir dipivoxil [(ADV]). Results of a Phase 1/II dose-escalating trial of ACH126,443 were presented at the 53rd AASLD in Boston. Following is a summary review of the study abstract: Early clinical pharmacokinetic (PK) data showed excellent oral bioavailability and animal studies showed no significant toxicity associated with plasma levels of several hundred to several thousand ng/mL, 10 to 100-fold higher than predicted for clinical use. In concert with in vitro activity against YMDD mutant HBV strains (IC50<50 ng/mL), these data suggest that, among the currently available HBV drugs, ACH-126,443 may provide potent in vivo activity against the resistant strains, while maintaining a wide safety margin. Methods: This multicenter, blinded, placebo-controlled, ascending-dose, Phase 1/2 trial was designed to evaluate safety, PK and early antiviral activity of 14 days of ACH-126,443 in chronic HBV infection. The study was conducted at 11 centers in North America and Dominican Republic. Thirty-six evaluable treatment-naive HBV-infected subjects were randomized sequentially to dose groups of 1, 5, 10, 20, 50 and 100 mg once daily given orally (5:1 active:placebo per dose group). PK profiles were measured after doses 1 and 14, safety was evaluated weekly during treatment and 2 weeks off therapy. Plasma HBV DNA (Roche COBAS® PCR) was measured bi-weekly during treatment and 2 weeks off therapy. Results: Subjects were 85% male, mean age was 39 years and the patients represented a broad ethnic diversity, including 43% Asian, 33% Caucasian, 10% black and 15% Hispanic. The mean ALT at baseline was 79 IU/mL and the mean plasma HBV DNA level was approximately 7.0 log10. The dose groups were well balanced, as were the placebo recipients within each group. No apparent drug-related adverse events were observed at any dose level. Pharmacokinetic profiles demonstrated peak plasma levels within 1 hour of oral administration 20 ng/mL which exceeded the IC50 of wild-type HBV by 50-fold with doses of 5 mg daily and above. Mean declines of 1.5 - 3.0 log10 plasma HBV DNA, achieved after 14 days of dosing, indicated potent suppression of viral replication in the 5-100 mg daily dose groups (p=0.018 for each active dose group vs placebo). The IC50 of YMDD mutant HBV was reached as a peak plasma drug level with 10 mg daily, and was exceeded by 2 to 20-fold with doses of 20 mg daily and above. No accumulation of free drug was observed in plasma, although sustained viral suppression after discontinuation of treatment with 50 and 100 mg daily suggested that active intracellular ß-L-Fd4C-triphosphate was eliminated more slowly. Conclusions: Studies with other HBV DNA polymerase inhibitors (lamivudine, adefovir) indicate that potent antiviral activity is observed when peak plasma levels meet or exceed the IC50 of the target virus, be it wild-type or YMDD mutant. Oral pharmacokinetics of ACH-126,443 indicate that peak plasma levels well in excess of IC50 of wild-type and YMDD mutant HBV are achieved with low dose levels anticipated to provide a wide safety margin. A Phase 2 trial in 3TC-failing HBV patients is underway; these data will provide support for evaluation of ACH-126,443 in combination regimens for optimal suppression of viral replication. 01/17/03 Reference N H Afdhal and others. POTENT ANTI-HBV ACTIVITY OF ACH-126,443 CORRELATED WITH 14-DAY PHARMACOKINETICS AND SAFETY: PREDICTIONS FOR ACTIVITY AGAINST YMDD MUTANT STRAINS. Abstract 837. 53rd AASLD. November 1-5, 2002. Boston, MA. Hepatology 2002: Vol 36 No 4, Pt 2 of 2