A Dose Escalating Trial of Clevudine

拉米夫定

A Dose Escalating Trial Evaluating the Safety and Activity of Clevudine in Patients with Chronic Hepatitis B

Clevudine (CLV, L-FMAU) is a potent inhibitor of HBV replication in vitro. In woodchucks, CLV produced a potent and sustained viral suppression following a 12-week dosing period.

This was a multicenter, open-label, dose escalation study evaluating 10, 50, 100 and 200 mg CLV QD for 28 days (n=5, 10, 10 and 7/arm, respectively). Patients were followed post-treatment for 24 weeks.

Eligible patients had chronic HBV infection, Baseline HBV DNA levels (VL) > or = 3x106 copies/mL, were nucleoside treatment naive and without HIV or HCV co-infection. VL was assayed using Digene Hybrid Capture II (with a lower limit of detection of 4700 c/mL) and genotype by di-deoxy sequencing.

32 patients were enrolled, 81% were male, 81% Asian, 88% HBeAg positive. At Baseline, median VLs were 7.3, 8.0, 8.8 and 8.4 log10 c/mL and median ALTs were 55, 119, 106 and 64 IU/L in the 10, 50, 100 and 200 mg QD cohorts, respectively.

After 28 days of dosing, the median log10 VL change from Baseline was -2.5, -2.7, -3.0 and -2.6 and median change in ALT from Baseline was -13, -14.5, +37 and -14 U/L, in the 10, 50, 100 and 200mg cohorts, respectively.

At 6 months post-dose, sustained biochemical and virologic responses were observed: 71% of the patients overall had normal ALT levels and median log10 VL changes from Baseline were -1.2, -1.4, -2.7 and -1.6 in the 10, 50, 100 and 200mg arms, respectively.

During the study, 8 patients lost HBeAg (30%) of whom 5 seroconverted to HBeAb (19%). CLV was well tolerated, without dose related adverse events. A transient increase in ALT was observed in the 100 mg cohort but not in the 200 mg group.

The pharmacokinetics of CLV were dose proportional with a long plasma half-life supporting a once daily regimen. No treatment emergent mutations in the HBV DNA pol domain were observed 5 months after treatment.

Conclusion: These results confirm the antiviral activity of once daily clevudine and further demonstrate, in humans, the uniquely sustained post-treatment antiviral effect seen previously in woodchucks.

Despite the short (4 weeks) duration of therapy, very favorable rates of HBeAg loss and seroconversion were observed without evidence to date of acquired resistance on CLV therapy.