Maximal viral suppression is an important objective of treatment for chronic hepatitis B virus (HBV) infection. Several new anti-HBV therapies have been evaluated in comparison with placebo or lamivudine (Epivir-HBV), but typically have not yet been subject to head-to-head comparisons.

Previous studies have shown that adefovir (Hepsera) has significantly greater efficacy than placebo. Telbivudine (LdT), an investigational HBV polymerase inhibitor, exhibited superior antiviral activity compared with lamivudine in a large Phase III trial. That study found that maximal HBV DNA reductions during the first six months of treatment were associated with viral suppression and clinical efficacy (ALT normalization, HBeAg loss or seroconversion) at one year.

Trial 018 is a randomized, open-label international study comparing the antiviral efficacy and safety of telbivudine vs adefovir. The study enrolled 135 previously untreated adults with HBeAg-positive chronic hepatitis B. At baseline, subjects were required to have HBV DNA > 6 log10 copies/mL, alanine aminotransferase (ALT) levels 1.3-10 times the upper limit of normal (ULN), and compensated liver disease. The baseline characteristics of the treatment groups were well matched; about three-quarters were male and more than 90% were Caucasian.

Patients were randomly assigned in a 2:1 ratio to receive 10 mg once-daily adefovir or 600 mg once-daily telbivudine. At week 24, one-half of the patients initially placed in the adefovir arm were randomly assigned to switch to telbivudine. Treatment will continue for a total of 52 weeks.

The primary endpoint defined by the study protocol was HBV DNA reduction at week 24, with secondary antiviral and clinical efficacy and safety endpoints assessed at weeks 24 and 52 (not presented in DDW abstract).

Results

• At week 24, telbivudine was superior to adefovir in terms of HBV DNA reduction (see table).
• The rates of treatment failure (not achieving HBV DNA < 5 log10 copies/mL) were 5% in the telbivudine arm vs 42% in the adefovir arm.
• ALT normalization and loss of HBeAg were similar in both arms.
• Both telbivudine and adefovir were well tolerated; the rate of adverse events was similar in both arms, and most side effects were mild to moderate.
  

† percent of patients with HBV DNA level < 5 log10 (AASLD & APASL guideline);
‡ COBAS PCR assay limit ≤300 copies/mL;
* p < 0.01, telbivudine vs. adefovir

Conclusion

The researchers concluded that after 24 weeks, telbivudine exhibited significantly greater and more consistent antiviral efficacy than adefovir in HBeAg-positive patients with chronic hepatitis B. Treatment will continue through week 52.

Link to Heathcote slide presentation:

http://www.hivandhepatitis.com/2006icr/ddw/pdf/Heathcote.pdf

Toxicity in Animal Studies

Another presentation described data from preclinical animal studies of telbivudine. Studies were conducted over the course of six months in rats and nine months in cynomolgus monkeys. The animals received many times the maximum recommended human dose of 600 mg/day. No telbivudine-related adverse physiological effects were observed in rats or monkeys.

In a two-year study, no evidence of carcinogenicity was observed in rats receiving high oral doses of telbivudine, up to 2000 mg/kg/day for ≥ 85 weeks. In a study using transgenic mice, no differences were found in the incidence of neoplastic or non-neoplastic changes in mice taking high-dose telbivudine for 26 weeks compared with control animals.

Finally, reproductive and developmental toxicity was assessed in rats and rabbits. No significant effects were observed in general fertility in rats treated with 2000 mg/kg/day telbivudine. No effects on embryo, fetal, or postnatal development were observed in rats or rabbits treated with 1000 mg/kg/day.

In conclusion, in preclinical studies to date, telbivudine has been shown to have no significant toxic effects in relevant animal models, suggesting minimal risk for cumulative toxicity, carcinogenicity, or reproductive toxicity in humans.

5/30/06

Reference

E Heathcote, HL Chan, M Cho, and others. A Randomized Trial of Telbivudine (LdT) vs. Adefovir for HBeAg-Positive Chronic Hepatitis B: Results of the Primary Week 24 Analysis. Abstract 479. DDW 2006. May 20-25, 2006. Los Angeles, CA.

Bridges E. Telbivudine Preclinical Safety Studies Suggest Minimal Risk of Chronic Toxicity, Reproductive Toxicity or Carcinogenicity. Abstract T1847. DDW 2006. May 20-25, 2006. Los Angeles, CA.