Final results of a phase I/II dose escalation trial of valtorcitabine in patients with chronic hepatitis B

Abstract

Objectives: There is a continuing need for more effective therapies for chronic hepatitis B (CHB). L-deoxycytidine (LdC) and L-thymidine (telbivudine; LdT) are potent inhibitors of hepatitis B virus (HBV) replication in vitro. A one-year phase IIb trial demonstrated significantly greater viral suppression and serum ALT normalization in CHB patients receiving telbivudine, compared with lamivudine (Lai, AASLD2004). Valtorcitabine, a well-absorbed prodrug of LdC, is synergistic with telbivudine for inhibiting HBV replication in vitro and in the woodchuck hepadnavirus model. Valtorcitabine has been evaluated in CHB patients as the first step towards the potential development of an effective combination therapy with telbivudine. Methods: The antiviral efficacy, safety, and pharmaco!dnetics of two valyl ester prodrugs of LdC were evaluated in a phase I/II dose escalation trial. First, a 31,5l-divalyl LdC prodrag was investigated in sequential dose cohorts of 50, 100, 200, and 400 mgjday. Subsequent cohorts (300, 600, 900, and 1200mg]day) investigated the more stable 3J-monovalyl form of valtorcitabine. The 300mg dose of monovalyl-LdC and the 400mg dose of divalyl-LdC contain similar arnounts of the LdC parent nucleoside and provided similar systemic LdC exposure. Each cohort comprised 7 HBeAg+ CHB patients, randomized 6:1 (drug vs. placebo). Patients were evaluated weekly during 28 days of treatment, with 12 weeks of followup, for serum HBV DNA levels and safety. Emax modeling was used to assess the quantitative relationship between dose and antiviral response at Week 4. Results: Consistent, dose-related HBV DNA reductions were observed, ranging from a mean 1.631og10 for the 50rag/day group at Day 28, to 3.04 log10 copies/ml at 900 mg/day. Emax modeling cottfirmed a progressive increase in HBV DNA suppression toward tile theoretical maximum at doses up to 900m~day, with a diminished effect thereafter. Safety appeared comparable to placebo, with no treammnt-related pattern of adverse events or laboratory abnormalities. Conclusions: Valtorcitabine demonstrated substantial suppression of serum HBV DNA and was well tolerated in patients with chronic hepatitis B. A close of 900rag/day maximized vital suppression, and was selected for ongoing clinical evaluation of valtorcitabine in combination with telbiwdine.