May 20-23, 2001
L-DT: New Hepatitis B Drug
L-DT: An Ongoing Phase I/IIA Dose-Escalation Trial In Patients with Chronic HBV Infection (NV-02B-001)
Seng Gee Lim, National Univ Hosp, Singapore Singapore; Ching-Lung Lai, Univ of Hong Kong, Hong Kong; Yin-Mei Lee, National Univ Hosp, Singapore Singapore; Deborah M. Pow, Maureen W. Myers, Novirio Pharmaceuticals, Inc, Cambridge, MA
Maureen Myers (Novirio Pharmaceuticals) reported at DDW (May 2001) that L-dT (b-L-2-deoxythymidine) is a new L-nucleoside that has been shown to be a highly specific and potent inhibitor of HBV DNA polymerase and HBV replication in vitro. NV-02B-001 is a blinded, placebo-controlled dose escalation trial to evaluate the pharmacokinetics, safety and antiviral activity of L-dT administered once daily at doses starting at 25 mg. 7 HBeAg (+) patients are to be enrolled in each of the sequential dose cohorts (25, 50, 100, 200 and 400 mg) at a ratio of 6:1 (L-dT:placebo). Dose limiting toxicities (DLTs) must be 2 or less in any given cohort in order to dose-escalate to subsequent cohorts. The primary efficacy measure is plasma HBV DNA, measured by COBAS Amplicor HBV Monitor Assay
Preliminary safety and antiviral activity data have shown L-dT to be active and well tolerated in patients enrolled in the first and lowest dose cohort.L-DT anti-HBV activity at nanomolar concentrations; no mitochondrial toxicity; up to 8 log reduction in WHV animal model; safe in 2 species in sub-chronic toxicology studies at doses as high as 2 g/kg/day. This study was to evaluate dosing, safety, and characterize PK profile. Patients received 5 sequential doses of L-DT:25 to 400 mg daily. 7 patients were in each dose group (1 receiving placebo). After 4 weeks of dosing at highest dose reported on (200 mg) HBV DNA log drop was about 3 logs. Myers reported no serious adverse events or dose limiting toxicity, so higher doses can be explored. Further trials are being planned including in combination with 3TC. Studies in HIV/HBV coinfection need to be planned.