Experimental HBV Drug Pradefovir: Safety, Tolerability, Antiviral Activity, and Pharmacokinetics

The experimental HBV drug pradefovir mesylate (PDV) is a cytochrome P450 (CYP) 3A4–activated, liver-targeted prodrug of PMEA with potentially improved efficacy and less nephrotoxicity than adefovir dipivoxil (ADV), according to a latebreaker presentation at the 56^th AASLD in San Francisco (November 11-15, 2005).

Phase 1 studies have demonstrated that PDV up to 60 mg/day for 4 weeks was safe, well tolerated and showed anti-hepatitis B virus (HBV) activity. In the current randomized Phase 2 study, Korean and Taiwanese researchers are evaluating the safety, tolerability, antiviral activity, and pharmacokinetics of PDV in patients with chronic HBV infection.

S G Lim presented 24-week preliminary data from the Phase 2 study in San Francisco.

In this randomized, open-label, parallel-group, multicenter study, the investigators compared ADV 10 mg/d and PDV 5, 10, 20, and 30 mg/d for 48 weeks. Inclusion/ exclusion criteria included HBV DNA >5 X 10⁵ c/mL; alanine aminotransferase (ALT) 1.2–10 X ULN; and no ADV, interferon, or anti-HBV antiviral within 3 months of screening. HBV DNA was measured by COBAS Taqman® (lower limit of quantitation 169 copies/mL). Safety assessments included physical examination, standard hematology, and serum chemistry.

Results

• 244 patients from S. Korea, Singapore, Taiwan, and the US were randomized and 242 received at least 1 dose (intent-to-treat).
• Of these, 6 (2%) discontinued, 3 (1%) for adverse events (AEs).
• The study population was 100% Asian, 83% male, and 70% hepatitis e antigen positive.
• The average age was 38 years, and virus was genotype A in 0.4%, genotype B in 32.6%, and genotype C in 66.9%.
• Mean baseline HBV DNA was 7.9–8.2 log ₁₀ c/mL, and median baseline ALT was 2.0 – 2.8 X ULN.
• The majority of patients had been treated with IFN or antivirals.
• PDV was absorbed rapidly (Tmax 1 hr) and converted to PMEA without significant accumulation.
• PMEA exposure with PDV 30 mg was less than with ADV 10 mg (AUC 224 vs 298 ng • h/mL).
• Reductions from baseline in HBV DNA were 3.39±0.19, 4.22±0.15, 4.33±0.14, and 5.02±0.14 (mean±SE log ₁₀ copies/mL) for the PDV 5 mg (n=47), 10 mg (n=49), 20 mg (n=48), or 30 mg (n=48) groups, respectively, vs –3.66±0.18 for the ADV 10 mg (n=50) group.
• The proportions of patients with HBV DNA <400 c/mL were 17%, 24%, 29%, and 38% for the PDV 5 mg, 10 mg, 20 mg, and 30 mg groups, respectively, and 16% for the ADV 10 mg group.
• There were no serious treatment-related adverse events and no ALT flares (ALT >/=10 X ULN and >/=2 X baseline).
• Adverse events and laboratory safety values were comparable between groups. There was no dose-response for any safety parameter and no renal toxicity in any group.

The study authors conclude, “The 24-week interim analysis demonstrates that PDV is safe, well tolerated, and has significantly greater anti-HBV activity than ADV with less systemic PMEA exposure.

11/21/05

Reference
S G Lim and others. Safety, Tolerability, Antiviral Activity, and Pharmacokinetics of Pradefovir Mesylate In Patients with Chronic Hepatitis B Virus Infection: 24-Week Interim Analysis Of A Phase 2 Study. Abstract LB07. Abstracts of the 56^th annual meeting of the American Association for the Study of Liver Diseases (56^th AASLD). November 11-15, 2005. San Francisco, CA.