Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis c virus

CPG 10101, a synthetic oligodeoxynucleotide (ODN), is a toll-like receptor 9 (TLR9) agonist with antiviral and immunomodulatory properties that could potentially influence chronic infection with HCV. In this multicenter Phase 1b trial, 60 HCV-positive patients (50 genotype I HCV) were randomized and received either placebo or CPG 10101 at 0.25, 1, 4, 10, or 20 mg subcutaneously (SC) twice weekly for 4 weeks or at 0.5 or 0.75 mg/kg SC once weekly for 4 weeks. Dose-dependent cytokine induction was observed after administration of CPG 10101. At 24 hours after administering the highest dose of 0.75 mg/kg CPG 10101, interferon (IFN)-gamma-inducible protein 10 (IP-10) had a mean increase over baseline levels (+/- SD) of 15,057 (+/- 9769) pg/ml (P < 0.01, compared to placebo); IFN-alpha had a 106 (+/- 63-3) pg/ml increase (P < 0.01); and 2'5'-oligoadenylate synthetase (OAS) had a 163 (+/- 120.6) pmol/dl increase (P < 0.01). Decreases in HCV RNA also were dose-dependent, with the greatest group geometric mean maximum reduction of 1.69 +/- 0.618 loglo (P < 0.05) observed in the 0.75 mg/kg dose group. Decreases 2:1 loglo were seen in 22 of 40 patients who received 2:1 mg CPG 10101, with 3 patients exceeding a 2.5-log(10) reduction. CPG 10101 was well tolerated, and adverse events were consistent with CPG 10101's mechanism of action. Conclusion: In this Phase I study, CPG 10101 was associated with dose-dependent increases in markers of immune activation and decreases in HCV RNA levels. The data support further clinical studies of CPG 10101 for treating chronic HCV infection.