A Phase I/Ii Study of Recombinant Human Interleukin–12 in Patients With Chronic Hepatitis C

Abstract

Interleukin–12 (IL–12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The present open–label, multicenter, dose–escalation phase I/II study was designed to assess tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneously administered recombinant human interleukin–12 (rHuIL–12) in the treatment of chronic hepatitis C. Sixty patients (42 men, 18 women, aged 24–60) were treated with 0.03 μg/kg (n = 16), 0.1 μg/kg (n = 14), 0.25 μg/kg (n = 15), or 0.5 μg/kg rHuIL–12 (n = 15) for 10 consecutive weeks. rHuIL–12 was generally well tolerated, with 2 patients (3.3%) being withdrawn from treatment for adverse events. Treatment was associated with temporary decreases in neutrophils and lymphocyte counts and with elevations in serum transaminases and bilirubin. Serum IL–12 levels observed were higher at 0.5 μg/kg compared with 0.25 μg/kg doses, suggesting a dose–related increase in systemic exposure of IL–12. Measurable levels of interferon gamma (IFN–γ) were also observed at the highest dose of 0.5 μg/kg. At the end of treatment hepatitis C virus (HCV) RNA was detectable in all patients. A more than 50% decrease in pretreatment HCV RNA levels was observed in 3 of 16 patients of the 0.03–μg/kg dose group, in 3 of 14 of the 0.10–μg/kg dose group, in 6 of 15 of the 0.25–μg/kg dose group, and in 8 of 15 patients of the 0.5–μg/kg dose group. Although in several cases serum alanine transaminase (ALT) levels decreased either during or after treatment, ALT normalization was observed in only 4 patients at the end of treatment and in 5 patients at the end of follow–up. Significant anti-rHuIL–12 antibody titers were not detectable in any patient. In conclusion, antiviral activity of rHuIL–12 in patients with chronic hepatitis C does not appear advantageous in comparison with other currently available treatments.