AASLD: Novel Drug Takes Toll on Hepatitis C

BOSTON, Nov. 1 -- An investigational immunomodulator -- a Toll-like receptor 9 (TLR9) agonist -- has shown early antiviral activity in patients with difficult-to-treat chronic hepatitis C infections.

The compound, called CPG 10101, or Actilon, appears to stimulate both innate immunity, in the form of antiviral cytokines such as native interferon ?, and antigen-specific adaptive immunity, reported Ira Jacobson, M.D., of Weill Cornell Medical College in New York, and colleagues.

"The ancient but only recently recognized Toll-like receptor system is widely distributed in nature, and has evolved to allow for immunologic recognition of pathogen-associated molecular patterns," Dr. Jacobson said at the American Association for the Study of Liver Diseases meeting here.

The compound directly activates plasmacytoid dendritic cells, the largest sources of interferon ? in the body, and B cells. It also indirectly activates natural killer and natural killer T cells, and appears to have synergistic antiviral activity with pegylated interferon and Rebetol (ribavirin), Dr. Jacobson said.

He and his colleagues investigated CPG 10101 in 74 patients who were infected with the treatment-refractory HCV genotype 1 and who had relapsed after a prior response to 24 or more weeks of treatment with Peg-IFN and Rebetol.

The patients were randomized and treated initially for 12 weeks with either Peg-IFN and Rebetol alone or with CPG 10101, and CPG 10101 alone or in combination with either Peg-IFN or Rebetol.

CPG 10101 was delivered in doses of 0.2 mg/kg subcutaneously weekly, Peg-IFN was given 1.5 ?g/kg subcutaneously weekly, and Rebetol was given at 800 to 1,400 mg orally daily.

Patients in a treatment arm containing CPG 10101 who achieved ?2 log₁₀ reduction at week 12 were eligible to continue treatment for up to 48 weeks. All patients in the control (Peg-IFN and ribavirin) group were eligible to roll-over to the triple therapy after completing the initial 12 weeks of treatment, regardless of their viral level.

The authors found that the mean log₁₀ HCV RNA reduction at week 12 was significantly greater among patients treated with CPG 10101 plus Peg-IFN and Rebetol (12 of 14 patients, or 86%) than with standard therapy alone (nine of 15 patients, or 60%).

In addition, 13% of patients receiving standard therapy alone or the CP10101-interferon combination had HCV RNA levels undetectable on an assay with a lower cutoff point of < 50 IU/mL, compared with 50% of patients on the triple-combination (P=0.05).

In all, 20 of 24 patients in treatment arms containing CPG 10101 elected to continue therapy, and of these, two on the triple combination and two on CPG 10101 and interferon head undetectable HCV RNA levels during the continuation phase.

On treatment responses, with HCV RNA < 50 IU/mL at week 24, occurred in seven of 14 patients (50%) on the triple therapy, three of 16 (19%) in the CPG 10101-interferon group, and none of the other groups.

Fourteen of the 15 patients who initially received standard therapy of Peg-IFN and Rebetol were rolled over to receive CPG 10101 after 12 weeks, and five of these patients also had HCV levels that fell off the radar screen.

CPG 10101 alone, however, had no effect on any of the clinical endpoints during the study.

Adverse events were predominantly mild to moderate, and consisted of headache, flu-like symptoms, fatigue and nausea. Injection-site reactions were more common among patients receiving CPG 10101, and there were two dropouts, one because of rash, and the other to injection-site cellulites and necrosis.

The investigators plan to follow patients for end of treatment response and sustained viral response out 48 or 72 weeks, Dr. Jacobson said.

Dr. Jacobson is a clinical investigator for Coley Pharmaceutical Group, maker of CPG 10101.