Antivirals
CPG 10101 Shows Significant Antiviral Activity in Chronic Hepatitis C Patients
By Coley Pharmaceutical Group
May 23, 2005, 11:21

Coley Pharmaceutical Group, Inc today announced at the Digestive Disease Week conference that Actilon(TM) (CPG 10101) was relatively well tolerated and showed antiviral activity in the company's Phase Ib clinical study in chronic Hepatitis C patients.

In this Phase Ib study forty-two adult patients with chronic Hepatitis C virus, or HCV, were enrolled. These patients had previously failed to achieve a sustained viral response after 24-48 weeks of standard therapy with interferon-alpha plus ribavirin or were intolerant of interferon-alpha and all but two were virus genotype 1. Patients receiving 20 mg of Actilon subcutaneously twice weekly achieved a maximum 1.4 mean log decrease ( 96% ) of virus within 4 weeks. Five of the six patients receiving the 20 mg dose of Actilon achieved at least a one log ( 90% ) reduction of virus while on therapy.

Actilon showed good safety and tolerability, pharmacodynamic immune responses consistent with the drug's mechanism of action, and dose-related blood pharmacokinetics when given to HCV patients, as had been previously shown in Coley's Phase Ia clinical trial in normal volunteers. Initial antiviral activity was observed in this double-blind trial after only 1 mg of Actilon given twice weekly, and dosing has been increased to 20 mg with acceptable tolerability.

Measurements of biomarker responses in blood indicated that Actilon stimulates the innate immune system and immune activation induced by Actilon correlates with partial clearance of virus. Decreases in HCV RNA levels began to be observed after a single dose and were observed to be dose dependent.

"We are very encouraged by the results of this Phase Ib study showing antiviral effects with Actilon given to patients with relapsed or treatment resistant genotype 1 Hepatitis C," said John Whisnant, M.D., Senior Vice President, Drug Development of Coley Pharmaceutical Group. "Actilon's observed ability to direct the immune system therapeutically is consistent with its mechanism and with our experience with other Coley TLR Therapeutics in clinical development."

Data from the Phase Ib study were presented by Dr. Bruce Bacon, Professor of Internal Medicine at Saint Louis University School of Medicine in an oral presentation entitled "Safety and Pharmacodynamic ( PD ) and Pharmacokinetic ( PK ) Profiles of CPG 10101 ( Actilon( TM ) ), a Novel TLR9 Agonist: Comparison in Normal Volunteers and HCV-Infected Individuals". Interim results from this study were presented previously at The American Association of Liver Disease ( AASLD ) meeting in November 2004.

About the Study

The Phase Ib double-blind study was designed to assess antiviral responses, safety and tolerability of Actilon over an 80-fold dose range. Forty-two adult subjects with chronic Hepatitis C virus were enrolled; virtually all were virus genotype 1 patients who had previously failed to achieve a sustained viral response after 24-48 weeks of standard therapy with interferon-alpha plus ribavirin. Patients were randomized to receive placebo or Actilon in sequentially higher dose cohorts ( 0.25, 1, 4, 10 and 20 mg ) by twice weekly subcutaneous injections for four weeks.

Researchers observed responses in immune system markers including drug- related increases in interferon-alpha plasma levels and other markers indicative of antiviral activity. Actilon was relatively well tolerated at all doses in most patients, including 20 mg, the highest dose cohort completed, with no dose limiting toxicities. Mild to moderate injection site reactions and mild flu-like symptoms were consistent with the expected pharmacological mode of action of Actilon.

About Actilon( TM )

Actilon is a member of a new class of investigational medicines known as TLR Therapeutics( TM ) being developed by Coley and its partners for the treatment of major medical conditions including cancers, infectious diseases, allergy and asthma.

TLR Therapeutics target Toll-like receptors ( TLRs ) which act as immune system sentinels that recognize the distinct molecular patterns characteristic of foreign pathogens. Coley is focusing its efforts initially on the discovery and development of TLR Therapeutics which target and stimulate Toll-like receptor 9 ( TLR9 ), which is found in a subset of dendritic and B cells.

Coley believes that Actilon stimulates TLR9, targeting dendritic cells and B cells, to induce both early and long term immune responses. The short-term innate immune response is thought to drive rapid reductions in viral load in the blood. Longer term, Actilon is thought to promote virus-specific adaptive immunity, including strong T cell responses, to provide sustained anti-viral effects.

About Hepatitis C Virus

Hepatitis C virus, which infects the liver and certain immune cells, leads to serious liver diseases such as cirrhosis and liver cancer more frequently than any other form of hepatitis. HCV is an RNA virus known to undergo a high rate of mutation that may help it both to avoid control by the immune system and to develop resistance to direct antiviral medications. According to the World Health Organization, HCV infects approximately 170 million people worldwide, including at least 2.7 million in the United States, and 10-20 percent of those chronically infected with HCV will ultimately develop liver cirrhosis, making HCV the leading cause of liver transplants in the United States. The Hepatitis Foundation International estimates that between 8,000 and 10,000 people die annually from HCV-related cirrhosis or liver cancer. Coley believes, there is an unmet need for therapies with better side effect profiles and equivalent or superior efficacy, especially in the difficult-to-treat population of genotype 1 patients, who have failed to achieve a sustained virologic response following interferon-alpha and ribavirin therapy.

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