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New HCV Drug Reduces HCV RNA
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Actilon (CPG 10101), Coley's lead clinical product for the treatment of viral disease, induces high levels of endogenous type I interferons and restores immune function that may be compromised by viral infection. Actilon is currently in Phase I/II trials for the treatment of chronic hepatitis C (HCV) infection.
Actilon induces high levels of endogenous type I interferons and restores immune function that may be compromised by viral infection.
Actilon is a synthetic agonist of the Toll-like receptor 9 (TLR9). By stimulating TLR9 in vitro, Actilon works directly and selectively on dendritic cells and B cells, inducing high levels of IFN-α to drive antiviral activities. Actilon achieves effective control of viral replication and induces viral clearance by:
* activating natural killer cells and stimulating endogenous type I IFN production for control of viral replication (innate immunity)
* enhancing dendritic cell function and reversing tolerance to viral antigens.
* inducing the generation of antigen-specific cytotoxic T cells and antibodies (adaptive immunity).
Coley is independently developing its Actilon products and will seek partners for select markets. Complete Phase I/II data, including viral load reduction data, will be available in late 2004. Controlled Phase II trials are planned for the second half of 2004. Additional viral disease indications are under consideration.
Coley Reports Results from Phase I Studies of ActilonTM for Hepatitis C
Antiviral Activity Demonstrated in Interim Phase Ib and Consistent with Phase Ia Dose Tolerance, Pharmacokinetics and Immune Response Findings
Wellesley, MA - January 06, 2005
Coley Pharmaceutical Group, Inc. today announced results from the company's Phase Ia study in normal volunteers and Phase Ib dosing of Hepatitis C patients with ActilonTM (CPG10101), the company's lead antiviral TLR TherapeuticTM. Actilon is a first-in-class Toll-like receptor 9 (TLR9) agonist initially being developed for the treatment of Hepatitis C.
The Phase Ia trial of Actilon in forty healthy volunteers demonstrated that the compound is well tolerated over a wide dose range, and that small subcutaneous doses induce measurable, dose-related immune responses consistent with the known pharmacologic mechanisms of this new class of antiviral activity drugs. The same range of doses were administrated twice weekly for four weeks to adults with chronic Hepatitis C virus (HCV) infection who had relapsed after, or were intolerant of, prior interferon therapy. One-third of these patients showed at least a 1.0 log reduction in HCV RNA (range 1.0 to 2.6).
"Coley staff is very pleased by the consistent and clear results in these randomized Phase I studies. The data confirm our expectations regarding Actilon's TLR9-mediated antiviral activity which was observed over a wide range of tolerable dose levels," said John Whisnant, M.D., Coley's Senior Vice President, Drug Development. "I am also encouraged by the fact that Actilon demonstrated antiviral activity even among patients with genotype 1 HCV, the viral genotype which is most difficult to treat. These results provide us with important insights on dosing regimens for further development."
"Actilon showed the predicted two phases of drug activity now characteristic of TLR9 Therapeutics. The early phase helps restore innate immune functions which are commonly dysfunctional in Hepatitis C infected hosts. This occurs through TLR9 activation of dendritic cells, leading to early antiviral cytokine and cellular changes. Actilon is designed then to drive long-term adaptive immune response, also through TLR9 and dendritic cells, to sustain the virus reduction," Dr. Whisnant added.
Detailed Study Results
The Phase Ia study, designed to assess the compound's safety, dose tolerability and immunological activity, randomized forty healthy volunteers within five sequential dosing cohorts (0.25, 1, 4, 10, or 20 mg). Two subcutaneous injections were administered double-blind fourteen days apart and subjects were evaluated for a total of 29 days. Researchers observed an immune system response demonstrating drug-related increases in interferon alpha (IFN-α) levels and other markers indicative of antiviral activity. Volunteers had no drug-related serious adverse events or dose-limiting toxicities. Mild injection site reactions and mild-to-moderate flu-like symptoms were consistent with the pharmacological mode of action of Actilon.
The ongoing Phase Ib study is evaluating anti-viral responses among chronic Hepatitis C patients as well as the safety and tolerability of twice weekly Actilon over the same dose range (0.25, 1, 4, 10, and 20 mg). Adult patients, who had relapsed after or were intolerant of prior IFN-α therapy were randomized to receive Actilon or a placebo two times weekly for four weeks with monitoring for up to four additional weeks (eight weeks total). Of 18 patients evaluated to date at the 1, 4, and 10 mg dose levels, six (33 percent) have demonstrated early viral level reduction equal to or better than 1.0 log decrease (or 90 percent) during the four weeks of treatment. The viral level reduction observed was consistent with the elevation of IFN-α and other markers associated with an antiviral immune response. Dose tolerance and laboratory safety were the same in HCV patients as in normal volunteers.
Both the Phase Ia and interim Phase Ib data were presented at national scientific meetings last fall. Phase Ia dose tolerance, pharmacokinetic (PK) and immune response data were presented at the 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in Washington DC., USA. Phase Ib data, including antiviral response, were reported at The American Association of Liver Disease (AASLD) meeting (November 2004) in a poster entitled "Human Pharmacologic Activity of a New TLR9 Agonist Antiviral, CPG 10101" in Boston, MA, USA.
About Actilon
Actilon is one of Coley's TLR TherapeuticTM family of compounds, a new class of investigational pharmaceutical products which activate and direct the immune system. Actilon is designed to act through the toll-like receptor 9 (TLR9) found in dendritic cells and B cells to induce a durable and natural immune response against the Hepatitis C virus. The compound is also designed to not only stimulate the body's own production of anti-viral interferons, but to also drive both early and sustained virus-specific memory immune responses to help clear the viral infection.
About Hepatitis C
According to the Center for Disease Control (CDC), approximately 200 million people worldwide are infected with the Hepatitis C virus (HCV), a blood-borne infectious disease of the liver and the leading cause of cirrhosis and a cause of liver cancer. An estimated four million people in the United States carry the Hepatitis C virus, and approximately 85 percent of those infected with the virus will progress to chronic infection. Further, 70 percent of those who are infected will develop chronic liver disease, making HCV the leading cause of liver transplants in the U.S. Currently, the most common treatments for Hepatitis C are recombinant forms of interferon alpha (IFN-α) intended to mimic the body's natural immune response in suppressing the virus. These therapies may be limited by toxicities and by viral resistance among some patients.
About Coley Pharmaceutical Group
Coley Pharmaceutical is an international biopharmaceutical company, headquartered in Wellesley, Massachusetts, USA, that discovers and develops TLR TherapeuticsTM, a new class of drugs that direct the human immune system to treat cancers, infectious diseases, asthma and allergy. Coley has partnered programs with Sanofi-Aventis, Chiron, GlaxoSmithKline and the United States Government. For further information please visit www.coleypharma.com.
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