Actilon, New HCV Drug Reduces HCV RNA
- doctors at natap.org doctors at natap.org
Sun Jan 9 08:49:13 EST 2005
NATAP - www.natap.org
New HCV Drug Reduces HCV RNA
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)
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-a to drive antiviral activities.
Actilon achieves effective control of viral replication and induces viral
* 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
* 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
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-a) 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-a 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-a 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.
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-a) 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.
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