Actilon, New HCV Drug Reduces HCV RNA

[Guest guest]

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

http://natap.org/pipermail/doctors_natap.org/2005-January/000450.html

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-a 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 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.

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-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.

[Guest guest]

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

http://natap.org/pipermail/doctors_natap.org/2005-January/000450.html

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-a 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 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.

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-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.