New Toll-like Receptor Drug Actilon for HCV Therapy

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New Toll-like Receptor Drug Actilon for HCV Therapy

UPDATE 1-Coley initiates trial of hepatitis C drug

Tue Sep 27, 2005

NEW YORK, Sept 27 (Reuters) - Coley Pharmaceutical Group Inc. on

Tuesday said it is starting an early-stage clinical trial of an

experimental drug to treat chronic Hepatitis C virus.

Coley expects preliminary data from the Phase Ib study of the drug,

Actilon, to be available in the second half of 2006.

The study will involve 60 patients infected with the virus, who will

be divided into different treatment groups over a period of three

months. Some patients will take only Actilon, some will take it in

combination with one or two standard treatments, and some will take

standard treatments without Actilon.

The company, which went public last month, has also attracted

attention because of three other promising experimental drugs,

especially ProMune, which is entering late-stage trials against non-

small cell lung cancer. Coley, based in Wellesley, Massachusetts, is

developing that product with Pfizer Inc.

Its drugs are designed to stimulate the immune system by acting on

proteins called Toll-like receptors. Actilon acts through the Toll-

like receptor 9 found in dendritic cells and B cells, which are

mainstays of the immune system.

Shares of Coley were up $1.52, or 9.4 percent, to $17.64 on Nasdaq.

(Additional reporting by Ransdell Pierson)

Coley Pharmaceutical Group Initiates Phase I Clinical Trials of ...

Articles. Coley Pharmaceutical Group Initiates Phase

I Clinical Trials of Actilon for Chronic Hepatitis C Infection ...

www.natap.org/2004/jan/011604_02.htm - 9k

SAFETY, PHARMACODYNAMIC (PD) & PHARMACOKINETIC (PK) PROFILES OF ...

SAFETY, PHARMACODYNAMIC (PD) & PHARMACOKINETIC (PK) PROFILES OF CPG

10101 (ACTILON),

A NOVEL TLR9 AGONIST: comparison in normal volunteers & HCV

infected ...

www.natap.org/2005/ddw/ddw_12.htm

Actilon, (CPG 10101)….

Coley's proprietary product candidate for the treatment of viral

infectious disease, is being developed for the treatment of patients

chronically infected with Hepatitis C virus (HCV) to address many of

the shortcomings of current therapies.

Actilon is a synthetic oligonucleotide and selective TLR9 agonist

which enhances the ability of dendritic cells to activate killer T

cells against invaders. Actilon appears to stimulate TLR9 in a

different way from CPG 7909 resulting in significantly stronger

activation of interferon-α production by the plasmacytoid dendritic

cells.

Actilon operates through a dual method of action consisting of both

innate and adaptive immunity antiviral mechanisms. Actilon was

designed to induce not only the early short-term innate immune

effects that temporarily control the virus, but also to trigger

adaptive immunity, with a strong killer T cell response, that we

believe may provide sustained anti-infective effects. We believe

Actilon therapy may allow the duration of HCV therapy to be reduced

significantly, thereby resulting in reduced toxicity and improved

patient compliance.

Based on results observed in our early clinical trials, we believe

that Actilon - like interferon α and ribavirin treatment -- will

trigger an innate immune response to HCV resulting in an early

virologic response in many people. In contrast to conventional

interferon-α therapy, we believe that Actilon may cause faster and

more effective dendritic cell maturation in the patients, followed by

more rapid enhancement of the adaptive immune response that is

thought to be required for controlling difficult-to-treat chronic

viral diseases, such as HCV and HIV. Thus, in HCV, we expect that

Actilon therapy may lead to more rapid and more frequent development

of a sustained viral response, even in the difficult to treat and

most common genotype 1 patients. We believe that Actilon will be

capable of inducing and amplifying potent and natural antiviral

mechanisms at relatively well-tolerated doses.

In addition, based on the preclinical tests we have conducted in

infection models, we believe that synthetic TLR9 agonists such as

Actilon may have broad utility in the treatment and prevention of

many types of infections because of their ability to activate both

the short-term innate and sustained adaptive responses of the immune

system. Coley believes that the ability of Actilon to at least

partially reverse dendritic cell dysfunction and enhance the Th1

response could lead to improved clinical outcomes not only in chronic

HCV, but also other chronic infections such as Human Immunodeficiency

Virus (HIV), Hepatitis B and herpes.

TLR Therapeutics

The human immune system has ten Toll-like receptors (TLRs), which

enable immune cells to sense threats from both intracellular

pathogens (such as viruses and retroviruses) and extracellular

pathogens (including most bacteria and fungi) that can cause human

disease. To fight off intracellular pathogens, which act by spreading

infection inside a cell in the body, TLRs help the immune system to

mount a type of response that is called a Th1 response. In order to

fight off extracellular pathogens, TLRs help the immune system to

mount a type of response that is called a Th2 response. Coley's TLR

Therapeutics are synthetic nucleic acids that function as stimulators

(agonists) or blockers (antagonists), of one or more TLRs that are

found in immune cells. To date, we have focused our development

efforts primarily on compounds targeting one specific TLR, known as

Toll-like receptor 9 (TLR9), for the treatment of cancers, infectious

diseases and asthma and allergy.

Tapping into TLR9

TLR9 is found in certain human immune cells, known as plasmacytoid

dendritic cells and B cells. TLR9 functions to detect a pattern that

is present in the DNA of invading intracellular pathogens, but is not

present in the body's own DNA. When TLR9 detects this pattern, which

is called a CpG motif, it triggers a Th1 response. Our TLR9 agonists

are synthetic oligodeoxynucleotides, comprising short, DNA-like

sequences, which mimic the CpG motifs found in some intracellular

pathogens, thereby triggering the body's immune response.

When TLR9 is stimulated by our TLR Therapeutics, we believe it

triggers both the innate, or short-term, immune response, and

adaptive, or sustained, immune response. This ability to induce a

highly specific, dual activation of the body's innate and adaptive

immune systems differentiates us from many other immune therapy

approaches, which are generally unable to create a sustained effect

on the adaptive immune system and non-specifically activate the

innate immune system, leading to undesirable side effects.

When administered, Coley's TLR9 agonists initiate a cascade of

cellular signals to direct a highly specific and targeted immune

response. TLR9 agonists initiate both an innate and an adaptive

immune response (see illustration), generating cytotoxic T cells

(CTLs) and disease-specific (pathogen or tumor) antibodies. In

addition, through activation of the dendritic cells, TLR9 agonists

fight against the development of immune tolerance to pathogens and

cancers.

Next-generation TLR Therapeutics

Our research spans the development of drug candidates that agonize or

antagonize TLRs. Our scientists have produced several different

classes of TLR9 agonists by combining CpG motifs in different

structures that stimulate TLR9 in different ways, leading to distinct

immune effects. By slightly altering the structure of our molecules,

we have designed them to have different stabilities in the body,

which allows us a certain amount of control over where the molecules

go, and how long they last. We believe that our understanding of the

biology of TLR9 agonists makes it possible for us to design different

molecules for treating different diseases.

Recent discoveries made by our scientists and some of our

collaborators have revealed that certain RNA molecules are agonists

for TLR7 and TLR8, which are related to TLR9. RNA differs from DNA

only by the presence or absence of an oxygen atom in the sugar of the

nucleic acid. Therefore, much of our knowledge and experience in

working to stimulate TLR9 may be applied to our development of new

RNA drugs to stimulate TLR7 or TLR8. TLR7 activation seems to trigger

many of the same effects as are seen with our TLR9 agonists, but TLR8

activation causes a very different pattern of immune activation. We

believe that RNA molecules designed to stimulate TLR7 or TLR8 could

become useful drugs for treating infectious diseases, and we intend

to conduct further research in this area.

Directing the Immune System

The immune system can be thought of as both an innate immune system

and adaptive immune system working together to protect the body

against bacteria, viruses and other disease-causing agents, and also

to detect, control and fight abnormal cells, such as cancer cells.

The innate immune system recognizes generic classes of molecules

produced by a variety of foreign invaders, or pathogens. The function

of the innate immune system is to rapidly contain an infection and to

limit its spread, until a more specific adaptive immune response can

be made that will eliminate the pathogen.

The adaptive immune system recognizes specific antigens, which are

unique to individual classes of pathogens. The adaptive immune

response is a highly specific, long-lasting response to a particular

pathogen or an antigen associated with a pathogen. The response

includes both fighting the existing pathogen and generating the

ability to recognize and respond more rapidly to a subsequent

encounter with the same pathogen. Adaptive immune responses are

induced by initial recognition of an antigen in the presence of

appropriate signals from the innate immune system. It is thought that

unless the innate immune system has been activated, little or no

adaptive immune response will be triggered. Once initiated, adaptive

immune responses are boosted or retriggered simply by being exposed

to the antigen again.

Dendritic cells are an important link between the innate and adaptive

immune systems. Dendritic cells patrol blood and tissues to sample

cellular debris in order to identify and classify immediate threats.

They recognize pathogens, such as viruses, bacteria, and parasites,

through specialized receptors for pathogen-associated molecular

patterns. When these patterns are recognized by innate immune cells,

they immediately signal other immune cells to attack and contain the

problem until a longer-term and more specific adaptive response can

be generated.

The appropriate type of immune response to reject intracellular

pathogens is known as a Th1 response, in contrast to the Th2 type of

response that is used to fight off extracellular pathogens. Th1

responses are characterized by the generation of killer T cells and

certain antibodies, and are very important in fighting intracellular

pathogens, and intracellular defects such as cancers. By contrast,

Th2 responses are characterized by the generation of other specific

types of antibodies, and are typical of allergic reactions, in which

an allergen is mistaken for a pathogen on a mucosal surface and

triggers an immune response which can result in symptoms such as

watery eyes, airway inflammation and contraction of airway muscle

cells in the lungs. Although Th2 responses are important for defense

against many types of pathogens that are located outside cells, they

are not particularly helpful for fighting pathogens that have invaded

cells.

Consequences of Inappropriate Immune Response

An appropriate immune response is required for the body to defend

against pathogens and abnormal cells. The immune system, however, may

fail to function properly by producing insufficient or inappropriate

responses. This can be due to a failure to recognize a particular

threat, or an impaired ability to mount an appropriate response due

to inherent immune system defects or suppression of the immune system

due to disease, such as the infection of immune cells which occurs

with the hepatitis C virus. For example:

* If the immune system responds insufficiently to a pathogen,

chronic infection can result. Many viruses that establish chronic

infection do so by also infecting dendritic cells and other immune

cells and rendering them dysfunctional, thereby preventing the

appropriate immune rejection of the infection.

* Failure of the immune system to recognize cancer cells as

abnormal may result in tumor growth and the spread of tumor cells to

other locations in the body, known as metastasis. Often tumor cells

have mechanisms to avoid appropriate immune responses or fool the

immune system by secreting immunosuppressive molecules.

* An inappropriate immune response, such as over activation of

the Th2 response to an allergen, can result in chronic inflammatory

diseases such as asthma and allergies.

Past efforts to develop immune activators to stimulate appropriate

immune responses have been hampered by a very limited understanding

of the regulation of the immune system, and by the use of relatively

nonspecific immune activators, which stimulated many types of immune

cells. This can result in toxicity from the immune activation, with

limited efficacy if the activation is not directed appropriately.

Creating a New Class of Medicines with High Specificity

We design our TLR Therapeutic product candidates based on our

understanding of their molecular mechanism of action and the human

immune system's response to the various alterations in the sequence

of a TLR Therapeutic. We develop TLR Therapeutic product candidates

that induce particular immune system effects by altering the sequence

of the motif, the number and relative positions of TLR Therapeutics

motifs, and the chemical linkages in the product candidate's

oligonucleotide structure. These alterations enable us to create TLR

Therapeutic product candidates with different characteristics that

may make them more useful to prevent or treat specific diseases. This

includes enhancing killer T cell responses for treating cancer,

maximizing IFN-α production for fighting hepatitis C infection, or

reducing Th2 type immune responses in treating asthma and allergy.