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New Toll-like Receptor Drug Actilon for HCV Therapy
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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(TM) 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-a 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 a 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-a 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-a production for fighting hepatitis C infection, or reducing Th2 type immune responses in treating asthma and allergy.
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