Hepatitis C (HCV) infects more than 170 million people worldwide and is the major cause of chronic liver disease, liver cirrhosis and primary liver cancer. HCV is also the most common cause for liver transplantation in the United States. The Hepatitis C virus is comprised of multiple genotypes, and significant heterogeneity exists even within genotype subgroups. Therefore, drug resistance is a major issue, and combinatorial drug therapy is required for sustained efficacy. The statistics of current treatment of HCV are sobering. The current standard of care is combination therapy with pegylated interferon and the nucleoside analogue ribavirin. The treatment has significant side effects, including depression and severe flu-like symptoms from interferon and hemolytic anemia from ribavirin. It is estimated that less than 10% of patients in a general clinical population can tolerate standard of care treatment to achieve a cure. To remedy this situation, both major pharma and biotech companies have mounted programs to develop better treatments. Current anti-HCV drugs in development almost exclusively target the viral enzymes - protease and polymerase - involved in viral replication. There are no new approved products from these programs yet and many of these have encountered safety issues in clinical trials. In addition, because HCV can mutate rapidly and become resistant to antiviral drug treatment, additional mechanisms involved in viral infection must be targeted for drug development to provide multiple agents which put pressure on the virus to bring it in check. Therefore, there is an urgent need for new classes of anti-HCV drugs.

At iTherX we have responded to this need by taking multiple mechanistic paths to pioneer a new class of HCV antivirals: entry inhibitors. The therapeutic rationale for entry inhibition is to block the earliest steps of infection of host liver cells by HCV: fusion with and entry into the host cell. This approach will be crucial to solving some of the fundamental problems of involved with achieving the goal of a cure for hepatitis C: cutting off the ability of the virus to reproduce itself and not allowing virus to escape by mutating to become drug resistant. Thus pressure can be put on the virus by inhibiting the enzymes required for copying itself - the emerging classes of HCV polymerase and protease inhibitors - and amplifying the pressure by blocking the ability of the virus to infect new host cells. This combination approach will also decrease the ability of the virus to escape eradication by reducing the ability to mutate to forms which can evade a drug. We are broadening the potential for entry inhibitor efficacy by targeting more than one mechanism involved in viral fusion and entry as a basis for independent subclasses of entry inhibitors.

In practical terms combination therapy for HCV is emerging, just as happened for HIV, where "drug cocktails" have resulted in a dramatic change in outcome for infected patients, converting HIV from a fatal to a chronic disease. Because of the differences between HIV and HCV, successful combination therapy of HCV can achieve an even better outcome than for HIV: a cure, defined as the sustained inability to detect HCV in the blood.

Given the above scenario, it can be anticipated that an entry inhibitor will be used with all of the drugs which target viral replicative enzymes. This wide use of entry inhibitors will drive the ability to establish very large franchises for commercialization. The worldwide dollar market for HCV antivirals has been projected to reach $ 12 - 14 B by 2010.

Host Cell Receptor Target Program

This is a program to develop orally bioavailable small molecule inhibitors which interact with SR-B1, the host hepatocyte cell membrane protein involved in the docking and entry of the virus. Using our knowhow in molecular virology, we have developed screening assays for HCV entry inhibitors and our chemists have generated libraries of small molecules for screening in these assays. This process generated lead compounds which were perfected for potency and selectivity and finally proprietary new chemical entities with good drug - like properties - oral bioavailability, metabolic stability and pharmacokinetics for convenient dosing. We are beginning preclinical safety studies with our lead candidate ITX4520 and project an IND filing and Phase 1 clinical studies in 2009.

In addition, we look for clinical stage compounds available for licensing, which can be re-purposed for HCV entry inhibition. This effort has led to our recent acquisition of ITX-5061, which has a good safety profile in animal toxicology studies and in clinical studies involving over 250 subjects. This compound exhibits picomolar potency in inhibiting both genotype 1 and genotype 2 HCV. We will begin a Phase 2a study of ITX-5061 in hepatitis C patients in Q1 2009.

Viral Envelope Target Program

This is a program to develop small molecule inhibitors of viral entry, which act by selectively binding to the viral envelope protein E2 and inhibiting its ability to bind to and infect liver cells. Thus in this approach we are attempting to block infection via a direct interaction with the viral particle. We have discovered a naturally occurring molecule that binds to the viral protein and are systematically making derivatives of it to impart drug - like properties. These semi-synthetic molecules are proprietary new chemical entities. Currently we are at the lead generation stage in this program.

Novel Host Cell Receptor Program

Our molecular virology team adopted the goal of attempting to discover a novel liver cell membrane protein required for infection by the hepatitis C virus. This was undertaken because current scientific understanding of HCV infection suggested that not all of the proteins involved had been identified. Using state of the art molecular biological and virological approaches, we have identifies a cell membrane protein gene which is required for infection by the virus and which, when introduced into non-host tissues, can impart infectivity. This is a powerful basis for validating this protein as a target for discovery of agents that prevent docking and internalization of the virus by host cells. We have recently shown that antibodies to the novel receptor inhibit virus infection, suggesting the feasibility of developing an antibody therapeutic against this receptor. In addition, we are developing a screening assay for small molecule drugs that inhibit the binding of the virus envelope protein to this receptor.

The Clinical Use of Entry Inhibitors in Treating HCV

Current standard therapy (a combination of modified interferon-alpha and ribavirin) provides a sustained viral response in only ca 10-50% of patients, and has considerable side effects, resulting in a high dropout rate. To obtain drugs with higher efficacy and fewer side effects, many companies are targeting the virus replication cycle, predominantly the viral polymerase and protease. Because HCV is an RNA virus with a high degree of intra- and inter-genotype heterogeneity, it is expected that a combination therapy is needed to overcome viral resistance. In infected patients only a fraction of the hepatocytes is infected and continuous recruitment of new infected cells is necessary for disease progression. We have focused our efforts on a novel class of HCV inhibitors that prevent entry of HCV into the host cell. Our diverse pipeline products utilize distinct mechanisms and can synergize with each other. This class of compounds can add significantly to a drug cocktail targeting multiple steps of the viral life cycle, with the goal of completely eliminating virus infection.