Inovio Pharmaceuticals, Inc. and its development partner VGX International, Inc. will initiate phase I/IIa clinical trial of its hepatitis C (HCV) DNA vaccine by the end of 2013. This advancement is based on outstanding results of a preclinical study which demonstrated for the first time that a multi-antigen SynCon HCV vaccine can generate robust T-cell responses not only in the blood but, more importantly, in the liver, an organ known to suppress T-cell activity.

VGX International is funding all preclinical and clinical development.

In preparation for entering clinical trials with its HCV vaccine (INO-8000), Inovio has completed manufacturing of its multi-antigen HCV vaccine and is performing IND (Investigational New Drug application)-enabling toxicity testing in animals. INO-8000 is a SynCon HCV therapeutic vaccine targeting NS3/4A, NS4B, and NS5A proteins of HCV. INO-8000 was designed with Inovio's SynCon process to broadly cover HCV genotypes 1a and 1b, the types that have been most difficult to treat with drug therapies.

It is estimated that more than five million people in the United States are infected with hepatitis C, and perhaps as many as 200 million around the world. This makes HCV one of the greatest public health threats of this century.

HCV vaccine research to date has mostly focused on one area of the virus (the NS3/4A proteins) to induce T-cell responses; however, there has been little research aimed at elucidating whether vaccines targeting proteins other than NS3/4A can induce potent T-cell responses within the liver. In this study, Inovio and its collaborators developed SynCon antigen constructs that targeted three other areas of the HCV virus (NS4B, NS5A and NS5B) and then demonstrated that each vaccine construct expressed its respective protein and that all three constructs induced potent HCV-specific T-cells in mice.

Prior research has also identified that a successful HCV vaccine must be able to induce not only strong HCV-specific T-cell responses that target several components of the virus but that these cells must migrate to the liver and remain activated. In this study, Inovio researchers observed in the liver not only NS4B-, NS5A- and NS5B-specific CD4+ and CD8+ (or killer T-cell) responses, but also a large pool of vaccine-specific T-cells. This pool of vaccine-specific T-cells was shown to be fully functional in an environment in which T-cell activity is usually suppressed. In fact, using a transient HCV infection model in mice, therapeutic immunization with INO-8000 was able to clear HCV antigens from the liver, demonstrating the therapeutic potential of this vaccine.

In addition to moving forward with INO-8000, Inovio has a long-standing partnership with ChronTech Pharma, which is developing its NS3/4A-based HCV DNA vaccine using Inovio's proprietary delivery technology. Interim results of ChronTech's open-label, randomized phase II trial are expected later in the first quarter of this year.

Dr J Joseph Kim, Inovio's president and CEO, said, "Inovio is a leader in developing therapeutic vaccines for HCV and HBV. The major hurdle to developing therapeutic vaccines for these ailments has been the inability to generate a functional T-cell response in the liver. The fact that our preclinical model demonstrated functional T-cells in the liver in this published study suggests that INO-8000 has the capacity to clear that hurdle. There have been important recent drug therapy advances for HCV; however, a safe and effective therapeutic vaccine could play a vital role in enhancing the potency of HCV treatments, especially for genotype 1, while achieving the desired goal of eliminating the use of interferon/ribavirin and their undesirable side effects."

Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). The infection is often asymptomatic, but chronic infection can lead to liver failure or liver cancer. Approximately 80 per cent of people who become infected with hepatitis C virus develop chronic infection.

The major obstacle to HCV vaccine development has been the extensive genetic variation between different strains and genotypes, and even the significant antigenic variation among virus within individual patients. In addition, the absence of a clearly defined protective immune response after natural infection has historically complicated the prospects of developing a vaccine against HCV infection.

However, unlike traditional vaccines constrained by the paradigm of matching a preventive or therapeutic vaccine to a single pathogen strain or strains, Inovio's SynCon vaccines are based on genetic code for a specific antigen from multiple strains of the target pathogen. Thus, while the SynCon antigens may not be perfectly (100 per cent) matched to the pathogenic strains, they are designed to protect against multiple existing strains as well as changing strains of a virus. Extensive preclinical data has validated their ability to protect against many strains of a disease; initial human data for our influenza vaccine has also provided evidence of this capability.

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