Influenza virus infection is one of the most common infectious diseases, typically causing mild to severe illness, which can sometimes lead to death. Influenza epidemics occur yearly during autumn and winter, resulting in about three to five million cases of severe illness, and about 250,000 to 500,000 deaths worldwide. Although the usual strains of influenza that circulate in the annual influenza cycle constitute a substantial public health concern, far more lethal influenza strains have emerged periodically leading to pandemics that kill millions of people. Of the different types of influenza virus, influenza A viruses can replicate and mutate very rapidly, typically involving more serious infections including recent pandemics: H1N1 caused the most deadly global pandemic Spanish flu in 1918, as well as the 2009 swine flu outbreak, H2N2 caused Asian flu in the late 1950s, and H3N2 caused the Hong Kong flu in the late 1960s.
At the general population level, the most effective way to prevent influenza or severe outcomes from the disease is vaccination. However, although safe and effective vaccines have been available and used for more than 60 years, influenza viruses are constantly changing, and the annual vaccine is developed based on an estimation of the three most prominent strains each season. An effective therapy that neutralizes all influenza A strains, offers potential for both prevention and treatment of seasonal influenza disease. Furthermore, during a pandemic with a new influenza strain, timely production and implementation of an effective vaccine that targets the pandemic strain is not feasible. However, a universally effective therapy could be immediately available and would be utilized for prevention in containment strategies as well as treatment for those at highest risk.
Our lead product, VIS410, is a monoclonal antibody designed to neutralize all influenza strains. Mechanistic studies indicate that VIS410 inhibits fusion of the influenza hemagglutinin (HA) protein with the cell membrane, thereby intervening in an early step in the influenza infection cycle by inhibiting the entry of the virus into the host cell. Utilizing our proprietary platform to identify novel targets and design drugs against these targets, we have identified a unique conformational epitope, or drug target site, on the stem region of the influenza hemagglutinin protein. This epitope has been mapped by peptide scanning and is not only conserved across all influenza subtypes, but is also resistant to virus mutation. Using our protein engineering approach, we designed >50 human antibodies that bind to and neutralize viruses from both Group 1 (i.e., H1, H5, H9) and Group 2 (i.e., H3, H7) influenza strains. VIS410 is our lead product candidate that we are progressing into clinical trials.
By targeting this unique, highly conserved epitope, VIS410 offers the potential for truly broad spectrum coverage, neutralizing all key potential seasonal and pandemic influenza A strains, including H1N1, H3N2 and H5N1 (or Avian Flu). Given the unique features of the epitope targeted with VIS410, we believe that the influenza virus may be less able to mutate and develop resistance to VIS410 therapy. By addressing both broad spectrum coverage and resistance development – the two key areas of clinical need – VIS410 has the potential to be a 'best-in-class' therapeutic for the treatment and prevention of both seasonal and pandemic influenza.
The key product characteristics of VIS410 are as follows:
We reported nonclinical data on September 10, 2012 in an oral presentation titled “Design of a Broadly Neutralizing Human Monoclonal Antibody to Influenza” at the ICAAC meeting in San Francisco, CA.
VIS410 targets the identified conserved region with picomolar binding affinity and demonstrates good physiochemical attributes, including solubility, stability and specificity. In vitro, VIS410 demonstrates dose-dependent viral inhibition with an EC50 in the range of 0.3–7 ug/ml against all Group 1 and Group 2 influenza strains tested. In mouse models, VIS410 provides 100% protection from lethal challenge of H1N1, H3N2, and H5N1 (Avian Flu). Furthermore, when the monoclonal antibody is administered up to 72 hours after infection, it is completely effective in treating the infection with 100% survival for H1N1, H3N2, and H5N1 virus subtypes.
Finally, the unique epitope that VIS410 targets also holds promise for the development of a universal vaccine. A universal vaccine or therapeutic that targets a common element in all strains of influenza would have significant worldwide impact on addressing both seasonal and pandemic influenza.