Between 10% and 20% of the United State population suffer from seasonal influenza each year. While most individuals recover from influenza in one to two weeks, the very young, the elderly and persons with chronic medical conditions can develop post-flu pneumonia and other lethal complications. The causative agent of influenza is influenza virus, a myxovirus that readily develops new strains through a process of reassortment and mutation of the segmented viral genome. Highly virulent strains of type A influenza virus can produce epidemics and pandemics. In recent years there has been emergence of a highly pathogenic strain of avian influenza A virus subtype H5N1. First detected in Thailand, Vietnam and other countries in Southeast Asia, this strain of """"""""bird flu"""""""" has now spread too many parts of the world. Some variants are capable of directly infecting humans and other mammals, inflicting a high mortality rate. Human-to human spread of current highly-pathogenic bird flu strains does occur, but not yet at the efficiency necessary to trigger a pandemic in which millions or even tens of millions of people could die. In preliminary studies, we identified a remarkably effective peptide entry inhibitor that blocks infection by different strains of influenza A virus of the H1, H3 and H5 subtypes as well as influenza B viruses (IC50 in the nanomolar to picomolar range depending on assay conditions). This 16mer peptide, Flufirvitide-3, potently inhibited signs of influenza in ferrets, generally considered the best animal model for influenza. Peak titers of influenza virus in ferret nasal washes were reduced by over two logs and in the lungs by over six logs. The scope of work for this Phase I/Phase II Fast Track application includes preclinical IND-enabling activities that can potentially lead to human clinical trials and Emergency Use Authorization (EUA).
In Specific Aim 1 (Phase I) optimal manufacturing, formulation, and delivery methods for Flufirvitide-3 will be developed and sufficient product for pharmacokinetic, bioavailability, toxicology and animal studies will be provided.
In Specific Aim 2 challenge studies in ferrets using seasonal strains of influenza A and B viruses and highly pathogenic influenza a viruses will be performed to define the optimal formulation and delivery mechanism for Flufirvitide- 3.
In Specific Aim 3 non-clinical pharmacokinetic and bioavailability analyses of Flufirvitide-3 will be performed and in Specific Aim 4 evaluation of the non-clinical safety profile of Flufirvitide-3 and related platform therapeutics will be initiated.
Because of the threat posed by influenza virus both to public health and as a potential agent of bioterrorism, developing therapeutics to control seasonal influenza and the increasing threat of pandemic influenza is one of this nation's highest priorities. Flufirvitide-3 is a potent inhibitor of infections by influenza virus in vitro and in the ferret model of influenza. We will develop a formulation and delivery regimen of Flufirvitide-3 that has broad-spectrum activity, high bioavailability in the respiratory tract, a simple dosing regimen, and safety in diverse populations for the prophylaxis and early treatment of seasonal and pandemic influenza.
|Chandra, Partha K; Hazari, Sidhartha; Poat, Bret et al. (2010) Intracytoplasmic stable expression of IgG1 antibody targeting NS3 helicase inhibits replication of highly efficient hepatitis C Virus 2a clone. Virol J 7:118|