Testing of a New Protein Drug for Toxin-Induced Sepsis

DESCRIPTION (provided by applicant): Sepsis or septic shock is a complex cascade of adverse host systemic inflammatory responses induced by infection. Severe sepsis is the most common type found in the intensive care unit (ICU) and it is a common, frequently fatal and expensive disease. In fact, severe sepsis is the number one cause of death in the non-coronary intensive care unit and the 11th leading cause of death overall in the US. Recent studies report that there are at least 750,000 new cases of severe sepsis annually in the United States with more than 2,000 new cases per day. Progression of sepsis can lead to organ dysfunction and ultimately death. Mortality from severe sepsis ranges from 30% to 50% or greater. We have developed VGX-300 (recombinant Vpr protein), as a potential novel therapy for Sepsis. We believe VGX- 300 has important therapeutic qualities relevant to the pathogenesis of severe sepsis. Our company has a diverse and proprietary patent position on the use of recombinant Vpr protein to treat sepsis and other inflammatory diseases. Successful completion of these Phase I studies will result in the demonstration of feasibility for using VGX-300 as a novel drug to treat sepsis. We will test our hypothesis through a collection of three specific aims using Staph Enterotoxin B (SEB) and Lipopolysaccharides (LPS) as model toxins from Gram-positive and Gram-negative bacteria, respectively. We will also test VGX-300's therapeutic effects against a polymicrobial challenge model. The three specific aims are: Aim I: Establish manufacturing process and potency assay for VGX-300 (recombinant Vpr protein), a potential novel therapy for Sepsis. Aim 2: Test the protective effects of VGX-300 in lethal toxin challenge models in mice. SEB and LPS will be used as model toxins for Gram-positive and -negative toxins, respectively. Aim 3: Test the protective effects of VGX-300 in mice against polybacterial sepsis challenge using the cecal ligation and puncture (CLP) model. This project will test the hypothesis that VGX-300 will be effective at preventing morbidity and mortality from toxin induced cytokine storm and sepsis in a murine model system. This proof of concept funding in this Phase I proposal will enable further testing of our company's drug candidate for sepsis in the Phase II funding of SBIR. With successful characterization of the protective effects of VGX-300 in Phase I of this SBIR, we will focus on bringing this product to clinical evaluation as expediently as possible. This would involve a scaling up of recombinant Vpr protein manufacturing process under both GLP and GMP conditions. In anticipation of carrying the Vpr protein into clinical evaluation, pre-clinical toxicity and pharmacokinetics studies in both mice and in macaques will also be performed as a part of Phase II studies. Lastly, we will be able to file an Investigative New Drug (IND) application for VGX-300 with the FDA at the conclusion of our Phase II studies.