Treatment of Surgical Sepsis with AM/AMBP-1

DESCRIPTION (provided by applicant): This SBIR Phase II proposal is a plan to further develop a new therapeutic approach that will save the lives of patients with sepsis (especially surgical sepsis), a condition that affects 750,000 people every year in the United States alone and also causes high mortality worldwide. Although activated protein C [APC, Drotrecogin alpha (activated), Xigris. marketed by Eli Lilly] is the only FDA- approved specific treatment for sepsis, it cannot be used in surgical patients with sepsis due to its adverse effects on coagulation. Thus, there is an even greater need for an effective novel treatment for surgical sepsis. Successful development of a new anti-sepsis therapy will not only have a positive impact on health care, but it will also have highly significant commercial benefits. The global market potential for sepsis treatment is estimated at over $30 billion annually. We have recently discovered that vascular responsiveness to adrenomedullin (AM), a newly-reported potent vasoactive peptide, decreases during sepsis in the rat and is markedly improved by its novel binding protein (i.e., AMBP-1). Treatment with rat AM combined with human AMBP-1 improved cardiovascular function, attenuated tissue injury and inflammatory responses, and reduced mortality in a rat cecal ligation and puncture (CLP, induced by surgery) model of sepsis, suggesting that AM/AMBP-1 may be an effective treatment for human sepsis. One obstacle hampering the development of AM/AMBP-1 as a therapeutic agent for sepsis is the potential immunogenicity of rat proteins in humans. In this regard, the primary objective of our Phase I proposal was to determine the effect of human AM/AMBP-1 on sepsis-induced organ injury, inflammation, and mortality. We have achieved these milestones using the rat CLP model of sepsis. In the Phase I project, we have clearly demonstrated the efficacy of human AM/AMBP-1 and thereby established the technical merit and feasibility of the proposed Phase II project. However, the extremely high cost of commercial human AMBP- 1 limits the further development of human AM/AMBP-1 as an anti-sepsis therapy. To overcome this difficulty, we have successfully isolated and purified AMBP-1 from normal human serum at a much lower cost. We therefore continue to hypothesize that the administration of human AM/AMBP-1 late after the onset of sepsis attenuates tissue injury and improves survival. In this Phase II proposal, we will first, scale up the production of human AMBP-1 and, then, perform additional efficacy studies in order to determine the optimal protective dosage of human AM/AMBP-1 in sepsis in the rat. Moreover, the pharmacokinetic characterization of human AM/AMBP-1 in sepsis will be assessed. To advance our technology to the clinical trials, the efficacy of human AM/AMBP-1 will be investigated in a swine model of sepsis. These proposed studies should provide sufficient preclinical data that will allow us to file an IND application to the FDA to initiate clinical trials in order to obtain the commercial utilization of human AM/AMBP-1 as a safe and effective therapy for patients with sepsis, especially those who develop sepsis after trauma or major surgery. PUBLIC HEALTH RELEVANCE Sepsis is one of the leading causes of death in most intensive care units. Over 210,000 people succumb to this overwhelming infection in the United States annually. A recent epidemiologic study estimated that about 750,000 people develop sepsis each year at a cost of $16.7 billion nationally. Given the intensive and prolonged care necessary to treat patients with sepsis, the economic burden is profound. Thus, there is an urgent unmet medical need for an effective novel therapy for septic patients.