1. Fundamentals New Anthrax Countermeasure* Vi Pham**, Zachary Taylor** and Miguel Bagajewicz University of Oklahoma - Chemical Engineering (*) This work was done as part of the capstone Chemical Engineering class at the University of Oklahoma (**) Capstone undergraduate students - Comparison of Anthrax Survival With and Without Key Agent Macrophages Engulf Bacteria Nuetrophils Secrete Enzymes to Kill Bacteria Macrophages A. Macrophages with anthrax not treated with key agent have not engulfed any bacteria. B. Macrophages with anthrax treated with one of key agents have engulfed many bacterial cells. Neutrophils A. Neutrophils with anthrax treated with key agent have killed all of the anthrax. B. Neutrophils with anthrax not treated with one of our key agents have not killed all of the anthrax. - We would like to thank Prof. David Schmidtke and Yahya Lazrak. Acknowledgements Discovery Preclinical Development: -safety -pharmacokinetics -proof of concept efficacy Preclinical Development: Animal trials -safety -efficacy Clinical Trials -safety -pharmacokinetics Production & Stockpiling Human Efficacy Trials in the event of product use FDA Approval Process for Countermeasure Drugs Pricing Models Model 1 Model 2 H1 = our benefits H2 = competitors benefits = constant based on consumer preference P2 = competitors drug price P* = price to make us equal to our competitor in terms of benefits and cost Models valid for: 0.75 < H2/H1 < 2.05 Abstract In this work, we investigated the production of a novel new anthrax treatment with minimal side effects and virtually no possibility of bacterial resistance. The probability of successful laboratory development is analyzed in detail. Next, a thorough evaluation of the FDA process for drug approval is described to assess failure risk. Finally, an in depth economic analysis is performed on the entire drug production process – from laboratory work to final product. Approval of this drug is expected to take seven years and cost approximately $12M. We performed 500 profitability trials for the development of a modified agent to treat anthrax. The program considered the following parameters: the probability of success for each pre-clinical experiment and FDA approval phase, the cost of each experiment and phase, the manufacturing cost based on the number of doses needed and the concentration required for each dose, and the pricing model developed for the final product. Our key agent is effective as an anthrax prophylactic. Our key agent is effective as an anthrax prophylactic. Our key agent can be cheaply produced in large quantities. Our key agent can be cheaply produced in large quantities. The probability of successfully developing our key agent as a pharmaceutical is approximately 30% with a predicted profit of approximately $600M. The probability of successfully developing our key agent as a pharmaceutical is approximately 30% with a predicted profit of approximately $600M. The predicted average loss for unsuccessfully developing the key agent as a pharmaceutical is approximately $2.4M with a maximum loss of $12M. The predicted average loss for unsuccessfully developing the key agent as a pharmaceutical is approximately $2.4M with a maximum loss of $12M. Survival of anthrax bacteria after treatment with key agent and incubation with human neutrophils for two hours. This kinetic data was used to determine dosing concentrations. This graph shows the effect of varying pharmacokinetics on serum concentration for a drug administered three times over 60 days. Process flow diagram (PFD). (Gray boxes cover sensitive material) Process Flow Diagram (modified agent 1) A. A flow diagram of the initial experiments required for pre-clinical research. The projected time and costs are given for each stage. (Gray boxes cover sensitive material) B. A flow diagram of the in vitro and in vivo experiments required for pre- clinical research for each successful modified key agent from the previous stage. The most successful modified key agent will proceed to the FDA approval process. The projected time and costs are given for each stage. C. A flow diagram of the stages required for the FDA approval process. It is assumed that Priority Review was obtained. The projected time and costs are given for each stage. *The projected time and cost are based on detailed experimental protocols not shown here. A. B. C. Preclinical Research and FDA Approval Process Flow Diagram Anti-Infective Mechanism Anthrax is one of the most significant bioterrorism threats to the United States today. Left untreated, inhalational anthrax, the form most likely to be employed in a bioterrorism event, would claim at least 75% of those infected. Although treatments and a vaccine against anthrax do exist, these also produce adverse side effects and are susceptible to bacterial resistance.. Inhalation of anthrax spores into the lungs. Spores are engulfed by macrophage cells. Macrophage cells with the engulfed anthrax spores travel to the lymph nodes for further instruction on how to proceed with the invader. The anthrax spores, however, are undetected by the immune system. Spores are able to change into toxic bacteria cells and proliferate within the macrophage cells. Anthrax bacteria cleave the macrophage cells and attack neighboring cells, eventually resulting in organ failure and death. Anthrax bacteria cleave the macrophage cells, but the drug eliminates the proliferated bacteria before they can attack neighboring cells. Key Agent Research & ProductionPre-Clinical & FDA Modeling Marketing Strategy Types of Infection Project BioShield $5.6 billion for improved vaccines and drugs against CBRN agents. Dept. of Health & Human Services RFP seeking 10,000-200,000 treatments for inhalational anthrax disease. Intended Market Stockpile, Military Major Incentives Key agent is newer and more effective. Cheap to produce. Project BioShield Contract Must be licensable Must be able to mass produce Delivery within 8 years Lobbying $1.8 Million Fast Track (Priority Review) $1 Million Pricing & Profitability Conclusions