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Development of Mycotoxin Medical Countermeasures


Mycotoxins are toxins produced by several species of fungi. Exposure to these toxins can result in incapacitation or even death of the exposed subject. From a biological warfare perspective, mycotoxins are relatively easy to produce in large quantities and many of them have nearly effortless accessibility. For these reasons, mycotoxins present a real threat to the warfighter. Trichothecene (T-2), a type of mycotoxin, can be delivered via food or water sources, droplets, aerosols, or smoke from various dispersal systems and exploding munitions. T-2 toxin has allegedly been used as a biological weapon in the past. For example, due to its high thermal stability, T-2 toxin has been baked into bread, yet maintains activity. T-2 toxin is also extremely resistant to ultraviolet light inactivation. As with virtually all toxins, T-2 toxin is far more toxic when inhaled rather than through oral, dermal, or injection exposure. Aflatoxin is a fungal toxin that commonly contaminates maize and other types of crops during production, harvest, storage or processing. Exposure to aflatoxin is known to cause both chronic and acute hepatocellular injury. In Kenya, acute aflatoxin poisoning results in liver failure and death in up to 40% of cases. Similar to the case for T-2 toxin, aflatoxins have high thermal and ultraviolet radiation resistance to inactivation, making them prime candidates for weapons of mass destruction (WMD) or weapons of mass casualties (WMC). The development of mycotoxin medical countermeasures, specifically against aflatoxins and T-2 toxin, addresses current technology requirements as defined by the Joint Requirements Office for Chemical and Biological Defense (JRO-CBD) and the Joint Program Executive Office for Chemical and Biological Defense (JPEO-CBD). Currently there are no FDA approved medical countermeasures available for either aflatoxin or T-2 mycotoxin exposure. These toxins are debilitating and sometimes lethal on their own. Reports in the open literature suggest that concurrent exposure of mycotoxins in combination with other toxins (or pathogens), results in the increased susceptibility to toxin induced organ damage/failure and to increased mortality than what is observed when either toxin is given alone. PHASE I: Offerors must propose proof of concept experiments to demonstrate neutralization or attenuation of mycotoxins (of particular interest is aflatoxin or T-2 toxin in a lethal in vitro model). Demonstration of efficacy in some form of an in vivo model is also acceptable, but not required for Phase I. Technologies of interest include, but are not limited to, antibodies (human antibodies are strongly preferred), small molecules, aptamers, and other novel approaches. Repurposing of FDA approved drugs or drugs with successful completion of FDA Phase I clinical trials are also to be considered. Exit criteria for successful completion of Phase I research would be the demonstration of efficacy at low molar concentration in in vitro studies or a 50% increase in survival in any animal model (assuming the animal model has already been developed and an animal use protocol approved). Information garnered from Phase I experiments may be more qualitative than quantitative. PHASE II: With successful completion of Phase I experiments, Phase II would further evaluate the medical countermeasure (MCM) in a small mammal study. In these studies the MCM would be administered to animals with mycotoxin only exposure and to mycotoxin plus another toxin such as Staphylococcal enterotoxin A (SEA) or Staphylococcal enterotoxin B (SEB). The animal model should be of sufficient size and scope to demonstrate a statistically significant increase in long-term survival in animals receiving the MCM. The SBIR Phase II studies shall design experiments in a manner that facilitates the collection of non-clinical GLP pharmacokinetic (PK) and pharmacodynamic (PD) data. The PK and PD information will be of paramount importance to inform subsequent Phase III studies. PHASE III: Phase III studies would further refine the animal model and the compound/drug dosing regimen. The goal would be to work towards FDA approval of a MCM for one or more mycotoxins to include aflatoxin(s) and/or T-2 toxin(s). FDA licensure/approval is not necessary for the project to be deemed successful. However, an objective demonstration of MCM efficacy in at least an animal model relevant to the human condition, and/or successful completion of an FDA approved clinical trial, with accompanying efficacy demonstrated in an animal model is required for success to be declared. One means for the offeror to document progress in the right direction is through a Technology Readiness Assessment (TRA) of the technology using the harmonized Quantitative Technology Readiness Level (Q-TRL) guidance document as described by the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE). A second means for demonstrating success is the establishment of funding and partnering with commercial companies (if necessary) to bring the product to market. PHASE III DUAL USE APPLICATIONS: Successful MCM products directed towards mycotoxins clearly have broad dual use applicability. Acute mycotoxin intoxication is a common occurrence throughout much of the world, usually due to the growth of mycotoxin producing fungi on grains stored under conditions conducive to fungal contamination.
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