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Broad Spectrum Envenomation Treatment

Description:

TECHNOLOGY AREA(S): Bio Medical 

OBJECTIVE: This topic focuses on developing a broad spectrum venom mitigation and treatment that will be effective without identification of the venomous species and which can be used in the field without fear of significant adverse side-effects (such as serum sickness). 

DESCRIPTION: Special Operations Forces (SOF) are deployed in austere areas within AFRICA Command (AFRICOM), Pacific Command (PACOM), and Southern Command (SOUTHCOM) that are associated with an increased risk of envenomation. Bites by venomous snakes cause: severe paralysis that may prevent breathing; bleeding disorders that can lead to fatal hemorrhage; irreversible kidney failure; and severe local tissue destruction that causes permanent disability and limb amputation. Traditional antivenins require correct identification of the venomous species to select the appropriate treatment and the risk is high for severe adverse reactions such as serum sickness and hypersensitivity. Identification of the specific species is frequently problematic or mistaken and treatment must be administered in in a higher echelon military treatment facility. Compounding this problem, reliable pharmaceutical companies no longer produce antivenins previously used in higher risk areas such as Africa. However, current research into the enzymatic structure and function of venoms indicates that a new direction for antivenin is on the horizon. Broad spectrum venom inhibitors that use novel approaches such as nanoparticles and phage that target enzymatic classes such as Phospholipase A2 and Metalloproteinase are possible. Not only are the new approaches likely to treat a broad spectrum of envenomations, lyophilization and reagent stabilization will enable therapeutics to remain stable over a broad range of temperatures, allowing treatment at the point of envenomation. The World Health Organization recently declared snake-bite a neglected tropical disease, with approximately 2.5 million poisonings from snake-bite occurring each year. Annually, snake bites result in at least 100,000 deaths and around three times as many amputations. While many antivenoms exist throughout the world, significant challenges exist in their manufacture and effective use. The majority of antivenoms are based on species-specific immune reaction to venom exposure. Very few antivenoms are approved for use by the Food and Drug Administration (FDA). Successful proposals to develop broad spectrum envenomation treatment may include, but are not limited to, toxin and/or enzymatic inhibition technologies. Proposals should focus on broad applicability and ease of use in austere conditions. The regions of particular interest are AFRICOM and PACOM. Consideration should be given to the systemic neurotoxic, myotoxic, hemorrhagic, coagulant, and hypotensive effects of envenomation. Proposals to improve existing polyvalent treatments that require high and/or repetitive dosing and/or require administration in a critical care facility are specifically excluded from this solicitation. 

PHASE I: Define the component technologies needed to develop a broad spectrum envenomation treatment that can be used in austere conditions without concern of serious side-effects. Investigate major venom component toxins and potential therapeutics for combined toxin inhibition. Treatment categorization must determine use without relying on speciation. Define and develop FDA regulatory approval plan for any initial and follow-on therapies. Begin in vitro screening for proposed treatment methodology safety and efficacy. Future in vivo animal model should be planned and outlined. Preliminary in vitro data should include cytotoxicity, binding affinities, and venom neutralization with proposed therapeutic and whole venoms including but not limited to Crotalus, Agkistrodon, Naja, Bungarua, and Dendroaspis, Where possible, available anti-venoms should be used as controls. Phase I deliverables include (1) Opportunities and limitations of potential developed treatments with regards to safety, efficacy, and manufacturability, (2) PK/PD model of therapeutic mechanism of action, (3) Preliminary in vitro data (4) Any therapeutic categorization (if required) (5) Phase II in vivo animal model and animal use plan, and (6) FDA regulatory approval plan. 

PHASE II: Synthesize and iteratively refine broad spectrum envenomation treatment with in vitro testing. Validate concept in a small animal model with unknown (or category) venom. Examine the PK/PD, biodistribution, safety, and efficacy of the concept. Demonstrate feasibility of GLP/GMP scale-up with appropriate yield efficiencies. The overall objective is to develop and validate a venom inhibitor effective against a broad spectrum of envenomations that can be safely administered by SOF medics in the field without identification of the venomous species. The FDA approval pathway will be outlined and considered at each developmental stage. The goal is to receive Food and Drug Administration (FDA) clearance on the venom inhibiting solution. Requirements: (1) Broad spectrum venom inhibitor a. Phospholipase, three-fingered toxins (cytotoxins, short-chain neurotoxins and long-chain neurotoxins), and metalloprotease classes (threshold) b. Other protease classes and toxins found within venoms (objective) (2) Administered by SOF medics in a field environment without immediate critical care facility availability (threshold) (3) Stable in ambient temperatures (threshold) (4) Two year shelf life (objective), one year shelf life (threshold) Phase II deliverables will include: (1) Report detailing design, synthesis, and validation of envenomation treatment system, (2) Plan for regulatory approval. The offeror shall initiate contact with FDA representatives and provide a clear plan on how FDA clearance will be obtained. 

PHASE III: Validate concept in large animal model and transition therapeutic to pharmaceutical company. A clear plan towards FDA approval for the therapeutic agent(s) and delivery platform will be in place, and additional testing to meet FDA requirements will be completed. Additionally, to expand the use of the device to medical diagnosis, FDA medical device certification will be pursued. Supplementary funding may be provided by DoD sources including, but not limited to US Special Operations Command and Air Force Medical Advanced Development. While additional funding may be provided for DoD applications, awardee should also look toward other Government to continue the process of translation and commercialization. 

REFERENCES: 

1: Arias, Ana Silvia, Alexandra Rucavado, and Jose María Gutierrez. Peptidomimetic hydroxamate metalloproteinase inhibitors abrogate local and systemic toxicity induced by Echis ocellatus (saw-scaled) snake venom. Toxicon 132 (2017) 40-49.

2:  Fox, J.W., Serrano, S.M.T., 2005. Structural considerations of the snake venom metalloproteinases, key members of the M12 reprolysin family of metalloproteinases. Toxicon 45, 969-985.

3:  Laustsen, A.H., Engmark, M., Milbo, C., Johanneses, J., Lomonte, B., Gutierrez, J.M., Lohse, B., 2016. From fangs to Pharmacology: the future of snakebite envenoming therapy. Curr. Pharm. Des. 22, 5270-5293.

4:  Lewin, M., Samuel, M., Merkel, J., Bickler, P., 2016. Varespladib (LY315920) appears to be a potent, broad-spectrum, inhibitor of snake venom phospholipase A2 and a possible pre-referral treatment for envenomation. Toxins 8, 248.

5:  World Health Organization, Snake antivenoms Fact sheet N° 337, 2010

6:  http://www.who.int/mediacentre/factsheets/fs337/en/

KEYWORDS: Venom Inhibitor, Phospholipase A2 Inhibitor, Metalloproteinase Inhibitor, Envenomation, Toxin, Neglected Tropical Disease 

CONTACT(S): 

Lt. Col. Rebecca Carter 

(850) 884-1935 

rebecca.carter.3@us.af.mil 

Dan Dumas 

(850) 884-1590 

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