Fast Track SBIR Phase I and Phase II Exposure to centrally acting military nerve agents and organophosphorus (OP) pesticides are known to cause death and neurological damage (Coupland 2005, Karalliedee 1989, Buckley 2004). Improved countermeasures to intoxication from these compounds are needed. In numerous studies (Albuquerque 2006) conducted at the University of Maryland, School of Medicine (UMB) supported by NIH grant NS059344, galantamine, has been shown to provide protection against the debilitating effects of these toxins. The purpose of this project is to complete IND enabling pre-clinical studies intended to move this drug with high potential for commercialization closer to availability. Countervail Corporation owns the commercialization rights to the intellectual property and is working as a business partner with the University of Maryland in advancing the drug technology toward availability. This SBIR grant proposal is being submitted under the NIH Fast Track mechanism. Phase I: Protective Ratio Studies to date, studies at UMB have evaluated OP exposures at levels where galantamine produces 100% survivability in guinea pig subjects. In published UMB studies (Albuquerque 2006), a pre-exposure dose of galantamine followed by a post exposure dose of atropine has been shown to enable survivability of 100% of the guinea pig animal subjects against OP toxin exposure levels of up to 2.0 x LD50. In studies referenced in the pyridostigmine bromide FDA Substantial Basis of Approval (SBA), a method referred to as the "Protective Ratio" was employed to evaluate protective capability against nerve agents. The purpose of the Protective Ratio method is to stress test the protective capability of the drug by determining the OP exposure level that produces a 1.0 x LD50 in the treated (protected) group of animals. The purpose of the phase I studies is to evaluate the protective characteristics of galantamine vs. pyridostigmine using the Protective Ratio method against exposure to soman and sarin. Phase II: PK and Efficacy GLP Studies Six IND enabling pre-clinical studies are planned for Phase II that will include non- primate and non-human primate species. 7 Pilot Guinea Pig Efficacy Studies 1 &2 Objective: Identify the optimal level of galantamine to protect against soman at exposure levels of 1.5 x LD50 and 2.0 x LD50 respectively. 7 Definitive Guinea Pig Efficacy Study Objective: GLP efficacy testing for survivability and neural tissue protection with soman exposure levels and galantamine dosing levels determined in first two studies. 7 Guinea Pig Pharmacokinetics Study Objective: Collection of PK data at selected time points following galantamine dosing and exposure to soman. 7 Pilot Non-Human Primate Study Objective: Identify the optimal level of galantamine to protect against soman at exposure levels of 1.5 x LD50 or 2.0 x LD50 in a second species. 7 Definitive Non-Human Primate Efficacy Study Objective: GLP efficacy testing for survivability and neural tissue protection against soman in a non-human primate model.
The public health value of providing an improved countermeasure to a nerve agent attack is self evident. These proposed pre-clinical trial studies will address comments raised in a recent FDA pre-IND meeting as well as directly support the goal of the NINDS CounterACT program to facilitate development and availability of new chemical countermeasures. We expect this research will help lay the groundwork for expanded applications both in nerve agents and organophosphorus pesticides.