Development of a Novel Gastrointestinal Radiomitigator

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DESCRIPTION (provided by applicant): Unintended exposure to radiation via a nuclear accident, or explosion of a "dirty bomb," can have devastating consequences to humankind. We developed a novel small molecular weight stable analog of the phospholipid growth factor lysophosphatidic acid, octadecenyl thiophosphate (OTP) that shows strong radioprotective and radiomitigating actions by rescuing intestinal and hemopoietic cells from apoptosis in mice irradiated with lethal doses of gamma-irradiation when applied at least up to 6 hours after radiation exposure. OTP also reduces diarrhea and barrier damage induced by reactive oxygen species to the epithelium. Here we propose to evaluate OTP in non-human primates. Following the Code of Federal Regulation (CFR) for the development of octadecenyl thiophosphate (OTP) as a radioprotector/radiomitigator toward a new drug application (NDA) here we propose to: 1) Set up OTP synthesis following the standards for chemistry, manufacturing and controls [CMC, 21 CFR 321 .23(a)(7)] (CGMP production) in a subcontract by Avanti Polar Lipids Inc.-an FDA licensed facility. 2) Conduct a limited comparative animal efficacy study in mice with the CGMP-manufactured OTP and the non-CGMP product we currently have. These experiments will first test acute toxicity using oral and subcutaneous application in mice and second, test the radiomitigating effect in mice irradiated with LD90/30 dose of gamma-radiation and treated with OTP 6h post hoc. 3) We will determine whether the no-observable adverse effect level (NOAEL) in adult Rhesus macaques is consistent with the low toxicity we determined in mice (ICH guidance S2A, S2B, S4A, S5A & S5B). 4) We will determine the therapeutic efficacy of OTP as a gastrointestinal radioprotectant and radiomitigator in Rhesus macaques following the Animal Efficacy Rule [21 CFR 314.610]. Specifically: a) Determine the radioprotective efficacy of OTP on crypt survival in the bone marrow shielding model using combined oral and subcutaneous application starting 1 h pre-irradiation. b) Determine the radiomitigating efficacy of OTP on crypt survival in the bone marrow shielding model using combined oral and subcutaneous application starting 6 h post-irradiation. This project will be conducted in close collaboration between the University of Tennessee Health Science Center and the California National Primate Research Center at the University of California Davis. The project when completed will provide data necessary for filing an INDA with the FDA and ultimately provide our country with an effective treatment for radiation injury to the gut.