Development of Cysteamine as a Medical Radiation Countermeasure

DESCRIPTION (provided by applicant): The detonation by a terrorist of an improvised nuclear device would expose hundreds of thousands of citizens to acute radiation syndrome (ARS), which untreated leads to death. There are currently no approved drugs available for the prevention or treatment of ARS. Effective drugs with acceptable safety profiles that can be easily stored and self-administered and which have a long shelf life are a high priority for development. Humanetics will develop BIO 600, a simple and stable aminothiol, as a drug that can be given prior to radiation exposure to prevent lethal effects and/or that can act as a therapeutic following exposure. In addition to research performed by Humanetics, others have documented a radioprotective effect with BIO 600. It is orally bioavailable, stable at room temperature, a potent antioxidant and has a favorable and tested safety profile in humans. BIO 600 has the potential to be a truly effective and safe medical radiation countermeasure that might ultimately rescue hundreds of thousands of people from death due to the lethal effects of ARS. The damage to the hematopoietic system by whole body radiation exposure is the result of oxidative damage and the onset of apoptosis in hematopoietic stem cell lines. For the past two years Humanetics has been involved in a program to discover safe and potentially effective antioxidant drug candidates that also inhibit apoptosis thereby preventing the hematopoietic syndrome of ARS. Using a bioassay that utilizes murine intestinal crypt stem cells, a series of candidate compounds were screened for their ability to promote stem cell survival after irradiation. We have discovered that treatment with BIO 600 results in a dramatic 5-fold greater decrease in apoptosis compared to the irradiation only group and a 3-fold greater decrease when compared to amifostine, a well-known radioprotectant. Here in Phase I we will assess the compound's efficacy as a medical radiation countermeasure. A series of experiments will be conducted to document BIO 600's ability to improve survival versus placebo in an LD90/30 murine irradiation model for BIO 600 given prior to exposure and as a therapeutic following exposure (Specific aims 1 and 2). In Aim 3 we will focus on determining the therapeutic blood levels and pharmacokinetics and the calculation of the dose reduction factor (DRF). In Phase II we will complete the efficacy studies in small and large animals under the guidelines of the FDA Animal Rule and the clinical safety studies needed for the filing of a New Drug Application (NDA) with the FDA. The goal of the Phase I and Phase II research is to document the safety and efficacy of BIO 600 in order to go towards FDA approval for the drug as a medical radiation countermeasure for ARS. PUBLIC HEALTH RELEVANCE: The detonation by a terrorist of an improvised nuclear device in a crowded urban area would expose hundreds of thousands of citizens to acute radiation syndrome (ARS) which untreated leads to death. There are currently no approved drugs available for the prevention or treatment of ARS. Humanetics is working to develop the small stable molecule BIO 600 as a radioprotective countermeasure to protect people from death due to the lethal effects of ARS.