Ex-RAD® (ON 01210.Na) is in Phase I clinical testing as a radiation protection agent. Radioactive contamination and injury from ionizing radiation can arise from accidents involving nuclear reactors and industrial or medical sources. Recent events have highlighted the potential for non-accidental radiation injury as a result of malicious, criminal, or terrorist actions. Pharmaceutical agents that can “prevent and repair” cellular radiation damage can help in mitigating radiation injury.
Using a cell biology-based screening approach, we identified Ex-RAD® that provided protection from lethal ionizing radiation. Ex-RAD® development, which is initially focused on military applications, is being supported by a funded collaboration with the U.S. Department of Defense (DoD). Ex RAD® is being developed according to the FDA’s Animal Rule – Marketing approval for new countermeasures for which human efficacy studies are not feasible or ethical would be based on animal studies and Phase I safety data in healthy volunteers, without Phase II or Phase III clinical studies.
Under the Animal Rule, the FDA requires adequate, well-controlled efficacy studies in animal models that establish that the drug product is reasonably likely to produce clinical benefit in humans. In multiple cell-based and whole animal models, Ex-RAD® has demonstrated protection from radiation injury when administered either before or after radiation exposure. Studies on efficacy have been conducted in collaboration with scientists at the DoD’s Armed Forces Radiobiology Research Institute (AFRRI). Results have recently been published (S.P. Ghosh, et al. “Radiation protection by a new chemical entity, Ex-RAD®: efficacy and mechanisms.” Radiat Res 171: 173-179, 2009).
UNIQUE MODE OF ACTION
Unlike most radiation protectors, Ex-RAD® is not a free-radical scavenger, chelator, nor cell cycle arrestor. Available data suggest that Ex-RAD® accesses a novel mechanism for radiation protection involving intracellular signaling, damage sensing, and DNA repair pathways. Ex-RAD® treated cells sustain less DNA damage upon exposure to irradiation. Results of the DNA comet assay (adapted from Ghosh et al., 2009) are shown in the accompanying figure.
Image Analysis of Irradiated HFL-1 Cells
In cells responding to radiation injury, Ex-RAD® significantly reduces levels of p53, p21, bax, c-abl and p73 proteins, which are key players in the DNA damage cascade. These effects likely cause a halt in cell death pathways and lead to increased recovery and survival of irradiated cells.
The novel mechanisms of action and virtual lack of side effects at effective dosage suggest that Ex-RAD® could be useful both as a prophylactic agent and as a therapeutic for mitigation.
PHASE I CLINICAL TRIALS
Onconova has completed two Phase I clinical studies of Ex-RAD® in healthy volunteer subjects. Following increasing single or double doses by subcutaneous administration, the drug was well-absorbed, reaching maximal blood levels in about two hours, with no evidence of systemic side effects and good local tolerance. . Ex-RAD® is formulated for injection and can be stored and transported without refrigeration. An auto-injection device is under development for field use. Development of an oral formulation for specialized and broader use is ongoing