Ex-RAD® (ON 01210.Na)

Protecting Healthy Cells

Ex-RAD provides protection from ionizing radiation with minimal observed adverse events in Phase I studies. The well-tolerated profile of Ex-RAD aligns well with needs of military or first responder personnel, as these individuals cannot afford to be affected by performance-limiting adverse events.

Unlike most radiation protectors, Ex-RAD is not a free-radical scavenger, chelator, or cell cycle arrestor. Ex-RAD employs a novel mode of action, involving the enhancement of internal DNA repair pathways, which significantly reduces levels of p53, p21, bax, c-abl and p73 proteins-key players in the DNA damage cascade induced upon exposure to harmful radiation. These mechanisms have been shown to cause a halt in cell death pathways and lead to increased recovery and survival of irradiated cells. These novel mechanisms of action accompanied by minimal side effects suggest that Ex-RAD could be useful both as a prophylactic agent and as an agent for mitigation. Ex-RAD is formulated for both injection and oral dosage providing potential flexibility in broad use settings.

Radioactive contamination and injury from ionizing radiation can arise from accidents involving nuclear reactors and industrial or medical sources. Recent events highlight the potential for non-accidental radiation injury as a result of malicious, criminal, or terrorist actions. The Ex-RAD development program has been initially focused on military applications and supported through a funded collaboration with the U.S. Department of Defense (DoD). Pharmaceutical agents that can prevent and repair cellular radiation damage can help in mitigating radiation injury.

Ex-RAD is being developed under the FDA's Animal Rule. The Animal Rule allows marketing approval for new countermeasures, for which human efficacy studies are not feasible or ethical, to be based on both animal efficacy studies and safety data in healthy volunteers. Under this approval pathway, the FDA requires adequate, well-controlled efficacy studies in animal models that establish the drug product as 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 through subcutaneous or oral administration.

Onconova has completed three Phase I clinical studies with Ex-RAD in healthy volunteer subjects. Following subcutaneous administration, the drug is well-absorbed, reaching maximal blood levels in approximately 2 hours, and demonstrates good local tolerance with no evidence of systemic side effects. Ex-RAD is formulated for subcutaneous injection or oral administration. Onconova is rapidly advancing the development of Ex-RAD for oral use under a new IND for clinical evaluation.

Oral administration of a radiation protectant would provide increased compliance, ease-of-use, and portability for an at-risk population in the event of nuclear radiation incidents. Additionally, Ex-RAD may serve as a future potential therapeutic agent in at risk populations in conjunction with cancer radiotherapy treatment by protecting healthy cells from the harmful effects of scatter radiation experienced by patients and healthcare providers, a known occupational hazard.

EFFICACY 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 three 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. Self-administration with a ready-to-use auto-injection device has also been successfully tested in the clinic. Ex-RAD is formulated for injection and oral administration and can be stored and transported without refrigeration. Development of orally-administered Ex-RAD for specialized and broader use is underway.