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You are here:  HOME  >  What's New  >  FDA clears 5-AED for human clinical studies
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FDA clears 5-AED for human clinical studies

 
BETHESDA, Md., July 29, 2005—The Armed Forces Radiobiology Research Institute and a research partner achieved a milestone in July when the U.S. Food and Drug Administration (FDA) cleared 5-AED (5-androstenediol) for Phase I human clinical trials. By granting 5-AED investigational new drug (IND) status, science moves a step closer toward providing a radiation countermeasure that is safe, effective, easily transported and stored, and cost-effective.

AFRRI researchers conducted pre-clinical trials of 5-AED, a steroid, as part of a cooperative research and development agreement (CRADA) with Hollis-Eden Pharmaceuticals. The drug is being developed to treat acute radiation syndrome (ARS), a potentially lethal condition resulting from high-dose radiation exposure.

Achieving IND status permits trials in the United States with humans, to test safety and pharmacokinetics (the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body). Hollis-Eden is already conducting clinical trials in The Netherlands. Following clinical tests, pivotal efficacy trials of 5-AED will commence in support of a new drug application (NDA) to the FDA, which will lead to marketing.

Protection and therapy
Current events attest to the growing global threat from terrorism, including the possibility of a radiological attack in the form of a small nuclear device, or conventional explosives packed with radioactive material. For example, AFRRI medical experts must consider how much worse the July attacks on London’s subway and bus systems would have been if "dirty bombs" had been used.

A major problem in preparing for such events is the lack of radioprotective (pre-exposure) and therapeutic (post-exposure) agents that are safe, effective, affordable, and approved for use. In addition to basic clinical support including antibiotics, one effective therapeutic strategy currently available for severely irradiated individuals is administration of recombinant cytokines (e.g., G-CSF, or granulocyte colony-stimulating factor) as soon as possible after irradiation. G-CSF in the form of Neupogen® enhances resistance to infection and is well-tolerated when administered at a medical facility under the supervision of a physician.

However, cytokines are costly to transport and store, unstable at room and high environmental temperatures, and must be used under the care of a physician. Those limitations make cytokines impractical for use in a mass-casualty radiation scenario, which could leave many victims without access to physicians, hospitals, or roads to access both. Moreover, while G-CSF causes elevations in certain types of white blood cells, it does not stimulate production of platelets.

AFRRI's preclinical trials showed 5-AED's safety and efficacy profile is such that it could be used as a single therapy— without need for physician or medical support—in a mass-casualty scenario. 5-AED addresses two of the major problems causing mortality after irradiation: loss of infection-fighting white blood cells and loss of platelets, which leads to excessive bleeding. It also ameliorates the drop in red blood cells seen after irradiation.

Bone marrow of a mouse treated with 5-AED
Bone marrow from a mouse treated with 5-AED (above), compared with marrow from a mouse treated with placebo (below). The many small, round, dark objects in the control section are nuclei in progenitors of red blood cells. Progenitors of granulocytes (mostly neutrophils) and monocytes possess lighter nuclei, often horseshoe-shaped. Four days after 5-AED treatment, there was a proliferation of granulocyte/monocyte progenitors.
Bone marrow of a mouse treated with a placebo

Acute radiation syndrome
ARS depletes a victim's hematopoietic (blood-cell forming) stem cells, resulting in an abnormal reduction in the number of white blood cells (neutro-penia) and platelets (thrombocytopenia). Both G-CSF and the 5-AED steroid stimulate the proliferation of progenitor cells and bolster the immune system. What differentiates them are the ability of 5-AED to elevate platelet numbers; their production, trans-portation, and storage costs; their toxicity levels; and the level of hospitalization and physician care each re-quires. Dr. Mark Whitnall, leader of AFRRI's Radiation Casualty Management Team, explains the im-portance of obtaining 5-AED IND status:

Q: How is the FDA's granting IND status to 5-AED significant?
A: IND status means the FDA has certified 5-AED is safe enough to conduct human safety and pharmacokinetics trials in the United States. Such trials are already under way in the Netherlands. Once safety and dosing have been established in humans, the same dosing regime will be used in nonhuman primates for pivotal efficacy trials.

Q: How successful was 5-AED in pre-clinical trials?
A: 5-AED caused remarkable increases in survival in irradiated rodents and increased the number of circulating blood cells and platelets. Similar elevations in the number of blood cells and platelets have been observed in nonhuman primates after irradiation. Preliminary evidence indicates 5-AED improves survival in irradiated nonhuman primates as well.

Q: How long were AFRRI's pre-clinical trials?
A: We started working on 5-AED in 1996 and presented the evidence for its efficacy as a countermeasure at the 1997 annual meeting of the American Society of Hematology.

Q: Ionizing radiation decreases blood cells and platelets which, in turn, weakens a body's immune system and causes bleeding. How does 5-AED counter this?
A: 5-AED stimulates production of white blood cell progenitors in bone marrow. These progenitors form mature blood cells that enter the circulation and fight infection. 5-AED also stimulates function in mature white blood cells. Moreover, 5-AED causes increases in the number of red blood cells after irradiation. In addition, 5-AED stimulates the production of the cells that form platelets. The wide variety of cell types whose numbers are elevated by 5-AED leads us to believe that 5-AED stimulates the production of primitive progenitors that give rise to all these lineages. We now have evidence that 5-AED stimulates the production of immune regulatory hormones called cytokines that stimulate these early progenitors in blood-forming tissue.

Q: Is 5-AED a synthetic steroid?
A: No, 5-AED is a naturally occurring steroid. The most abundant steroid secreted from the human adrenal cortex is DHEA. 5-AED is a direct metabolite of DHEA and is a natural circulating hormone.

Q: How many phases must a drug pass before the FDA approves use for the general public?
A: A drug must go through a phase of pre-clinical testing to obtain safety and efficacy data to present to the FDA in an IND submission. Once IND status is granted, human trials can commence in the United States to establish safety and efficacy. Phase 1 is the preliminary assessment of safety and pharmacokinetics in a small group of subjects. Phase 2 expands the study to larger numbers of subjects, and Phase 3 uses thousands of subjects. Normally, the efficacy trials are conducted in patients who have the disease to be treated by the drug. However, in the case of a radiation countermeasure, the pivotal efficacy trials will be performed in nonhuman primates because it would be unethical to expose humans to lethal doses of radiation for the purpose of testing efficacy. The use of animals to demonstrate efficacy in this type of situation is allowed by the FDA under its Animal Efficacy Rule. These data are then submitted to the FDA in a new drug application (NDA), in which a company asks for approval for the sale and marketing of the drug in the United States. Safety and efficacy trials conducted after an NDA is granted are termed "Phase 4."

Q: Is 5-AED the only substance granted IND status for acute radiation syndrome by the FDA?
A: No. Neupogen®, or G-CSF, is a cytokine marketed by Amgen that stimulates production of white blood cell progenitors. It is generally used in patients who have received radiation therapy or chemotherapy for cancer. Neupogen has been granted an IND by the FDA that allows use of Neupogen when government authorities have determined that civilians have been exposed to high doses of penetrating ionizing radiation. In the event of an emergency involving ARS, the president of the United States would have to sign an authorization permitting the use of Neupogen.

Q: Are humans tested in Phase 1 clinical trials already radiation contaminated or is radiation introduced as part of the trials?
A: The volunteers in these Phase 1 trials are not exposed to radiation either before or during the trials. The purpose of the trials is simply to test for safety and pharmacokinetics in healthy subjects.

Q: If the FDA approves 5-AED for public use, how would it be administered (i.e., a pill or an inoculation)?
A: The first approval being sought is for intramuscular injection.

Q: During AFRRI's pre-clinical studies, did 5-AED's effectiveness show different results when taken after irradiation as compared to results when used before irradiation (i.e., as a radioprotectant)?
A: Yes. When one injection was given 24 to 48 hours before irradiation in rodents, maximal survival enhancement and amelioration of blood cell deficits were achieved. When one injection was given 2 hours after irradiation, amelioration of radiation injury was much poorer. In nonhuman primates, the situation was different. One injection 24 hours before irradiation was not protective. However, AFRRI and Hollis-Eden have performed studies showing that giving 5-AED in multiple daily injections after irradiation provides excellent protection in rodents and nonhuman primates.

Q: Will AFRRI trials continue now that 5-AED has been granted IND status and entered Phase 1?
A: Yes. Because we can't test efficacy against lethal doses of radiation in humans, efficacy studies will be performed in animals under the FDA's Animal Efficacy Rule for countermeasures to weapons of mass destruction. Also, in order for the FDA to approve a drug under this rule, a greater emphasis is placed on understanding how the drug works, including what the target cells are. So, AFRRI will be involved both in pivotal efficacy studies in an animal model and in the mechanistic research necessary for FDA approval.

Q: How do researchers determine drug dosages for humans from dosages that proved effective in lab animals?
A: In this case, dose-ranging studies were performed in nonhuman primates in order to determine countermeasure dosages for humans. The preliminary dose range tested in nonhuman primates was based on rodent results.

Q: Does 5-AED seem potentially cost effective, easily stored/transported, and nontoxic?
A: Yes. Unlike cytokines, which have to be transported and stored refrigerated and have to be administered under the care of a physician, 5-AED is very stable at high environmental temperatures, and its toxicity is so low that we envision its eventual use without physician supervision. It is also very inexpensive compared to cytokines. These factors are important because, in many scenarios, cities would be paralyzed—victims would not be able to get to medical facilities, and emergency responders would not be able to get to victims.

Q: In the event of an emergency involving ARS, the president could authorize use of Neupogen. Because 5-AED has achieved IND status, could it also be used in an emergency if the president approves—even though 5-AED is still in the Phase I stage of the FDA’s exhaustive process?
A: No. The IND for emergency use of Neupogen is a special case because so much is known about its efficacy already. In the case of 5-AED, we still need to do the pivotal efficacy trials in irradiated nonhuman primates. The purpose of the IND was to allow Hollis-Eden to conduct the human safety and pharmacokinetics trials in the United States. Once that data is in hand, we can commence the pivotal efficacy trials in nonhuman primates. That data will then be used in support of a new drug application to the FDA.

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