Despite the wide availability of potassium iodine to mitigate ingestion exposure to radioactive iodine in the air, food or beverages, there is still no magic medicine to give to people who have been—or will be—exposed to high levels of direct radiation.

But years before the disaster at the Fukushima Daiichi nuclear power plant in Japan, the U.S. government had started lobbing millions of dollars at contracts to speed the development of drugs to combat dangerous doses of ionizing radiation.

The military is "very interested in drugs that you can give before radiation or very shortly after," says Mark Whitnall, program advisor for Radiation Countermeasures at the U.S. Department of Defense's Armed Forces Radiobiology Research Institute (AFRRI), which has spearheaded recent development efforts.

Aside from radiation sickness caused by nuclear attacks or accidents, anti-radiation drugs could have applications for people receiving radiation therapy for cancer, those with weakened immune systems or even for astronauts undertaking long-distance space travel.

Lethal exposures
Depending on the type of exposure, radiation can pose a wide range of health risks. Acute radiation syndrome—often called radiation sickness—is different from health effects related to contact with airborne or foodborne radioactive isotopes (including iodine 131, strontium 90 or plutonium), which are linked to more long-term issues, such as cancer.

People exposed to intense radiation emitted directly from a source such as a nuclear reactor core or weapon, as has occurred with some workers addressing the crisis at the stricken Fukushima power plant in Japan, can suffer from severe infection and gastrointestinal damage (in addition to skin burns, hair loss and other symptoms), which can lead to death within days or months.

Radiation exposure also damages bone marrow, reducing the body's supply of white blood cells and platelets. This renders people more prone to infection as well as uncontrolled bleeding. At extreme levels, it can also harm the lining of the stomach and central nervous system.

Available treatments have leaned on antibiotics to stave off infection, along with blood transfusions to replace white blood cells and platelets.

Another drug that's already out there, a granulocyte colony-stimulating factor (G-CSF) called filgrastim (sold as Neupogen), incites the bone marrow to make more white blood cells. It is indicated for cancer patients whose counts have dropped as a result of radiation treatment and has been noted as a possible treatment for a nuclear power plant radiation emergency, according to the U.S. Centers for Disease Control and Prevention. It does not, however, address the risk of excess bleeding, Whitnall says, noting that, "a loss of platelets [clotting bodies] is really a major cause of death after radiation."

So researchers have been trying to develop drugs that could target blood loss as well and radiation's other effects on the body—both before and after exposure. A prophylactic "radio-protector" for first-responders and military personnel whose work puts them in harms way would be particularly desirable.

But for many people who could unwittingly be caught up in a nuclear accident or attack, "there's a need for a mitigating agent that can be given as long as possible after the event of radiation," says Andrei Gudkov, chief scientific officer of Cleveland BioLabs a company that is currently testing one anti-radiation drug. Their drug, called CBLB502, seems to protect primates for some 48 hours after radiation exposure.

Another drug that is in the works, Ex-RAD (made by Onconova Therapeutics) has been shown to protect mice from long-term damage caused by direct radiation if given either pre- or post-exposure. They hope to make it effective if given up to 24 hours before exposure. Animal studies suggest that it can have a protective effect for exposures even weeks after a dose.

A different type of therapy, CLT-008 (made by Cellerant Therapeutics), is cell-based and administered intravenously; it promises a different type of treatment to boost white blood cells. In animal studies it was effective given as long as three to five days after radiation exposure. Although it would require more substantial medical facilities, it might be a follow-up treatment for those who were able to receive first-line meds. "You could actually triage the people and then appropriately administer this product," says Ram Mandalam, president of Cellerant. Whitnall describes it as "a bridging therapy that will allow the patient to survive for awhile, while his own immune system and blood-forming system can recover."

Ascertaining effectiveness
As tough as it is to develop these drugs, testing them can be even trickier. They can only be systematically checked for safety—not effectiveness—in people. "We can only evaluate in healthy volunteers because we cannot expose people to radiation," explains Manoj Maniar, senior vice president of product development at Onconova, which makes Ex-RAD.

Because companies cannot go around irradiating human subjects, the U.S. Food and Drug Administration allows these sorts of drugs to be tested for efficacy in two animal models—usually mice and monkeys—and for safety alone in healthy people.

So far, the human safety trials have been small: CBLB502 has been tested in about 150 people in the U.S., Ex-RAD in fewer than 100 subjects. "The results were extremely encouraging," Maniar says of the initial human Ex-RAD safety studies. "We did not see any drug-related adverse events in the trial."

With such a small pipeline to work with, Whitnall and his group try to do due diligence in assessing compounds early in the development phase. Researchers must "look for toxicity pretty early to make sure there's no show-stopper," he notes.

But the safety trials will need to be considerably larger before the drugs can be considered for approval. And as part of the modified approval process, regulators also "want to understand the mechanism of injury very well," along with how the drug itself is working, Whitnall says.

Although some of the specifics might still need to be parsed out for the FDA, researchers can already explain the basics. CBLB502 helps to trigger the release of cytokines and chemokines—involved in intracellular communication—which boosts bone marrow and gastrointestinal tract regeneration. Ex-RAD also works via intracellular communication, repairing damaged DNA and preventing cell death (apoptosis).

Despite the possible applications, millions of research dollars from the government, and fast-track status from the FDA, drugs to keep people from dying after intense radiation exposure still face additional hurdles before they are ready to distribute in the event of the next nuclear emergency.

Although Neupogen—a cancer drug—has been indicated for people exposed to extreme radiation, it has to be refrigerated and must be injected or given intravenously. And, Whitnall notes, "it does have occasional severe side effects, so it does need to be administered under the care of an MD."

In the event of a natural disaster, accident or nuclear attack, the likelihood that these supplies—and the clinical environment in which to administer them—would be easily and rapidly accessible for people in the immediate vicinity is dubious.

Nevertheless, the Defense Department "wanted an injectable form of the drug, which could be used by first responders as well as military personnel in the battlefield," Maniar says. But a pill form would be much easier to distribute on a wider scale.

CBLB502 will need to be injected because it contains a protein that would be digested in the stomach if swallowed. Gudkov notes, however, that the liquid is very stable even at high temperatures.

Likewise, Ex-RAD has only been tested in humans via injection. But researchers are working on an oral formulation. They also have a device that would make it easy for people to inject it themselves. "We have developed an auto-injector where the volunteers could self-administer to mimic a real-life scenario where people would be administering the drug by themselves," Maniar says.

Sparking investment

Pitching a medication that might be picked up by the government as a just-in-case measure does not always appeal to investors the same way a new blockbuster cholesterol drug might.

As Whitnall points out "none of these are Big Pharma," and although the government has been helping out with contracts and grants, assembling larger scale human trials to prove safety requires "a huge amount of money."

But broadening the application of some of these drugs might eventually be able to generate additional interest. As Whitnall notes, "there are a lot of patients who need their blood system stimulated."

Some of them could also find a home in cancer treatment regimens. Animal and in vitro research has shown that CBLB502 might be effective in helping to mitigate damage done to healthy cells during radiation therapy—without protecting the tumor cells. Researchers are not exactly sure why this seems to be the case. It might be that because the nuclear factor-kappa B (NF-kB) light chain–enhancer of activated B-cell signaling—which boosts the survival of progenitor cells in bone marrow as well as a resistance to cell death (apoptosis)—is already activated in tumor cells, the drug boosts it in healthy cells but cannot increase its activity any more in the tumor cells. But more work remains to be done. And those at Onconova note that they are not currently pursuing a cancer angle with Ex-RAD because the approval process is so different from the one they are currently undertaking for radiation sickness.

And new drug candidates are cropping up all the time. As Whitnall notes, they have had to develop an initial screening program just to prioritize which compounds to test further because they "only have the funds to test one or two a year." A next step will also include trying to "increase the efficacy [by] combining drugs with different mechanisms in hopes that there is some kind of synergy."

But the drugs will first have to be shown to be safe on their own.

Whitnall, who works with several of the drugs in development through his role at the AFRRI, says that he does not want to pick favorites to guess which drug might come up for approval first. But in all likelihood it will still be at least a couple years before any of these therapies are ready to battle against the effects of gamma rays. Cleveland BioLabs is aiming to submit CBLB502 to the FDA for approval by late 2012. Onconova hopes to be able to file for agency approval for Ex-RAD in 2013 at the earliest. And Cellerant isn't expecting to have enough data together to submit its compound for at least another four years.