EpiStem this week announced that it has been contracted by Exponential Biotherapies to test the efficacy of EBI’s candidate compounds designed to protect the bone marrow and the crypt cells of the gastrointestinal tract against medical or accidental radiation exposure, or radiation exposure during a terrorist attack.
EpiStem supplies assays that measure qualitatively and quantitatively the effects of radiation damage in the gut. The assays provide quantitative and mechanism of action data to assess the efficacy of novel drug candidates.
The first compound that EpiStem will evaluate, a small-molecule immunoregulator called EA-230, has demonstrated the potential to minimize the effects of a radiation and could be administered following an attack by nuclear weapons, Zsolt Harsanyi, chairman and chief executive of EBI, told CBA News this week.
Terms of the agreement call for EpiStem to test the compound on mice “to see whether the compound confers a radioprotective effect on the crypt cells of mice via the histological evaluation of the cells,” Harsanyi said.
He said that the initial results are expected in about one month.
“If EA-230 has a radioprotective effect, I would expect they would look at other agents that we have, and we would look at some of their other assays,” Harsanyi said.
Financial details of the agreement were not disclosed.
EA-230 was tested in mouse models at the Albert Einstein College of Medicine in New York under a material transfer agreement between EBI and Albert Einstein, said Harsanyi.
The mice were exposed to radiation at various doses at various time periods, after which they were administered EA-230, Harsanyi explained. “We found that the drug was radioprotective at different time periods, significantly after the radiation insult.”
Almost every compound being tested today to protect against radiation exposure is administered before or very soon after exposure, Harsanyi said. “From a practical standpoint, for radiation protection, that really is not very helpful because you cannot go around injecting yourself ahead of time with a drug to protect against an exposure that you cannot predict will happen.”
Privately held EBI discussed this issue with the National Institutes of Health, whose Medical Countermeasures against Radiological and Nuclear Threats, or MCART, program has been charged with developing new medical countermeasures against radiological and nuclear threats.
MCART is a joint program for which the US Department of Health and Human Services has assigned the National Institute of Allergy Immunology and Infectious Diseases to develop a strategic plan and research agenda.
NIAID’s Division of Allergy, Immunology, and Transplantation has been asked to coordinate and administer the MCART effort.
According to the NIAID Web site, through collaboration with the National Cancer Institute, other federal agencies, academia, and industry, MCART promotes research aimed at creating new medical countermeasures to assess, diagnose, and care for those exposed to radiation.
“If EA-230 has a radioprotective effect, I would expect they would look at other agents that we have, and we would look at some of their other assays.”
According to Harsanyi, the MCART program screens compounds in a three-step process: Compounds are first screened to see if they protect against low-dose radiation, which usually results in bone marrow damage and leads to conditions such as neutropenia, thrombocytopenia, and anemia.
If a compound protects against low dose radiation, “the MCART program wants to see if it protects against one of the consequences of higher-dose radiation insult, acute gastrointestinal syndrome” that results in damage to the GI tract, Harsanyi explained
“What is thought to happen is that the crypt cells of the intestine are damaged to such an extent that bacteria are released into the circulation, and with compromised immunity because of bone marrow damage, a significant risk of sepsis and septic shock exists,” he said.
EBI, based in McLean, Va., had been looking at other investigators who do these kinds of assays, said Harsanyi. He said that the MCART scientists had been working with EpiStem and told EBI that EpiStem’s assays were fairly standardized for this application.
“That was important for EBI, because we wanted an equal basis for comparison to others’ compounds,” said Harsanyi.
EBI found that after being administered EA-230, the animals were able to survive radiation at various doses better than those given other compounds, “at least as far as we know,” said Harsanyi.
“Now that we had the feed-up, feed-down experiment results, we wanted to take a closer look at the mechanisms by which the compound protects the animals against radiation insult,” Harsanyi said. Is it protecting the GI tract and the bone marrow? If so, how?
“It is with EpiStem that we are looking at the radioprotective effects of the compounds on the bone marrow and GI tract, and hopefully in a month or so, we will have our results,“he said.
The next step is for MCART to test the drug in larger animals, said Harsanyi. If it proves safe and efficacious under the FDA’s two-animal rule, which states that efficacy in two animal models is sufficient for approval if efficacy studies in humans are not practical or ethical, it could be eligible for approval for human use, said Harsanyi.
EpiStem has primary epithelial tissue culture assays in which EBI can start examining at a more molecular level the mechanism of action of these compounds, said Harsanyi. “It will be a combination of trying to discern the mechanism of action of these compounds, or how they exert their radioprotective effect, because that is still a question mark, and identifying other compounds that have this effect.”
EBI has a family of immunomodulatory compounds with applications in sepsis/systemic inflammatory response syndrome, renal failure, radiation sickness (including that related to radiation treatment for cancer), anthrax, and avian flu.
“We have several candidate peptides that have a radioprotective effect to different degrees,” said Harsanyi. EBI would screen these other compounds compounds to discover a drug that has the optimum efficacy. “And of course, we use the model also for dosing studies, looking at the route of administration of a drug and time of administration following radiation insult.”
“Biodefense was a first possible indication for our peptides, even before oncology,” said Harsanyi. “I have had experience since 1988 working with the Department of Defense on developing agents against terrorist threat compounds. It was natural for me to be thinking, ‘Here is a compound that can be used to protect those exposed to radiation during an attack against the US.’”
If EBI is able to demonstrate that its compounds protect any mucosal tissue in the body against radiation treatment, and possibly even against chemotherapy, then it would a have a completely separate market, he said.
When asked about the current biodefense market, Harsanyi said the drug keratinocyte growth factor, which is used to treat ulcers/mucositis, costs approximately $6,000 per treatment, and that it “is the only drug that is considered usable, I think, for that indication.”
“I am not sure that [the biodefense market] is a growing market in the traditional sense, but it is one in which, as with the biological agent vaccines, the government plans to stockpile these kinds of drugs,” he said.