The Drugs That May Never Be Used

Concerns about radiation exposure have been around since the nuclear age began, but they have mounted over the past decade thanks to terrorist attacks, the prospect of a rogue nation using nuclear weapons, and the Fukushima power plant accident in Japan. If an event were to occur, there’s almost nothing to prevent or treat all the effects of ionizing radiation.

To be better prepared, the federal government has launched programs to support the development of medical countermeasures (MCMs) against radiological, nuclear, and other threats. Within the National Institutes of Health, the National Institute of Allergy & Infectious Diseases (NIAID) guides radiation MCM research. The Biomedical Advanced Research & Development Authority (BARDA), part of the Department of Health & Human Services, supports later-stage product development at small firms and university centers.

A number of small and start-up drug companies see the federal programs as a business opportunity. Unlike larger firms, they are willing to accept government support—and the strictures that go with it—to develop therapies that will likely have only one buyer and may never be used.

Success is far from ensured. The Food & Drug Administration, which launched its MCM initiative in 2010, has yet to approve a single drug for treating acute radiation syndrome (ARS).

Moreover, in recently published strategic plans, NIH, BARDA, and FDA acknowledge many challenges to finding, advancing, making, and testing radiation countermeasures. NIH lists more than 30 already licensed drugs and clinical-stage candidates for which preliminary animal data on radiation syndromes have or will be obtained, but none of them is very advanced.

Depending on the dose, radiation can damage all the major organ systems in the body. It hits rapidly dividing cells, such as those in the bone marrow and gastrointestinal tract, which are the most radiation sensitive. Damage to the bone marrow, called hematopoietic-ARS, causes a drop in the production of blood cells, resulting in anemia, bleeding, and a susceptibility to infections.

The government can use existing drugs to treat at least some victims of radiation poisoning. “We have the ability to support people with hematopoietic-ARS and possibly save the majority of their lives if they were to be identified and hospitalized,” says Amesh Adalja, a physician and associate at the University of Pittsburgh Medical Center’s Center for Biosecurity. They would likely receive a combination of growth factors and antibiotics, which is also standard therapy to minimize the side effects of cancer treatment.

Such treatment includes the granulocyte-colony-stimulating factor Neupogen and a PEGylated version called Neulasta, both developed and marketed by Amgen. With combined annual sales for the two drugs around $5 billion for oncology patients, Amgen had all the incentive it needed to develop the products.

Indeed, repurposing drugs is desirable, because the heavy lifting has been done and the risks are lower. Not only will a drug have been tested for safety, but manufacturing is in place. If the drug is being sold for another purpose and is later approved for ARS, supply will be available for the government’s Strategic National Stockpile, a storehouse of medical supplies kept in the event of an emergency.

BARDA encourages drug companies and their partners to consider dual uses. For example, in late 2011, the University of Arkansas for Medical Sciences, in Little Rock, got a two-year, $4.5 million BARDA contract to evaluate SOM230, a drug Novartis developed for a hormone disorder. The university’s work is designed to give the drug firm the data it would need to pursue approval for treating gastrointestinal radiation syndrome, or GI-ARS.

Many drugs in the pipeline target hematopoietic-ARS, which emerges at lower doses of radiation, but far fewer look to treat the effects of higher doses, Adalja says. “The bigger challenge is going to be moving from the hematopoietic syndrome and actually making a dent in gastrointestinal, cardiovascular, and central nervous system ARS.” Without effective treatment, injury to these organ systems leads to death.

In these areas, he believes it will be hard to find an overlap with other uses that would be an incentive to develop products. “You are not really going to see those kinds of diseases other than in someone who has been exposed to a huge amount of radiation,” Adalja says, which means the government is the only customer. “These are medicines that ideally would always sit on the shelf and never have to be used.”

Drugs in development fall into different categories. Radiation mitigators are used to reduce the potential severity of injury and can be taken prior to or soon after exposure. Radiation therapeutics are generally given later, after symptoms appear. The goal is to reduce the bad physiological outcomes, assist in tissue repair or recovery, or reverse other long-term effects that develop over time.

Radioprotectants decontaminate or otherwise protect the body from radioactive species but don’t directly treat ARS. Diethylene­triamine pentaacetate (DTPA), one of three radioprotectants that FDA has approved and stockpiled, chelates americium, curium, and plutonium. Prussian blue binds thallium and cesium-137, and potassium iodide protects the thyroid from radioactive iodine.

DTPA is now given intravenously or with a nebulizer. Because MCMs should be easy to distribute and administer to a large number of people, late last year BARDA awarded an 18-month, $4.8 million contract to Nanotherapeutics for its oral NanoDTPA. The Florida-based company will improve manufacturing and conduct clinical testing. The contract can be extended for up to five years and $31 million.

Radiation also causes the formation of free radicals in the body that set off a chain reaction of ill effects. One of the more deadly and delayed effects is lung damage, which doesn’t manifest itself for two to three months and can occur in patients who have survived hematopoietic- and GI-ARS, says John L. McManus, chief executive officer of Aeolus Pharmaceuticals.

Aeolus has been developing AEOL-10150, a manganoporphyrin catalytic antioxidant, to protect healthy tissue during cancer radiation therapy. “The drug’s principal effect is in managing oxidative stress created by the radiation,” McManus says. “It basically neutralizes the radicals and, in doing that, also down-regulates inflammation and apoptosis.” In early 2011, Aeolus signed a five-year, up-to-$118 million contract with BARDA for lung-ARS. NIH is studying AEOL-10150 for GI-ARS as well.

The BARDA contract is designed to produce the data needed for FDA approval under the agency’s “animal rule.” Under the rule, drugs that can’t be tested in humans can be approved on the basis of studies in two validated animal models. Although efficacy is demonstrated in animals, all other requirements for licensure apply. Developers must also understand a drug’s action and extrapolate dosage and response between animals and humans. And they must have a robust manufacturing process in place.

Meeting approval requirements under the animal rule is not likely to be faster or cheaper than traditional clinical development, according to company executives. Nonhuman primate studies can be quite large and expensive because the animals require a high level of care and only a few institutions are licensed to conduct the studies.

“The animal rule is fairly new and there is not much precedent,” Adalja points out. FDA has approved only two drugs—one for nerve gas and the other for cyanide poisoning—using this route. “One of the major regulatory hurdles may be getting the appropriate type of data from the appropriate animal models that would allow these drugs to be approved.”

Cleveland BioLabs has been trying to move its lead candidate, CBLB502, along this development path. The drug is an injectable recombinant derivative of a bacterial protein flagellin that activates signaling pathways and suppresses apoptotic cell death in hematopoietic and GI cells. The firm also is exploring CBLB502 as a radioprotectant in medical procedures. It has completed animal efficacy and human safety studies, and it has regulatory-compliant manufacturing.

Although BARDA, NIH, and the Department of Defense have backed Cleveland Bio­Labs’ ARS work, the company announced in April that BARDA had decided against the further funding it needs for advanced development. To address the government’s concerns about the development path for CBLB502, the company has been talking with FDA about its testing programs. On the basis of these discussions, Cleveland BioLabs says it can return to BARDA and other agencies to request support. BioLabs also has a 2010 contract that includes an option for DOD to make $30 million in purchases of the drug.

At Aeolus, McManus says its BARDA contract anticipates a regulatory filing at the start of 2016. “Most of the work done in the first 12 months of the contract was in the chemistry, manufacturing, and controls area,” he says. The company has also met with FDA to discuss the appropriate animal models.

Aeolus envisions being able to leverage the preclinical, toxicology, safety, and product development work for its commercial program, according to McManus. “Roughly one-third and up to a half of the contract value is in areas where we could use the data for MCM as well as our cancer indication,” McManus says.

Aeolus also anticipates that it could be granted an emergency use authorization in the second half of 2013. Such authorization allows for the use of unapproved drugs that might be effective when there’s no alternative. At that time, BARDA could buy the drug for the stockpile. Although BARDA has not yet said how much it would buy, because of federal threat assessments and the agency’s sizeable purchases of biodefense agents, McManus believes the opportunity could be quite large.

“It is risky, obviously, because you have only one customer, but it is a lot less costly to sell to them because you really don’t need a sales force,” he adds. Although the U.S. would lead in making purchases, countries such as Japan, South Korea, and Israel might follow. Eventually, sales could expand if the drug is approved for use in oncology to treat the side effects of radiation, which 50–60% of cancer patient undergo.

The U.S. government will probably be the first and main customer for prophylactic agents given before radiation exposure, points out John L. Zenk, chief medical and scientific officer at Humanetics, a specialty drug firm located near Minneapolis. Although BARDA generally looks for agents that can be used at least 24 hours after exposure, prophylactic measures could be given to military personnel, emergency responders, and people at risk of fallout.

Humanetics has been working with DOD’s Armed Forces Radiobiology Research Institute (AFRRI) to develop several low-cost, oral ARS agents, some of which are already approved drugs. Its lead compound, BIO 300, is a soy isoflavone called genistein. It has antioxidant properties and is being studied as a prophylactic measure.

BIO 300 works by locking stem cells into a resting phase of mitosis. “Since the stem cells are not rapidly dividing, they are not nearly as susceptible to harm or programmed cell death,” Zenk says. When the drug is no longer administered, the cells start dividing again. The company is also developing BIO 300 as a protectant during CT scans.

“We have been running the drug through the paces and doing survival experiments in mice primarily,” he says. A single injection, 24 hours before irradiation, protects about 86% of mice tested compared with 15% in a control group. “Funding permitted, we will soon be moving into large animals.” In June 2011, Humanetics got a two-year, $3.5 million BARDA contract to study BIO 300 as a treatment for lung damage.

Similarly, RxBio, a spin-off from the University of Tennessee Health Science Center, in Memphis, has been working with NIAID to promote cell survival and inhibit cell death in GI-ARS. In the small intestine, crypts and villi making up the mucosal barrier are anchored by stem cells that replenish these units every three to five days, explains RxBio CEO W. Shannon McCool. Rx100, a metabolically stable analog of lysophosphatidic acid, protects these stem cells.

“It seems to protect against pretty much anything that we have thrown at it,” he adds, including chemotherapeutics, radiation, and cholera toxin. For countermeasure purposes, Rx100 acts as both a radioprotectant and radiomitigator, working if given before exposure and up to 72 hours after, and at high radiation doses, according to McCool.

Late last year, RxBio graduated from the NIAID program, which had invested nearly $5 million in the firm, and is now working under a two-year, $15 million BARDA contract that has another $9 million in options. In April, DOD came on board to support some of the work. Besides testing, the company is working on manufacturing and formulation.

If successful at this stage, RxBio will be ready to move to the next level of BARDA funding by late 2013, which could take Rx100 through approval. In January, McCool says, the company had a “very productive session with FDA” and left with “the ability to start revising our studies to be more aggressive in terms of development.”

Meanwhile, Onconova Therapeutics’ ARS treatment strategy is to control intracellular signaling and DNA repair pathways. The firm’s Ex-RAD is a chlorobenzylsulfone derivative that works after free radicals have damaged DNA. CEO Ramesh Kumar believes this is a better approach than trying to scavenge free radicals. “Free radicals are very short-lived, and so the window of opportunity to give a drug is very narrow,” he says. In cell and animal models, Ex-RAD protects hematopoietic and GI tissues from radiation injury when given either before or after exposure.

Ex-RAD was initially developed through a $10 million collaboration with AFRRI. “We don’t have any active government support, and we are seeking money for the remaining development activities,” Kumar says. Although Ex-RAD has potential in oncology, “the development path would be very long and expensive for a small company, and that’s why it is so important we get government support. The funding will allow us to also carry the radiation therapy indication forward,” he adds.

Other agents are being developed by Apogee Biotechnology, which is getting $2 million over two years from BARDA, and Avaxia Biologics, which has a two-year, $2.9 million contract. Both firms will conduct preliminary efficacy studies to see whether their candidates work 24 or more hours after radiation exposure.

First developed to treat inflammatory bowel diseases, Avaxia’s AVX-470 oral anti-TNF antibody inhibits the effects of a tumor necrosis factor. Apogee’s ABC294640 inhibits sphingosine kinase, which regulates cell proliferation and activation. The Pennsylvania State University spin-off has been studying ABC294640’s antitumor activity for many years and working on radiation aspects for about three, CEO Charles D. Smith says. The company’s work with BARDA will look at GI-ARS.

Such contracts are written as a series of experiments that, after completion, undergo intensive reviews. “There is a lot of involvement of the sponsor, and that’s very good,” Smith says. “BARDA is obviously the expert in radiation biology, and they know exactly what FDA will be looking for in terms of applying the animal rule.”

However, it will still be a few years before any of these contracts are ready to bear fruit. Over the past five years, NIH’s radiation countermeasures program has interacted with more than 130 companies. In the coming five years, the agency plans to expand outreach efforts to both small and large drug companies. And BARDA continues to seek proposals, especially for products that could treat illness and injury from high levels of radiation.