Ebola virus disease has infected more than 10,000 people in West Africa and killed nearly 5,000, and the epidemic continues. Yet for those caught in this historically deadly outbreak, no anti-Ebola virus medicines have yet been approved by national authorities for human use.
The lack of Ebola virus drugs, or therapeutics, has to do with the illness’s relative rarity, which provides little incentive for pharmaceutical companies to spend money to develop and manufacture them and apply for Food and Drug Administration approval.
But one organization whose scientists have spent decades working on diagnostics, vaccines and therapeutics for Ebola virus and other deadly pathogens doesn’t care about making a profit from its products. At the U.S. Army Medical Research Institute of Infectious Diseases, the mission since 1969 has been to protect warfighters from biological threats and to be prepared to investigate disease outbreaks or threats to public health.
Last week, at USAMRIID in Frederick, Maryland, DoD News interviewed Dr. Travis K. Warren, a principal investigator in the Division of Molecular and Translational Sciences; Army Maj. (Dr.) Matthew Chambers, chief of field studies in the Division of Medicine; and Dr. John M. Dye Jr., Viral Immunology branch chief.
“No private company is going to undertake that kind of an endeavor,” Chambers explained, “because it could go all the way to animal studies and [then] they've just spent hundreds of millions of dollars and the whole thing could crash when they get to human trials. But we can take on that burden and field something that looks very promising, and take it to the field and get it into human beings.”
Not a billion-dollar market
Even now, with more than 10,000 confirmed and suspected Ebola cases worldwide, Warren added, “from a pharmaceutical perspective … this is not a billion-dollar market we're talking about.”
In its work developing medical countermeasures, USAMRIID's therapeutics program focuses on broad-spectrum antiviral and antimicrobial drugs against multiple biological agents, including the Ebola and Marburg viruses. Both viruses are filoviruses, which belong to a virus family called Filoviridae and can cause severe hemorrhagic fever in people and nonhuman primates.
In their work with therapeutics and vaccines, USAMRIID scientists move the products toward FDA approval by conducting nonclinical trials using “the animal rule.” Under this rule, designed in part for biodefense drugs and vaccines, products can be considered for FDA licensing using data from animal studies when it’s too dangerous or simply not possible to conduct clinical trials in people.
Chambers and others expect the availability of drugs that can help Ebola patients to be limited in the current outbreak.
“Some therapeutics may be applicable, but … we're kind of in a sticking-our-finger-in-the-dyke phase right now,” Warren said.
Medicines that do gain regulatory approval during the current outbreak, the chief of field studies said, will be produced in small quantities and used on a relatively small scale to treat Defense Department personnel returning from deployments to West Africa to help in controlling the outbreak, as well as health care workers involved in the effort.
“It's difficult to imagine a scenario where we have widespread treatment of individuals in Liberia” and other countries severely affected now by the outbreak, he added.
Investigating all therapeutic options
In the meantime, Warren said, USAMRIID is investigating all therapeutic options to counteract Ebola virus.
“We have a number of high-profile products that have been discussed in the media, and we are further investigating whether or not they can and should be used in the context of this current crisis,” he said. Especially over the past three months, he noted, organizations have approached USAMRIID about potential products they want to explore, and the institute is looking into every one.
One product USAMRIID helped to develop is in Phase 1 clinical trials: TKM-Ebola, an Ebola antiviral drug from a company called Tekmira. Tekmira conducted studies on the drug in 2010 to 2013 with USAMRIID, and the DoD Joint Project Manager Transformational Medical Technologies Office, now called Medical Countermeasures Systems, contributed to funding.
In 2010, Tekmira signed a $140 million contract with DoD to advance an RNA-interference, or RNAi, drug designed to eliminate the production of disease-causing proteins. The drug uses Tekmira’s lipid nanoparticle, or LPN, technology to deliver the Ebola drug to tissues in the body. In 2013, the collaboration expanded to include advances in LNP formulation technology, and in March, the FDA granted Tekmira a fast-track designation to develop the TKM-Ebola antiviral.
“Tekmira is one therapeutic [for which] the product supply is the primary missing factor, and there are some questions about human safety as well,” Warren said. “But we have been working with Tekmira for many years and have already demonstrated the product’s efficacy.”
Product supplies are a problem for another drug called ZMapp from Mapp Biopharmaceutical, he added.
“We have a study going on right now with ZMapp in nonhuman primates, and we've been doing ZMapp studies with earlier versions of ZMapp for years here at USAMRIID,” Dye said.
An experimental treatment
ZMapp, an experimental treatment for Ebola patients, is in Phase 1 clinical trials, but it has not yet completed testing in people for safety or effectiveness. The drug is a cocktail of three different monoclonal, or genetically engineered, antibodies that bind to an Ebola virus protein.
The concept of using antibodies to help Ebola patients also was the basis for an ongoing project Dye began four years ago in Uganda. The project looks at the immune systems of Ebola survivors to understand how the systems change over time and how they respond to different parts of the Ebola virus.
“We’re doing studies to look at their neutralizing antibody levels, [and] we're looking at T-cell responses [and at] other cells in the immune system, … because we have vaccines and therapeutics that we want to mimic that immune response,” Dye explained.
The idea, he added, is “can we take a survivor's B cell that produces an antibody that we know protected that person, fuse it with a cancer cell so it produces the antibody forever, and make large quantities of that antibody and then put it back into humans? That’s exactly what ZMapp is.”
ZMapp has been used compassionately in a few Ebola patients, Dye said, but the number is too small to allow an assessment of safety or efficacy. “Multiple government agencies have infused a large amount of money in the production of ZMapp and other therapeutics in bulk quantities by different mechanisms to try to develop a large base of the therapeutics for future use,” he added.
No product satisfies optimal requirements
Warren said an optimal drug product for Ebola is one for which there is a ready supply, human safety data exists, and substantive efficacy has been demonstrated at least in nonhuman primates.
“Right now, no products fully satisfy those requirements,” he said, “so USAMRIID is making successful efforts to fill those gaps, primarily in the realm of efficacy,” or effectiveness.
Warren said the Ebola crisis, which would have been hard to imagine as little as six months ago, has been a wake-up call for the filovirus community and for the world that the Ebola virus, despite preparations that have taken place over many years, can present a real problem.
But the outbreak has offered an opportunity for scientists to understand how well potential therapeutics work in human patients rather than in monkey studies alone, he added.
Chambers said the outbreak inevitably will usher in a new Defense Department mindset for therapeutic development.
A real wake-up call
“We've focused almost exclusively on filoviruses up to this point from the standpoint of protecting against the potential deployment of a bioweaponized version of filovirus,” Warren said. “I think [the Ebola crisis] has been a real wake-up call that there is another distinct way DoD should be prepared for filoviruses to enter the United States and potentially infect medical personnel and the population at large.”
Warren said USAMRIID has been doing work with Ebola virus for many years, and while he’s not sure the institute was ready for the outbreak, it was prepared.
“We had teams in place to do the efficacy assessments we needed, and we are responding rapidly to new potential therapies that are being introduced and developed,” he said, adding that the many individuals who are part of USAMRIID “all are working very hard to come up with solutions to the current outbreak.”
(Follow Cheryl Pellerin on Twitter: @PellerinDoDNews)