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Ebola Drug Race Ramps Up in Earnest

When it started developing an Ebola drug in 2010, Tekmira Pharmaceuticals Corp. wasn’t counting on finding infected humans to test it in. Instead, the company planned to seek approval based on animal studies, which regulators sometimes allow.Now the current outbreak in West Africa is presenting Tekmira and other drug makers with thousands of potential patients desperate for treatment—and setting off a rush among companies and health officials to find anything that might work.“We’re now faced with a situation that none of us ever anticipated, and that is the possibility that you could collect efficacy data in actual humans,” said Mark Murray, chief executive of Tekmira, a 100-person firm based in Vancouver, Canada.There are no drugs on the market today designed specifically to treat Ebola. Without one, doctors in West Africa have largely been treating patients’ symptoms—which include fever, vomiting and diarrhea—and trying to replace the body fluids they lose. Several Western and African patients have been given experimental treatments, including from Tekmira, Mapp Biopharmaceutical Inc. and Chimerix Inc., with the hope they might be effective.The companies are rushing to increase production of these experimental drugs and to expedite clinical trials in infected patients. Other drug makers are scanning their chemical libraries for drugs that might attack the Ebola virus. Some doctors have tried giving infected patients the blood plasma of people who have recovered from the disease, because it contains antibodies that could help fight the virus.The National Institutes of Health, the Food and Drug Administration, and other parts of the Department of Health and Human Services are helping coordinate and fund the efforts. The Bill & Melinda Gates Foundation has pledged $50 million to support emergency efforts to contain the epidemic, including investments in drugs, vaccines, diagnostics and blood plasma. But while human studies of drugs and vaccines are getting under way, it isn’t clear the efforts will yield quantities of an effective therapy in time to make a big difference in the current epidemic. Health authorities instead are looking more seriously at survivors’ blood plasma as a short-term solution, and the World Health Organization has issued guidance on its use on patients in West Africa.The pharmaceutical industry has invested relatively little in Ebola research since the first known outbreak in humans in 1976. Most outbreaks have been sporadic and limited in scope, and have occurred in poor countries, limiting the commercial appeal of developing a treatment.But the current outbreak—the worst ever, with at least 4,400 deaths—has heightened the sense of urgency. FDA Commissioner Margaret Hamburg said the agency has shifted more employees to help speed the development of drugs, vaccines and diagnostics. “We’ve been up in the middle of the night in order to make product available” on an emergency basis to infected patients in the U.S., she said in an interview this week. The agency also is helping shape the design of clinical trials.“My hope is that we will be able to get some meaningful answers in the time frame of this outbreak, which sadly is not going to resolve in the immediate near term,” she said. “I think we certainly want to be better equipped for the next outbreak, as well.”Even companies that haven’t been active in Ebola research are diving in. Merck & Co. is screening its library of chemical compounds, including experimental antivirals, to see if any could be effective, said Julie Gerberding, a former director of the U.S. Centers for Disease Control and Prevention who now heads Merck’s vaccines division.CSL Ltd., a maker of plasma-based therapies, said it is exploring whether it can develop a plasma treatment, at the request of the Gates Foundation. The idea would be to collect antibody-rich plasma from people who have recovered from Ebola, purify it and develop it into a “hyper-immune” product that could be transfused into patients, said Chief Executive Paul Perreault.“Technically, we can do it,” but the logistics could be difficult, he said, requiring Australia-based CSL to collect large amounts of plasma donations in West Africa. CSL would likely then send the plasma to its facilities in Switzerland for processing, then ship the final product back to Africa, he said. A handful of companies have been working on Ebola treatments in recent years, building on government-funded research that has sought to understand the virus’s structure and vulnerabilities. An expert panel of the World Health Organization is deciding which of these treatments to test in a clinical trial in infected people in West Africa. A consortium including the WHO, the University of Oxford and others is currently identifying sites in West Africa for fast-tracked clinical trials with a £3.2 million grant, or about $5.15 million, from the U.K.’s Wellcome Trust. One challenge: to identify a trial design that is acceptable to governments, regulators, clinicians and patients with a deadly disease, said Piero Olliaro, senior research manager at a special program for research and training in tropical diseases at the WHO. “The moral imperative now for all of us is to study these drugs in the best way possible in West Africa without further delay,” he said Another problem: Some of the experimental drugs are in short supply.Tekmira’s inventory of its drug, TKM-Ebola, is “limited,” Dr. Murray said, but the company is taking steps to increase production. If Tekmira’s approach is chosen for the planned trials in West Africa, the company expects to modify its drug to target the specific viral variant of Ebola responsible for this outbreak and expects to have a sufficient supply.TKM-Ebola is designed to throw a wrench into the Ebola virus’s replication process, allowing the body’s immune system to catch up with the virus and destroy it. Tekmira received a $140 million Defense Department contract in 2010 to develop the drug, and carried out some research with the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Md., which develops ways to protect service members from biological threats.Tekmira said TKM-Ebola has shown efficacy in studies of Ebola-infected animals. With the FDA’s permission, the company said, it has given the drug to “a small number” of infected people in recent weeks. The company didn’t specify how many. Dr. Murray said it was premature to make any conclusions about TKM-Ebola’s effects on the infected patients. “We are responding to a compassionate use, we’re cooperating with the physicians and FDA. But I don’t think we’re in a position to draw conclusions about the activity of the drug,” he said.Clinical trials of another experimental drug—ZMapp from Mapp Biopharmaceutical—could get under way in West Africa in January or February, said Alan Magill, who heads the Gates Foundation’s malaria-eradication efforts and is now also overseeing Ebola-related investments. The drug has been provided to seven infected patients on an emergency basis but hasn’t yet been studied in human clinical trials. ZMapp protected 100% of 18 monkeys infected with Ebola, while three monkeys that didn’t receive ZMapp died from the virus, according to study results published in the journal Nature in August.Testing the drug in 25 to 50 people would “probably be enough to let us know whether these products are going to work,” Dr. Magill said. Designing a trial is ethically complicated. A randomized controlled trial in which some patients are given ZMapp and others a placebo isn’t realistic in the current epidemic, so investigators must come up with other solutions, he said. “We have to balance the correct scientific answer with what is reasonable and feasible,” he said. Mapp exhausted supplies of the drug in August, when it was given to seven American and non-American patients. It is now rushing to make more, but the process is complicated. The drug is manufactured by infecting tobacco leaves with proteins, which proliferate as the plants grow. The proteins are then extracted and turned into ZMapp. The process takes several weeks.Mapp said earlier this month that it was attempting to expand its tobacco-growing facilities, and was working with the Gates Foundation and an outside pharmaceutical partner to manufacture the antibodies in Chinese hamster ovary cells instead of tobacco plants. One challenge to overcome with that approach, though: One of the antibodies in the drug doesn’t reproduce as well in animals as in plants.The Gates Foundation also is helping Mapp determine the best dose for the drug. If two doses rather than three prove effective, that would help stretch limited supplies, Dr. Magill said. The foundation has specialists examining the drug’s effects in nonhuman primates, and the data available on the seven human patients who received it, five of whom survived, he said.The drug could be tested on patients in one or two treatment centers or other facilities in West Africa that are well staffed, said Dr. Magill. But he cautioned that the ultimate decision on how and where ZMapp is tested will be made together with the WHO and the countries themselves.Several patients in Western hospitals have received experimental drugs that were designed to fight viruses other than Ebola. FujiFilm’s Avigan antiviral, marketed as a flu treatment, has been given to several infected patients, including an Ebola-infected nurse in France, who recovered. Fujifilm said it plans to cooperate with a request from French and Guinean officials for supplies of the drug, to be used in a clinical trial of Ebola patients in Guinea that may start in November. The company said it has supplies for more than 20,000 patients. And brincidofovir, a drug from Chimerix primarily designed to treat cytomegalovirus and adenovirus, has been given to at least two Ebola-infected patients: Thomas Eric Duncan, a patient in Dallas who died; and Ashoka Mukpo, who is being treated in Nebraska. When Phil Smith, medical director of the biocontainment unit at the University of Nebraska Medical Center, admitted his two Ebola patients, ZMapp was no longer available. So he had some research to do. He said he read medical literature, consulted with a clinical coordinator at the CDC, and talked with other doctors who have treated Ebola patients in Western hospitals.“There’s a lot of art to it, and people are exchanging information,” he said. He chose brincidofovir for Mr. Mukpo, he said, because it had worked in a test tube and appeared to be a safe drug.Chimerix said this week that it plans to begin a clinical trial “immediately” in Ebola-infected patients in the U.S. and Europe.The company said it believes it has an adequate supply of the tablets, and it plans to continue making the drug available on an emergency basis in the U.S. and Europe, as well. Chimerix is in talks with U.S. government agencies and international organizations “to determine the best way forward to evaluating whether brincidofovir is effective in the West African theater,” said the company’s chief medical officer, Garrett Nichols.The company said it sent brincidofovir to the CDC and the National Institutes of Health as the West African outbreak began this spring, to be tested for activity against Ebola virus. The test-tube evaluations appeared to show the drug could eliminate the virus from cells, Chimerix said. The drug has already been tested in human clinical trials to treat cytomegalovirus and adenovirus, but regulators haven’t yet approved it for sale.

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