When it comes to treatments for Ebola, there has been a nearly four-decade-long drought. Nothing in the medical arsenal attacks the virus directly. For the most part, patients receive only supportive care, offered at a minimum level if too few health-care workers struggle to keep too many patients alive.
The current extraordinary outbreak in West Africa provides, really for the first time, a chance to change that. This, the largest outbreak on record, presents an opportunity to test some therapies in the hopes that those caring for future Ebola patients will never again despair at the fact that the best they can offer is a bed, fluids, nutrition and human kindness.
But that drought could give way to a free-for-all if the world is not careful, some experts worry. Driven by the enormity of this epidemic and the prospect of months more to come, there is a sharp desire in some quarters to try almost anything that might help.
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It is not a position all endorse. “I think we have to go forward based on scientific evidence, not on belief,” says Martin Friede, the World Health Organization’s team leader for work on experimental Ebola drugs. “There are situations where doing nothing is actually better than doing something that is not justified.”
Drug shortages
The drugs people really want to test are not currently available in sufficient quantities to run clinical trials in West Africa. And that status will not change anytime soon.
The monoclonal antibody cocktail ZMapp gained nearly mythical status last summer when Kent Brantly, an American missionary doctor infected with Ebola in Liberia, became the first person to receive the treatment. Media reports suggest Brantly, gravely ill when his first transfusion started, improved rapidly, getting up to shower the next day. There were fewer than a dozen treatment courses (three transfusions equal one course) in existence when Brantly was treated; within a couple of weeks, they were gone.
The three antibodies in the cocktail—developed by researchers at the Public Health Agency of Canada’s National Microbiology Laboratory and the U.S. National Institute of Allergy and Infectious Diseases—are generated in genetically modified tobacco plants by Kentucky BioProcessing for license holder Mapp Biopharmaceutical. Kentucky Bio can produce enough antibodies for between 17 and 25 treatment courses per batch; it takes 12 weeks to grow the plants and a couple more to process the material.
Efforts are afoot to try to substantially ramp up ZMapp output. The Biomedical Advanced Research and Development Authority (BARDA), tasked with meeting America’s vaccine, drug and diagnostic needs during public health emergencies, is considering bringing on board another producer, a move that could potentially increase ZMapp output four- or fivefold, says director Robin Robinson. In addition, researchers are conducting studies in nonhuman primates to determine whether the number or volume of the infusions in a treatment course could be reduced, allowing supplies to be stretched.
The other leading therapeutic is the small interfering RNA drug TKM-Ebola, made by Tekmira Pharmaceuticals. The Vancouver-based company had in hand a modest number of doses when the outbreak took off; it had commenced phase 1 human trials on the drug.
That work—designed to determine if TKM-Ebola is safe and what a dose should entail—is actually on a partial clinical hold because the U.S. Food and Drug Administration raised concerns about some of the safety data. Still, the drug can be released under “emergency use” rules, and it has been given to a small number of confirmed or suspected Ebola patients who have received care in the U.S. or Europe. Tekmira says clinical trials in West Africa are planned for the first half of next year.
Dangerous enthusiasm
But the lack of Ebola-specific treatments has not deterred the search for magic bullets—or ammunition of any sort. To the contrary: The drug vacuum, coupled with the severity of this outbreak, has inspired a curious phenomenon. Everybody and his uncle, it seems, has an idea of something that might work to cure people infected with the deadly virus.
A tsunami of treatment proposals has flooded the in-boxes of staff at the WHO and research funding agencies. Silver nanoparticles. Cholesterol-controlling statins. A breast cancer drug. Intravenous ozone. Vulture gastric fluids. An influenza antiviral. Interferon. Almost anything you can think of is being advocated as a potential Ebola curative, often with few or no data to support the case.
Some of the suggestions are easy to strike from the list, says Friede. For example, there will be no WHO-led push to see if exposing infected blood to ultraviolet light will cure the disease. Likewise, vultures can rest easy.
But the vast majority of the proposals are not in the readily dismissed class. Many are being proposed by scientists who hypothesize if a certain drug treats such and such a symptom in the course of one disease, it may well do the same for Ebola patients.
“The problem then is that there are hundreds of these.... People say, ‘This is an antiviral. Ebola is a virus. Therefore we should try this.’ Now, that’s a bit of a jump,” Friede says, noting relatively few scientists understand the Ebola disease course thoroughly.
The scientific quest for an at-hand answer to a horrible outbreak could actually waste time and resources and potentially endanger lives. Some people have argued that there is no time to test if licensed drugs that might work against Ebola are protective and safe in animal studies; they advocate using them in patients because of the disease’s high death toll. The WHO is powerless to stop that kind of study, Friede admits. If a researcher can get financial support for a trial and secure regulatory agency approval in an Ebola-affected country and persuade staff in an Ebola treatment unit to go along with the idea, this kind of study could happen.
And will, it seems, despite the WHO’s reservations. Italian doctors announced last week they will test the antiarrhythmia drug amiodarone at a treatment center in Sierra Leone. The drug has some action against Ebola virus in the test tube, but the fear is that the concentrations required for it to have an effect might be unsafe in people. Friede has reached out to the principal investigator to convey those concerns.
The situation underscores how poorly served science is when researchers do not write up negative study findings, or journals choose not to publish them. Many of the compounds being proposed have been tested against Ebola in vitro or in animal models already, but there may be no evidence of the work in the literature. Repeating the research—or worse, taking one of these failed compounds directly to the field to test in people—would be wasteful and potentially unwise.
In this respect, the small size of the Ebola research community is an advantage for those who want to forestall that possibility. Ebola research must be done in laboratories with the highest degree of biosafety and biosecurity, BSL-4, and there are not many of them around. The WHO’s Scientific and Technical Advisory Committee on Ebola Experimental Interventions is working with those labs to draw up a list of compounds that have been studied. They plan to publish a registry on the global health agency’s website, listing compound, testing method and results. The hope is this will prevent duplication of work that is unlikely to bear fruit.
Next steps
So what will be tested? In the first round, starting in December, three therapies will be studied; two are drugs and the other is transfused blood from Ebola survivors. These studies will start in Ebola treatment units operated by Médecins Sans Frontières (MSF, known as Doctors Without Borders in English) in Guéckédou and Conakry, Guinea, and in a third site yet to be named.
The drugs are antivirals, though not specifically designed to target Ebola. Favipiravir, an influenza drug also known as T-705, is licensed in Japan for use against novel influenza strains. In test tubes and in mice, the drug shows some inhibitory activity against Ebola virus—although the rodents are not the most reliable of animal gauges. There has been some testing in nonhuman primates, but those results have not yet been published. Still, with this degree of evidence and the fact of an available drug, the WHO committee felt favipiravir should be tried.
The other is an antiviral called brincidofovir, which is in development for treatment of cytomegalovirus and adenovirus infections. It works against Ebola in vitro but cannot be tested in nonhuman primates; they lack an enzyme needed to metabolize the drug, Friede says.
The MSF trials will not be placebo controlled; the group shares the views of a number of experts that randomly assigning some people to forgo a treatment that might improve their survival chances is not acceptable under the current circumstances. “MSF does feel that at this stage it will be ethically and operationally very challenging to have an RCT”—randomized controlled trial—“in one of our settings,” says Annick Antierens, who is heading the organization’s work on experimental Ebola drugs.
Those who oppose placebo-controlled trials for Ebola patients hope instead that comparing outcomes from treated patients to those who were previously cared for in the same facility will show if a drug being tested increases survival rates. But that may be challenging. If care has improved because patient numbers have dropped, survival rates could rise on their own. A drug that does nothing might look like a winner.
That may not be merely a theoretic possibility. The mortality rate seems to be dropping in some locations. Centers that reported losing 70 percent of their patients are now seeing half survive. “Nobody can actually currently explain why, because it does not appear to be due to better care being available,” Friede says, noting that for trials without control arms, “this creates a real challenge.”
Survivors’ blood
The trial at Conakry, the Guinean capital, will test whether the blood of survivors can help Ebola patients overcome their illness. In theory, it should: the acquisition of antibodies through blood transfusion works for some other diseases. And this technique has been used previously, during a 1995 Ebola outbreak at Kikwit, in what is now the Democratic Republic of Congo. Eight patients received blood from Ebola survivors; seven lived.
But Ebola experts have long disputed that the transfusions contributed to the patients’ survival. The transfusions were given late into the disease course; patients who do not succumb early tend to survive. And convalescent serum does not save primates from Ebola. “The data is just foggy,” says Luciana Borio, who leads the FDA’s Ebola response.
Still, it is something the WHO and others have pushed, a therapy they believe is worth testing. There was hope the project could have gotten off the ground weeks ago. But even something as seemingly simple as blood transfusions is complex in countries where health-care systems are in disarray. “Yes, it’s frustrating. You want to move quicker. But this is just the reality of the situation that we're facing,” says David Wood, the WHO’s lead on the convalescent blood project.
There is huge stigma attached to Ebola, and it is not clear how willing survivors will be to step forward to donate blood. “We are planning that there will be a trickle rather than a flood to start with,” Wood says.
There are other challenges. Few Ebola treatment units can provide the consistent care to do clinical trials. And case counts wax and wane. This month’s hot spot may have few patients next month when a trial begins. Says Friede, “This outbreak is like quicksand. It’s continually moving.”
Simple things researchers take for granted—access to a tablet or laptop for entering data while assessing a patient—are anything but easy in Ebola treatment units. Only items that can be decontaminated can be taken out of the hot zones in these centers. That rules out tablets, smartphones, even pieces of paper. Some health-care workers have reported devising systems in which someone on the inside holds a piece of paper containing patient data up to a window or aperture while someone on the outside takes a photo, thereby capturing the data.
As well, these units cannot run the gamut of blood tests researchers would normally need to assess a drug or therapy in clinical trial in the U.S. or Europe. Given these complexities, it is little wonder that the WHO’s Scientific and Technical Advisory Committee is urging use of a standardized minimum data set, to ease the demands on treatment centers while still generating evidence that could be compared from one location to the next.