Tough challenges for testing Ebola therapeutics

Abstract

At a briefing of United Nations officials on treating Ebola patients in western Africa with medicines and blood products in November last year, one question came up again and again: Why is it taking so long? Officials wanted to know why Ebola patients who have been evacuated to Europe or North America have had higher survival rates than those who remained in the outbreak countries, says scientist Martin Friede, who leads the technology transfer team at the World Health Organization (WHO) in Geneva. of these patients had received a whole range of drugs--everything and the kitchen sink--but I explained to them that we don't know what helped them to recover. Was it the clinical care? Was it the kitchen sink? he says. That's why we must do clinical trials to find out which drugs are safe and effective in these patients, says Friede, a former vice-president of development at California biotech company Apovia Inc., who joined WHO in 2003. Since WHO announced news of the Ebola outbreak in Guinea last March, the United Nations health agency has received more than 200 proposals of all kinds of therapies to treat Ebola virus disease suggestions. Some suggestions--such as ingesting vulture gastric juices and plant root extracts or wearing magnets--were rejected for their lack of scientific evidence. Others, including some drugs already licensed for other diseases, as well as novel drugs specifically aimed at Ebola that are under development, have been given to Ebola patients on compassionate grounds. far, however, there are no definitive data available to suggest that these interventions are either effective or safe in Ebola patients. Given the urgent need for additional therapies for Ebola--currently the only recommended management is replacement of fluids and electrolytes, and good control of symptoms--WHO is taking the lead in a major international drive to test potential therapies. Since August, the UN agency has organized a series of meetings of experts to review the pipeline of potential therapies for Ebola virus disease. As of 13 January, there were 21 373 cases and 8468 deaths in Guinea, Liberia and Sierra Leone, the three countries worst affected by the epidemic. Past Ebola outbreaks were often small, confined to one community, and halted quickly by detecting and isolating cases, identifying contacts and safely burying the deceased--reasons why drug development for Ebola stalled in the past. Clinical trials of potential therapies for Ebola can only be conducted during an outbreak, but there are enormous challenges with this. We identified only three products that work in the test tube and also give 100% protection in infected monkeys: ZMAPP (a cocktail of monoclonal antibodies), small inhibitory RNA, and anti-sense phosphorodiamidate morpholino oligomers, all targeting Ebola. [ILLUSTRATION OMITTED] But we don't know whether these are safe or effective in Ebola-infected patients and current supplies are nonexistent or limited to quantities that are sufficient only to conduct very small clinical trials, Friede says. So we drew up a short-list of repurposed drugs--i.e. ones developed for other conditions--including favipiravir, brincidofovir, toremefin and interferons, and we are continually reviewing this list as fresh data comes in on other drugs. With these repurposed drugs, there is less problem with supply, but a lack of clinical evidence of their effect against Ebola, Friede says, adding that testing these drugs in animals infected with Ebola is hampered by the fact that they must be done in participating biosafety-level 4 laboratories, of which there are only a handful in the world. Each of these facilities can only handle a small number of animals at a time. Favipiravir was developed by a Japanese company, Toyama Chemical, to treat influenza and some other viral infections and is being tested in Guinea for safety and efficacy in Ebola-infected humans by a team from the Institute of Health and Medical Research (INSERM) and Paris Diderot University in France. …