One of the highly anticipated trials of an Ebola drug that showed promising results in monkeys has been stopped early after it apparently failed to show a benefit to patients.
The company that developed the drug, Tekmira Pharmaceuticals of Burnaby, Canada, and the Wellcome Trust, which sponsored the trial, announced today that they would not enroll any more patients because the trial had reached “a predefined statistical endpoint.” Early results suggest that adding more patients to the study “was unlikely to demonstrate an overall therapeutic benefit to patients,” the Wellcome Trust said in its statement.
Scientists still have to analyze the data collected to learn more about how well the drug, called TKM-Ebola-Guinea, was tolerated and what specific effects it had on disease outcomes, says Peter Horby of the University of Oxford in the United Kingdom, who headed the study. The trial, which started in March in Port Loko, Sierra Leone, aimed to enroll 100 patients. The company did not say how many patients had been enrolled so far.
The drug faced several hurdles in the trial, says Thomas Geisbert of the University of Texas Medical Branch in Galveston, who tested TKM-Ebola in monkeys and found it protected all three of the animals that received it from an otherwise lethal dose of Ebola. TKM-Ebola-Guinea is a set of small RNA molecules packaged in lipid nanoparticles. The RNA interferes with three Ebola proteins and prevents the virus from replicating. Geisbert says the lipid nanoparticles used in the human trial are an older formulation than the one in the recent monkey trials. The older version protected only about half the monkeys in earlier tests, he says. “You’re comparing apples and kumquats,” he says. But the new formulation hadn’t been through phase I safety trials in humans and so couldn’t be used in Ebola patients.
The design of the trial was also a challenge, Geisbert says. Many say that assigning patients to a placebo arm is not ethical, so the TKM-Ebola trial was a so-called single-arm study in which everyone at a treatment center receives the drug and their survival is compared with patients at centers not involved in the trial. But that makes outcome data very hard to interpret, Geisbert says. “You can’t draw any reasonable conclusions. I doubt that anything comes out that is going to say one way or another” whether the drug benefits patients. The trial’s end shouldn’t be the end of the drug, he says. “If you can’t get an answer, and then you want to kill the drug? That’s crazy.”
The other drug seen as the best shot at fighting Ebola, the antibody cocktail ZMapp, is still being evaluated in a trial. The National Institute of Allergy and Infectious Diseases (NIAID) launched the trial in February in Liberia and the United States. It later expanded to Sierra Leone and is about to enroll patients in Guinea as well, says Anthony Fauci, who heads NIAID, located in Bethesda, Maryland.
The ZMapp trial is a different design from the TKM-Ebola trial. It randomly assigns patients to receive either three infusions of ZMapp plus supportive care or only supportive care, which includes intravenous fluids and treatment of secondary infections. Fauci is optimistic that the ZMapp trial will yield a clear answer. More than 30 patients have been enrolled already, he says. “We are likely to need many more patients than that to get a result, but less than 100.” With Guinea added to the trial, that goal should be reachable, he says.
*The Ebola Files: Science and Science Translational Medicine have made a collection of research and news articles on the Ebola virus and the current outbreak freely available to researchers and the general public.