A historic clinical trial has shown that two therapies made from antibodies harvested from Ebola survivors appear to be improving survival rates among people who receive them, health officials announced Monday. The announcement marks the first time a clinical trial has successfully shown that an Ebola therapy improves survival in people who have been infected.
Two other therapies used in the clinical trial performed less well and will be discontinued.
The therapies that have improved survival rates are REGN-EB3, a cocktail of three monoclonal Ebola antibodies made by Regeneron Pharmaceuticals (REGN), and mAb114, a single monoclonal antibody developed by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. The clinical trial will continue comparing these two drugs in Ebola treatment centers in the Democratic Republic of the Congo.
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“It means that we do have now what looks like treatments for a disease which not too long ago we really had no therapeutic approach at all,” said Dr. Anthony Fauci, director of NIAID.
“We feel that with agents such as these … that we may be able to improve the survival of people with Ebola and … might even make people more enthusiastic about coming for care,” he said. “Because when you have something to offer an individual, it makes it much more likely that you might get to them early. And the earlier the better, as in any disease.”
A number of clinical trials were started near the end of the 2014-2016 West African Ebola outbreak, but they either revealed that proposed therapies did not work or failed to reach a result before the outbreak ended.
One of the drugs tested in West Africa, ZMapp, had shown a signal that it was improving survival, but the outbreak ended before the trial could conclude. In the current clinical trial, called the PALM study — the acronym stands for Pamoja Tulinde Maisha, which is Swahili for Together Save Lives — three therapeutics were tested against ZMapp.
The original plan for the trial involved enrolling 725 patients. But the trial’s data and safety monitoring board, which has conducted sporadic reviews of the data, analyzed findings based on 499 patients late last week.
That analysis showed REGN-EB3 was performing better than ZMapp at statistically significant rates, doing well enough that it crossed a pre-established threshold that requires altering the protocol of the study. Close behind was mAb114, which will be developed by Ridgeback Biotherapeutics. The antiviral drug remdesivir, made by Gilead, underperformed ZMapp.
The board decided the trial should be revamped to test REGN-EB3 and mAB114 against each other. Remdesivir and ZMapp have been dropped from the trial.
The clinical trial was conducted at Ebola treatment centers in Beni, Katwa, Butembo, and Mangina, all hotspots at various points in the outbreak. Patients who are cared for in treatment centers that are not involved in the trial have been receiving the drugs under compassionate use protocols. Going forward, only the two drugs will be used in those circumstances as well.
Dr. Sumathi Sivapalasingam, Regeneron’s medical lead on the REGN-EB3 project, said the company was in a state of shock. They had expected the drug to work, she said, but were still surprised at how well it performed vis-à-vis the other therapies.
There were only limited and preliminary data available at this point. But they showed mortality rates of 49% in people treated with ZMapp, 53% in those who received remdesivir, 34% in people treated with mAb114, and 29% for people who received the Regeneron cocktail. The fatality rate for the outbreak as a whole is 67%.
Leah Lipsich, Regeneron’s vice president for strategic program direction, said the company believes it has adequate supplies of REGN-EB3, with current stock “in the high hundreds” of doses, with another round of production about to start.
The NIH has about 300 doses of mAb114 at the moment, Fauci said, with addition product coming available in early September.
To date more than 1,400 people have received one of the experimental therapies.
The results put into question the future of ZMapp, the first monoclonal antibody preparation to be used to fight Ebola.
Mapp Bio President Larry Zeitlin would not immediately comment on what the finding mean for ZMapp. “We look forward to reviewing the data, and more importantly, hope resources continue to be mobilized to end the outbreak as quickly as possible,” Zeitlin said in an email.
A statement from Gilead said the company remains committed to studying remdesivir as a possible treatment for Ebola and other emerging viral diseases. “A full analysis of the PALM trial data will help to inform future study [and] use of remdesivir. Potential learnings may include insight into the impact of viral strain and severity of disease progression on treatment strategies and the potential for both single agent and combination treatment approaches,” it said.
The new results are based on a trial that was started last November. At the time, it was thought that it might take multiple Ebola outbreaks before researchers had enough data. It was designed to be a rolling trial that could incorporate data from future outbreaks in other countries, if needed.
But the ongoing outbreak in the Democratic Republic of the Congo, now in its second year, has been so large there were enough patients enrolled to come up with answers.
The outbreak, occurring in the northeastern provinces of North Kivu and Ituri, is the second largest on record. To date, 2,831 people have been infected with the virus, and nearly 1,900 have died.
Dr. Jean-Jacques Muyembe, director of DRC’s National Institute of Biomedical Research, and the first scientist to propose using blood from Ebola survivors to help people suffering from the disease, said for years he could not have imagined the development announced Monday, predicting thousands of lives will be saved in future Ebola outbreaks.
