A trial of four experimental Ebola treatments carried out in the Democratic Republic of the Congo (DRC) has been stopped early after two of them showed strong signs of being able to save patients’ lives, says a Science Mag report. The preliminary results were reported by Dr Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, one of the partners in the study. The two treatments will now be made widely available and could help end the yearlong outbreak in the DRC, which has already killed more than 1,800 people, scientists say.
The PALM trial (short for the Swahili expression pamoja tulinde maisha, which means “together save lives”) evaluated three Ebola antibody preparations and one antiviral drug in a randomised controlled trial conducted in the midst of the devastating outbreak, which has hit two provinces in the eastern DRC mired in violence. “Today, we have started a new chapter. From now on, we will no longer say that Ebola is not curable,” Jean-Jacques Muyembe-Tamfum, head of the DRC’s National Institute for Biomedical Research in Kinshasa, a partner in the trial, said. “This advance will, in the future, help save thousands of lives.” (Muyembe, who was part of the team that discovered Ebola 43 years ago, took over command of the outbreak response in the DRC on 22 July.)
Jeremy Farrar, head of the Wellcome Trust in London, concurs: “This will undoubtedly save lives,” he said. “In the middle of the worst possible conditions, a very solid clinical trial was done that has given us very important information,” Fauci is quoted in the report as saying. “And the beauty of it is that you can now immediately apply it in the field.”
So far, no drugs exist for Ebola; in the current outbreak, two-thirds of all known patients have died. Scientists have tried to treat the disease with existing drugs and develop new treatments tailored to the virus. One of these, the antibody cocktail ZMapp, was hailed as a potential game changer during the West African epidemic, but a trial conducted during in 71 patients, 36 of whom received ZMapp in addition to the standard of care, did not show a significant effect on mortality. Many other therapeutic studies came up empty-handed as well.
Still, the data on ZMapp were deemed good enough to use the drug as a control in future trials. In the PALM trial, three other trials were compared to ZMapp:
The monoclonal antibody mAb114, which has its roots in the 1995 Ebola outbreak in Kikwit, DRC. During that episode, Muyembe attempted to treat patients with a mixture of antibodies from Ebola survivors. Years later, researchers at NIAID isolated antibodies from those survivors; mAb114, which is now being developed with Ridgeback Biotherapeutics in Miami, Florida, was the most promising one.
REGN-EB3, a cocktail of three monoclonal antibodies developed by Regeneron Pharmaceuticals in Eastview, New York. The antibodies were generated by inoculating mice with “humanised” immune systems with the Ebola virus.
The antiviral drug remdesivir, produced by Gilead Sciences in Foster City, California.
The trial started in November 2018 in four Ebola treatment units in the communities of Beni, Butembo, Katwa, and Mangina, with the aim of enrolling 725 patients. On 9 August, an independent data and safety monitoring board reviewed data for 499 patients and found that REGN-EB3 was much better than ZMapp.
Overall, 49% of patients receiving ZMapp – and 53% of those who received remdesivir – died, compared with only 29% of those on REGN-EB3. That difference was big enough to meet the predetermined criterion for stopping the trial early. In the group that received mAb114, mortality was 34%, a rate deemed close enough to that of the Regeneron cocktail that its use should continue.
In the 41% of trial participants who sought treatment early after infection and had lower levels of Ebola virus in their blood, the two new treatments had astonishing success:
Mortality plummeted to 6% in the Regeneron antibody group and to 11% with mAb114. (With ZMapp and remdesivir, mortality rates in people with low viral load were 24% and 33%, respectively.) There is far less hope for patients with a high viral load, however: Even with the best treatment, REGN-EB3, their death rate was 60%.
Fauci stressed that the data are preliminary. “The only thing that is sure is that mAb114 and (REGN-EB3) are clearly better than ZMapp and remdesivir,” he says.
(A separate study taking place in the DRC has shown that Merck’s Ebola vaccine, which has been given to 180,000 people in the current epidemic, also powerfully reduces mortality, even when it fails to prevent infection. Of the people enrolled in the four-arm treatment study, 15% had been vaccinated; the study’s preliminary data do not factor in the impact of vaccination.)
In an extension of the original trial, patients in the four treatment centres will now be randomized either to REGN-EB3 or mAb114. Patients in all other DRC treatment centres will also be eligible to receive one of the two treatments, despite the fact that they are not yet licensed; this is possible thanks to a framework called Monitored Emergency Use of Unregistered and Investigational Interventions, developed by the World Health Organisation (WHO) in Geneva, Switzerland. Fauci says there is enough of the two therapies available. ZMapp and remdesvir will no longer be used.
Gary Kobinger, a virologist at the Public Health Agency of Canada’s laboratory in Winnipeg who developed ZMapp, says he is happy to see the other drugs do well. “ZMapp was a proof of concept,” he wrote in an email. “Without it, (the other treatments) would never have been developed.”
The encouraging results could aid efforts to end the epidemic, because better treatment outcomes may convince more people to seek help in Ebola treatment units, which makes them less likely to infect others. Now, “People think that if you enter a treatment centre, you’ll leave in a coffin,” Muyembe said. But with cure rates of 90% or higher, “We have a great message,” he said: “A treatment centre is a place where you can recover and that you leave alive.” Public health officials are also likely to emphasize the fact that people who seek treatment early have a higher chance of surviving their ordeal.
Still, scientists stress that the challenges remain daunting. “I think the news today is fantastic. It gives us a new tool in our toolbox against Ebola,” says Mike Ryan, executive director of WHO’s Health Emergencies Programme. “But it doesn’t stop Ebola. What will stop Ebola, under professor Muyembe’s leadership and that of the government of the DRC, is good surveillance, good infection prevention and control, good community engagement, excellent vaccinations, and the use of these therapeutics in the most effective way possible.”Science Mag report