Final data from a landmark clinical trial of four Ebola therapies conducted in the current outbreak in the Democratic Republic of the Congo show two of the drugs dramatically reduced the risk of dying from the disease, especially in people who started treatment quickly after onset of their illness.
Findings of the PALM trial, published in the New England Journal of Medicine on Wednesday, show that two treatments based on Ebola antibodies led to a survival rate of about 65% in treated patients, compared to 33% in the outbreak overall.
Put another way, about 35% of the patients treated with a monoclonal antibody cocktail called REGN-EB3 made by Regeneron Pharmaceuticals (REGN) and a single monoclonal antibody developed by the National Institute for Allergy and Infectious Diseases called mAb114 succumbed to their infections. The overall mortality rate in the outbreak, which enters its 17th month next week, stands at 67%.
“It was a substantial decrease [in mortality],’’ said Dr. Anthony Fauci, director of NIAID, which designed and helped conduct the trial. “When you look at people who have a low viral load,” — people who hadn’t yet progressed to severe illness when they began treatment — “it’s even more impressive. It goes down to 10%, 11%.”
The trial tested the two treatments against a third antibody product, ZMapp, and the antiviral drug remdesivir, made by Gilead Sciences (GILD). They did not perform as well, saving only about half of the patients who were treated with one of those two therapies.
The trial began in November of last year, eventually enrolling 673 people who were randomized to get one of the four treatments. It ended early, in August of this year, because an interim analysis showed the two drugs were statistically better than ZMapp and remdesivir. It was conducted under extraordinarily difficult conditions. The part of DRC where the outbreak is occurring has been a conflict zone for decades; two of the four Ebola treatment centers where the trial was conducted were firebombed earlier this year.
Erica Ollmann Saphire, a scientist whose research focuses on monoclonal antibodies for Ebola and other diseases, was impressed by the study — and that it was even able to be conducted.
“I think a lot of us were not sure that we would ever see this,” said Ollmann Saphire, a professor at the La Jolla Institute for Immunology.
Under the topline findings were some interesting and even puzzling results.
The percentage of patients in the trial who said they’d been vaccinated with Merck’s Ebola vaccine was 25% — higher than might be expected given the vaccine is estimated to be about 95% effective. However, at least half of those people had been vaccinated for fewer than 10 days when they became ill, suggesting the vaccine hadn’t had time to generate a protective response.
Nearly 40% of that group of patients — 60 patients in total — said they had been vaccinated more than 10 days before getting sick, at which point they should have been protected.
But these are self-reported data. In an email, a World Health Organization spokeswoman said data like these can be subject to recall bias; people may not accurately remember when they were vaccinated or know the difference between a vaccine or a drug. “WHO’s analysis of vaccine data … show vaccine efficacy around 95% at 10 or more days after vaccination,” she said.
The authors of the PALM study did not check the names of their patients against the master list of the more than 255,000 people who have been vaccinated in this outbreak. To date, just over 3,300 people have been infected and nearly 2,200 have died.
Data released last spring by the WHO suggested that people who were vaccinated were less likely to die if they developed Ebola. Fauci said the data in the PALM trial indicate the vaccine may provide a survival advantage to people who later contract Ebola, but the study was not designed to examine that and cannot conclude that definitively.
Ollman Saphire said mAb114 performed better than she had expected, given that it is a single antibody, not a cocktail of several antibodies. The fear with a single antibody is that the virus will evolve to escape it, which is harder to do with a cocktail of antibodies. She noted, though, that this will have to be monitored as the therapy continues to be used in this and in future outbreaks.
MAb114 has been licensed to both Ridgeback Biotherapeutics and to Mapp Biopharmaceuticals, which makes ZMapp.
Interestingly, the study authors noted the patients who randomly received remdesivir and ZMapp were generally sicker than those who received REGN-EB3 and mAb114 — which could have affected the outcome.
They flagged another factor that may have contributed to poorer performance of ZMapp and remdesivir. Both were given in treatments over a longer period of time. REGN-EB3 and mAb114 were given in a single dose. And because ZMapp is infused slowly, patients who came in late in the day who were randomized to get it didn’t start treatment until the following day.
The authors noted that it was puzzling that ZMapp hadn’t performed as well in this trial as it did in a trial in West Africa during the 2014-2016 Ebola outbreak. There, mortality among people who received the antibody cocktail — made by Mapp Biopharmaceuticals — was 22%. In the PALM trial, it was 50%. Fauci said more study is underway to try to figure out why the outcomes were so different.
Gary Kobinger, the scientist who led the development of ZMapp, said that difference could be a red flag, signaling that outcomes from the use of antibody preparations may vary from outbreak to outbreak.
Still, Kobinger, director of the Infectious Disease Research Center at Laval University in Quebec, said the most important message of the study is that monoclonal antibodies are effective in treating Ebola. For years, scientists argued the opposite, he said.
Going forward, it will be important to develop better antibody products, he said, noting some antibodies that work against all species of Ebola viruses have been identified and their development should be fast-tracked. This outbreak is caused by Zaire ebolaviruses. Treatments that target it alone would probably not be effective against Sudan ebolaviruses or others in the family.
“I think the take-home message is … the approach is good, it’s promising. And there are better treatments,” Kobinger said.