Stopped early for favorable results, an African trial testing four Ebola drugs has found two of the therapies, Regeneron Pharmaceuticals Inc.'s REGN-EB3 and the NIH-developed MAb-114, gave Ebola-infected participants a greater chance of survival than either Gilead Sciences Inc.'s remdesivir or Zmapp (Mapp Biopharmaceutical Inc., Defryus Inc.), considered the standard of care based on the previous Prevail II trial. Following the result, the study's data and safety monitoring board (DSMB) has recommended all future patients be randomized to receive either REGN-EB3 or MAb-114 in what is being considered an extension phase of the study.
Initially developed by the NIH, MAb-114 was licensed by Miami-based Ridgeback Biotherapeutics LP in the fourth quarter of 2018. (See BioWorld, June 3, 2019.)
"Although these recommendations are based on preliminary study data, the encouraging clear-cut findings are a ringing endorsement for conducting randomized controlled clinical trials to advanced medical research and quickly provide better therapeutic options for patients based on sound scientific data," said National Institute of Allergy and Infectious Diseases (NIAID) Director Anthony Fauci during a briefing on the news.
There are more than 2,800 cases of Ebola known to the World Health Organization (WHO). The average Ebola virus disease (EVD) case fatality rate is around 50%. Case fatality rates have varied from 25% to 90% in past outbreaks. The current 2018-2019 outbreak in the eastern part of the Democratic Republic of the Congo (DRC) is "highly complex, with insecurity adversely affecting public health response activities," according to WHO.
Launched in November 2018 and jointly sponsored by the NIAID and the Institut National de Recherche Biomédicale, the randomized controlled Palm trial is being conducted in the DRC. It's taking placed during the largest Ebola outbreak that country has ever experienced, one that has now persisted for more than a year, Fauci said.
While the trial initially tested just MAb-114 and remdesivir against Zmapp, its protocol was amended to include a fourth arm for Regeneron's candidate after an advisory meeting in which the candidate was discussed.
REGN-EB3 is a fixed-dose combination of a cocktail mixture of three recombinant fully human IgG1 monoclonal antibodies (REGN-3470, REGN-3471 and REGN-3479) directed against different epitopes on Ebola virus glycoprotein, developed using Regeneron's Velocisuite, including its Velocimmune rapid response technology.
MAb-114 is the lead from a series of lyophilized human IgG1 MAbs also targeting the Zaire ebolavirus glycoprotein. It was isolated and characterized in Switzerland at the Institute for Research in Biomedicine in collaboration with Humabs Biomed SA, a subsidiary of Vir Biotechnology Inc., of San Francisco.
As of Aug. 9, the trial had enrolled 681 patients toward an enrollment total of 725. Following an interim evaluation, it was "stopped because the Regeneron product crossed the efficacy threshold that would halt the study," Fauci said. "However, the differences between the Regeneron product and monoclonal antibody 114 were small, and it was clear to the DSMB that those two agents are more effective than the other two," he added.
While the primary endpoint of the trial is a comparison of the drugs based on mortality at day 28, the interim review that narrowed testing to just REGN-EB3 and MAb-114 was based on day 10 mortality data. The overall mortality among patients randomized to Zmapp was about 49% vs. 53% for remdesivir, 34% for MAb-114 and 29% for REGN-EB3.
For patients with low viral loads, suggesting they were receiving treatment early in the course of the disease, the results "are even more impressive," Fauci said. For Zmapp, the day 10 mortality for patients with a low viral load was 24% vs. 33% for remdesivir, 11% for MAb-114, and 6% for REGN-EB3.
Fauci cautioned against misinterpreting the preliminary data as a sign that one of the two remaining drugs in the study was clearly better than the other. "The only thing that is sure," he said, is that the MAb-114 and REGN-EB3 "are clearly better than Zmapp and remdesivir."
With preliminary findings on mortality from Palm in hand, the extension study will further evaluate safety until final results of the trial are known. An expanded access phase of the study will follow.
"I think both in the overall mortality, low viral load and high viral load, the Regeneron cocktail is superior to MAb-114," Christos Kyratsous, Regeneron's vice president of research, infectious diseases and viral vector technologies, told BioWorld.
"This is the first excellent example of a Velocimmune antibody for infectious diseases using the rapid response platform, where we are trying to go from immunization of mouse all the way into testing in the field and showing the efficacy as fast as we can," Kyratsous said. Regeneron and the U.S. Biomedical Advanced Research and Development Authority (BARDA) have several ongoing research collaborations in addition to the Ebola program, including a collaboration to develop treatments for Middle East respiratory syndrome and a collaboration for the discovery, research, development and manufacturing of a portfolio of antibodies targeting up to 10 pathogens that pose significant risk to public health.
"We're in conversation with EMA and FDA to plot a pathway for registration on Regeneron EB3. We have an open IND in the U.S and we're in discussions to move this product forward to registration," Leah Lipsich, Regeneron's vice president of strategic program direction, told BioWorld.
On Monday, Fauci said that about 300 doses of MAb-114 are "on hand" now, with the manufacture of second and third production lots already in progress. Regeneron also has "several hundred" treatment courses that could be made available for treatment in the DRC, and arrangements are being made to make additional lots, Fauci said.
Given the availability of trial drug supplies and the new interim evidence, investigators on the ground in the DRC are likely to be able to project improved confidence to potential participants in the trial. However, patients are still staying too long in their home communities before seeking treatment, said Mike Ryan, executive director of WHO's Health Emergencies Program. "Having effective drugs is fantastic and great news. But if we don't get to use them in time in patients, then this is a problem," he said.