Independent Monitoring Board Recommends Early Termination of Ebola Trial due to Favorable Results

The Pamoja Tulinde Maisha (PALM [together save lives]) study is a randomized, controlled trial of four investigational agents (ZMapp, remdesivir, mAb114 and REGN-EB3) for the treatment of patients with Ebola virus disease. The study began on Nov. 20, 2018 in the Democratic Republic of the Congo (DRC) as part of the emergency response to an ongoing Ebola outbreak in the North Kivu and Ituri Provinces.

As of Aug. 9, 2019, the trial had enrolled 681 patients toward an enrollment total of 725. Patients were enrolled at four Ebola Treatment Centers (ETCs) in Beni, Katwa, Butembo and Mangina. These ETCs have been overseen by staff from the Institut National de Recherche Biomédicale (INRB); the DRC Ministry of Health; and three medical humanitarian organizations: the Alliance for International Medical Action (ALIMA), the International Medical Corps (IMC), and Médecins Sans Frontières (MSF).

The trial is monitored by an independent data and safety monitoring board (DSMB) that meets periodically to review interim safety and efficacy data and to make recommendations to the study team and the sponsors. As a result of their Aug. 9, 2019 review, the DSMB recommended that the study be stopped and that all future patients be randomized to receive either REGN-EB3 or mAb114 in what is being considered an extension phase of the study. This recommendation was based on the fact that an early stopping criterion in the protocol had been me by one of the products, REGN-EB3. The preliminary results in 499 study participants indicated that individuals receiving REGN-EB3 or mAb114 had a greater chance of survival compared to participants in the other two arms.

The principal investigators of the study, its statistician and its co-sponsors accepted this recommendation, and the ETC staff at the sites were promptly informed. In addition to limiting future patient randomizations to REGN-EB3 and mAb114, patients who were randomized to ZMapp or remdesivir in the last 10 days now have the option, at the discretion of their treating physician, to receive either REGN-EB3 or mAb114.

While the final analysis of the data can occur only after all the data are generated and collected (likely late September/early October 2019), the DSMB and the study leadership felt the preliminary analysis of the existing data was compelling enough to recommend and implement these changes in the trial immediately. The complete results will be submitted for publication in the peer-reviewed medical literature as soon as possible.

The study is co-sponsored and funded by the INRB and the National Institute of Allergy and Infectious Diseases (NIAID) of the U.S. National Institutes of Health; carried out by an international research consortium coordinated by the World Health Organization (WHO); and supported by four pharmaceutical companies (MappBio, Gilead, Regeneron, and Ridgeback Biotherapeutics).

"The PALM trial is an extraordinary example of how multiple countries, government agencies and pharmaceutical companies can work together to help patients in need.  The leaders of the PALM trial have done an amazing job conducting a scientifically rigorous trial during an extremely complicated Ebola outbreak.  Focused leadership combined with an incredibly dedicated team of selfless people have made the PALM trial a possibility.  While pursuing rigorous research to determine the best treatments for patients; the primary goal of the PALM team members has always been clear – to help Ebola patients suffering from this aggressive disease that knows no boundaries.  None of this could have happened without the support and trust of patients and their families and à vous, nous disons le plus grand merci (to you we say the biggest thank you)," said Wendy Holman, CEO and co-founder of Ridgeback Biotherapeutics LP.

mAb114 is a monoclonal antibody — a protein that binds to a single target on a pathogen — isolated from a human survivor of the 1995 Ebola outbreak in Kikwit, a city in the DRC. Nancy Sullivan, Ph.D., chief of the Biodefense Research Section in NIAID's Vaccine Research Center (VRC), and her team, in collaboration with researchers from the National Institute of Biomedical Research (INRB) in the DRC and the Institute for Research in Biomedicine and Vir Biotechnology, Inc.'s subsidiary Humabs BioMed, both based in Bellinzona, Switzerland, discovered that the survivor retained antibodies against Ebola 11 years after infection. They isolated the antibodies and tested the most favorable ones in the laboratory and non-human primate studies, and selected mAb114 as the most promising. Professor Jean-Jacques Muyembe, director general of INRB and one of the scientists involved in the original detection of the Ebola virus in 1976, played a key role in discovering mAb114.

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