Experimental Ebola Drugs Reduce Mortality in Early Results

Tara Haelle

August 12, 2019

A clinical trial to test four Ebola drugs has ended early after preliminary data indicated higher survival rates with two of the drugs, the US National Institute of Allergy and Infectious Diseases (NIAID) announced today.

"We will no longer say that EVD [Ebola virus disease] is not curable," Jean-Jacques Muyembe-Tamfum, MD, PhD, director-general of the Institut National de Recherche Biomédicale (INRB) in the Democratic Republic of Congo, said through a translator during a telebriefing. The INRB is co-sponsoring and helping oversee the trial. "This advance will, in the future, help with saving thousands of lives that would have had a fatal outcome in the past."

The Pamoja Tulinde Maisha open-label randomized trial (ClinicalTrials.gov: NCT03719586) has been comparing the safety and efficacy of ZMapp, remdesivir, mAb114, and Regeneron EB-3 (REGN-EB3) for treating Ebola virus disease in two Congo provinces since November 2018. The monoclonal antibody drug ZMapp, previously shown to result in better outcomes than supportive care alone, was the control. The nucleotide analog antiviral remdesivir and monoclonal antibodies mAb114 and REGN-EB3 had not previously been used to treat Ebola virus disease, explained NIAID Director Anthony Fauci, MD, in the telebriefing.

Interim analysis of the trial data from 499 participants revealed that patients treated with REGN-EB3 or mAb114 were more likely to survive than those who received one of the other two interventions. Overall mortality was 29% with REGN-EB3 and 34% with mAb114, compared with a 49% mortality rate with ZMapp and a 53% rate with remdesivir (P = .002), Fauci said.

"If you look at the low viral load, namely, assuming someone who got in early — and that would argue for early treatment — the results are even more impressive," he continued, though he cautioned that the data remain preliminary. Mortality rates at low viral load were 6% for REGN-EB3, 11% for mAb114, 24% for ZMapp, and 33% for remdesivir.

Based on the interim data, the independent data and safety monitoring board recommended early termination of the study with an extension phase in which all future patients be randomly assigned to receive REGN-EB3 or mAb114. Those who had received ZMapp or remdesivir within the previous 10 days could also choose to receive one of the two other drugs.

"When you look at the difference between Regeneron [REGN-EB3] and monoclonal antibody 114 [mAb114], it's close enough that, since these are preliminary data, the [data and safety monitoring board] felt that it would be appropriate to go ahead with both of them since the data were very close, even though it is clear that the triggering point to stop the study was the Regeneron product," Fauci said.

Final data analysis from the trial is expected in September or early October.

Until the announcement to terminate the trial, all other Ebola treatment centers in the region had been using the compassionate use protocol in place before the trial, but those centers will now begin using REGN-EB3 or mAb114, said Michael J. Ryan, MD, executive director of the WHO Health Emergencies Programme, during the telebriefing.

"So all patients will have access to the same type of therapeutic interventions regardless of whether their center was involved in the [randomized controlled trial] or not," he said.

Fauci said approximately 300 doses of mAb114 remain at the moment, and second and third production lots are in progress with the second expected in early September. Several hundred REGN-EB3 treatment courses are also currently available, and the manufacturer is "committed to making Regeneron EB3 available to every patient who needs it" and "believes they have sufficient quantities to continue uninterrupted supply to patients in the current outbreak," Fauci said.

No decision has been made regarding whether the two drugs might be offered or tested as a combination treatment, he said, but doing so is theoretically possible following additional preclinical research.

Through August 9, investigators have enrolled 681 of the 725 planned patients from North Kivu and Ituri Provinces, where an Ebola outbreak has grown to 2753 cases since August 2018, according to the most recent update from the European Centre for Disease Prevention and Control (ECDC). The Alliance for International Medical Action, the International Medical Corps, and Médecins Sans Frontières are overseeing the four Ebola treatment centers participating in the trial in the cities of Beni, Katwa, Butembo, and Mangina.

The study protocol called for patients of any age with an Ebola infection to receive one of four drugs:

  • intravenous ZMapp over 4 hours, administered three times 3 days apart

  • intravenous remdesivir over 1 hour, administered daily for 10 days

  • intravenous mAb114 over 30-60 minutes, administered once

  • intravenous REGN-EB3 over 2 hours, administered once

All patients received supportive care, including fluid replacement, for at least 1 week while isolated in clinic. The primary end point was mortality by day 28. Secondary outcomes included time to first negative Ebola virus RT-PCR in blood, viremia, and incidence of serious adverse events.

The current Ebola outbreak is the largest ever in the Congo and second largest globally, with 1749 confirmed deaths, including 41 healthcare workers. Among the obstacles to disease control are a high population density "experiencing a long-lasting humanitarian and security crisis" in a region with "insufficient prevention control practices in many health facilities and persistent reluctance in the community to accept EVD response activities," the ECDC reported.

"There are successes here, but there's also tragedy linked to the success. The tragedy is that not enough people are being treated," Ryan said during the telebriefing. The median time from symptom onset to admission to an Ebola treatment center was previously 5-6 days and has improved to about 4 days, he said.

"We are still seeing too many people staying away from Ebola treatment units, too many people not coming to hospital or not being found in time to benefit from these therapies," Ryan said.

Those who do receive prompt care do well, but those found late have very poor outcomes. "Getting people into care more quickly is absolutely vital for both containing the epidemic and also increasing survival rates for those people who are exposed to them and infected." He said plans are being developed for communicating these recent findings to the community and for incorporating the findings into the Ebola outbreak response.

The trial is funded by the Institut National de Recherche Biomédicale and the US National Institute of Allergy and Infectious Diseases with support from the World Health Organization and from MappBio, Gilead, Regeneron, and Ridgeback Biotherapeutics. Information on investigator disclosures was unavailable.

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