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Two monoclonal antibody treatments for Ebola were associated with a significantly lower mortality rate among patients with the virus in the Democratic Republic of the Congo, a randomized trial found.

The single monoclonal antibody MAb114 and triple monoclonal antibody REGN-EB3 delivered lower mortality rates after 28 days compared to the novel antiviral agent remdesivir in development for Ebola and compared with another triple monoclonal antibody, ZMapp, which showed .

Indeed, 35.1% of patients on MAb114 and 33.5% the REGN-EB3 group had died after 28 days versus 49.7% of patients in the remdesivir group and 51.3% of patients in the ZMapp group, H. Clifford Lane, MD, of the National Institute of Allergy and Infectious Diseases (NIAID), and colleagues reported in the .

The NIAID previously announced these results in August, when an independent Data Safety and Monitoring Board said that the trial should be stopped early and patients should be treated either with Regeneron's REGN-EB3 treatment or MAb114, which was developed by the agency itself.

Moreover, the board recommended that anyone being treated for Ebola should now be given the option of those two monoclonal antibody therapies, at their doctor's discretion.

"These clear-cut findings are a ringing endorsement to conduct randomized clinical trials ... and provide options based on scientific data to determine the best intervention," NIAID director, Anthony Fauci, MD, said back in August.

The authors noted that nearly all deaths occurred within 10 days after enrollment, and that REGN-EB3 and MAb114 patients had faster rates of viral clearance compared to the remdesivir and ZMapp groups. They noted that the former two treatments only required one dose, while the latter two required multiple infusions, as a potential reason for the differences.

An by Myron Levine, MD, of the University of Maryland in Baltimore, noted many differences between the two treatments. REGN-EB3 was obtained by immunizing mice that encode human antibody gene segments that generate fully human antibodies, while MAb114 was derived from cells of a surviving Ebola patient. But both had success in preclinical studies.

"MAb114 and REGN-EB3 had been shown to reduce mortality among nonhuman primates in controlled challenge studies with Z. ebolavirus strains," Levine wrote.

In the Pamoja Tulinde Maisha (Swahili for "together save lives"), or PALM trial, Lane and colleagues included patients who tested positive for Ebola RNA, including pregnant women.

The 673 participants were assigned to receive remdesivir, MAb114, REGN-EB3, or ZMapp as the control. The trial was originally designed in November 2018 with three groups. REGN-EB3 was a late addition in January 2019.

About three-quarters of patients were adults, and the rest were split between children ages 6-17 and those age 5 and younger. Over half of the patients were female, and about 6% were pregnant at the time of diagnosis. Patients were enrolled within an average of about 6 days after diagnosis.

Vaccination information was available for 620 patients. Among the quarter who said they had received the Ebola vaccine, 39% said they had received it at least 10 days prior to enrollment in the study.

An interim efficacy analysis of 499 patients was performed in August 2019, when it was discovered that REGN-EB3 had crossed an efficacy threshold, as the NIAID noted back in August. In addition, they found a "clear separation" between REGN-EB3 and MAb114 and remdesivir and ZMapp.

Overall, death occurred in 43% of patients by day 28 -- about 13% with a low viral load and 77% with a high viral load.

Death rates were 14.6 percentage points lower with MAb114 than ZMapp (P=0.007) and 17.8 percentage points lower with REGN-EB3 than ZMapp (P=0.002). However, there was only a nonsignificant 3.4-percentage point difference between remdesivir and ZMapp (95% CI -7.2 to 14.0).

Examining safety, there were 29 serious adverse events, but only three patients had four events judged to be potentially related to the study drug:

• One in the ZMapp group with worsening of GI symptoms
• One in the ZMapp group with peri-infusional hypotension and hypoxia resulting in death within 24 hours
• One in the remdesivir group with hypotension that eventually resulted in cardiac arrest

While all these patients died, the authors noted that it could not be determined if the cause of death was the adverse event or the Ebola infection itself.

Levine said that the effects of these treatments are sufficiently promising "that it is worth exploring the cost, the number of doses that can be manufactured, and the target population." Though certain programmatic issues remain, such as which product "would be more suitable for large-scale economically viable production," as well as storage requirements and stability, he said.

"A single monoclonal antibody-based product offers some advantages. It would be desirable to have stockpiles of both products if licensure is obtained for them," Levine wrote.