A single monoclonal antibody, mAb114, targeting the receptor-binding domain of Ebola virus glycoprotein showed linear pharmacokinetics and was easily and rapidly infused, according to data published in the Lancet. Researchers, therefore, believe it may be a viable treatment option in outbreak settings
The mAb114 antibody is known to prevent mortality of rhesus macaques after a lethal challenge of Zaire ebolavirus. Therefore, researchers conducted a phase 1 dose escalation study at the National Institutes of Health and enrolled healthy adults aged 18 to 60 years. Participants (N=19) were sequentially enrolled in 3 dose groups (5 mg/kg, 25 mg/kg, and 50 mg/kg). The drug was administered intravenously for 30 minutes, and participants were followed for 24 weeks to assess safety and tolerability; in addition, pharmacokinetic and anti-drug antibody assessments were obtained as secondary endpoints. Researchers noted that as a result of lack of intravenous access, 1 participant enrolled in the 5mg/kg group withdrew before receiving treatment.
Fifteen participants completed the trial: 2 of 3 in the 5 mg/kg group, 5 of 5 in the 25 mg/kg group, and 8 of 11 in the 50 mg/kg group. All the drug infusions were tolerated with no reactions or rate adjustments, and all participants completed the safety assessment of local and systemic reactogenicity. There were no reported infusion site symptoms, and systemic symptoms were all mild and present in 4 individuals. The antibody had dose-dependent linear pharmacokinetics, and results demonstrated a half-life of 24.2 days (standard error of measurement, 1.8) across all dose levels. There was no evidence of anti-drug antibody development.
Although it is typical to have such a small number of participants enrolled in a phase 1 trial, the study investigators noted that this is the main limitation of the study. To improve the accuracy of their analysis, researchers included only data from participants with 28 days of data (n=13) in the analysis of pharmacokinetic parameters, and only data from participants with 56 days of data for half-life calculations (n=9).
Researchers concluded that mAb114 is “an attractive and deployable option for treatment in outbreak settings.” Further, they noted that there are ongoing trials and future work planned that will provide additional data from mAb114 recipients and populations living in potential outbreak settings. To date, 54 people have received this drug during the North Kivu outbreak under an expanded access protocol, followed by remdesivir, REGN3470-3471-3479, and ZMapp. According to the study investigators, “great care will be required when analysing mortality among recipients of investigational treatments within the expanded access protocols to discern possible sources of bias among efficacy signals.” There is also a multinational randomized controlled trial, “assess[ing] multiple therapeutic agents, including mAb114, in the current Ebola virus disease outbreak,” that is still underway.
Gaudinski MR, Coates EE, Novik L, et al. Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study. Lancet. 2019;393:889-898.