Clinical trials in an Ebola outbreak seek to find an evidence-based cure.

Ebola virus (EBOV) outbreaks are unpredictable, sporadic, and historically occur in remote locations of equatorial Africa. Traditionally, outbreak control consists of identifying EBOV-infected patients and contact tracing. Ebola treatment centers provide limited supportive care with rigorous infection control. Communication, education, and establishing trust with the community to allow continued surveillance and altering funeral rituals to ensure safe and dignified burials have been the focus for stopping EBOV spread since its discovery in 1976. High case fatality rates of EBOV infection have justified administering unproven candidate therapeutics, convalescent plasma, or repurposed medicines on a compassionate use basis. In 2014, WHO declared the Ebola outbreak in West Africa (the largest to date) an international public health emergency. Subsequently, international institutes began requesting unproven but promising experimental therapeutics to combat EBOV [[1]World Health Organization G. Emergency Use Assessment and Listing Procedure (EUAL) for candidate medicines for use in the context of a public health emergency n.d. http://apps.who.int/medicinedocs/en/m/abstract/Js21985en/(accessed November 24, 2019).Google Scholar]. Federal and academic research programs had been evaluating candidate therapies in cell culture, small animal, and non-human primate models of EBOV infection, but there had not been a registered clinical trial. While compassionate use guidelines were accepted, ethics of performing clinical trials during an outbreak were heavily debated [[2]WHO | Ethical considerations for use of unregistered interventions for Ebola virus disease n.d. https://www.who.int/csr/resources/publications/ebola/ethical-considerations/en/ (accessed November 24, 2019).Google Scholar]. Patients’ need for the highest therapeutic benefits precluded placebo controls. Reallocation of limited resources from supportive care was a concern, and sufficient quantities of trial therapeutics were needed. Regulatory, ethical, pharmaceutical, and governmental committees had to be coordinated to approve clinical guidelines, in hindsight causing significant delays in starting trials. The outbreak peaked between August and December 2014, and the earliest trials began in 2015. As case numbers declined, matching location of trial centers with sufficient numbers of infected patients became problematic. Despite these enormous hurdles, diligent scientists insisted that Ebola patients deserved evidence-based effective treatment. Clinical trials were initiated evaluating small molecular inhibitors favipiravir and brincidofovir; host response modulator interferon beta; monoclonal antibody cocktail Zmapp; and convalescent plasma [[3]Rojek A. Horby P. Dunning J. Insights from clinical research completed during the west Africa Ebola virus disease epidemic.Lancet Infect Dis. 2017; 17: e280-e292https://doi.org/10.1016/S1473-3099(17)30234-7Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar,[4]Cross R.W. Mire C.E. Feldmann H. Geisbert T.W. Post-exposure treatments for Ebola and Marburg virus infections.Nat Rev Drug Discov. 2018; 17: 413-434https://doi.org/10.1038/nrd.2017.251Crossref PubMed Scopus (83) Google Scholar]. Most incorporated an initial safety study and were multi-staged to rapidly (typically within 14 days) assess benefits or harm of the experimental treatment versus historical case fatality rates. Conservative, low-dose regimens were chosen based on pre-clinical animal experiments or available phase 1 safety data on healthy human volunteers. Trials were conducted within Ebola treatment centers run by different aid agencies, used different laboratory tests, and provided varied supportive care. A single-arm, phase 2 trial testing the efficacy of TKM-130803 (TKM-Ebola) was conducted in Sierra Leone in March 2015 [[5]Dunning J. Sahr F. Rojek A. Gannon F. Carson G. Idriss B. et al.Experimental treatment of Ebola virus disease with TKM-130803: a single-arm phase 2 clinical trial.PLoS Med. 2016; 13e1001997https://doi.org/10.1371/journal.pmed.1001997Crossref Scopus (122) Google Scholar]. TKM-Ebola is a lipid nanoparticle (LNP) containing small interfering RNAs (siRNAs) targeting the viral polymerase and VP35. Pre-clinical studies evaluated the formulation, TKM-100802, based on virus from the 1995 EBOV outbreak in Kikwit, DRC. One siRNA out of two failed to inhibit the West African EBOV strain, which differed from target siRNA sequences [[6]Thi E.P. Mire C.E. Lee A.C.H. Geisbert J.B. Zhou J.Z. Agans K.N. et al.Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates.Nature. 2015; 521: 362-365https://doi.org/10.1038/nature14442Crossref PubMed Scopus (204) Google Scholar]. This highlights the importance of testing therapeutics using appropriate outbreak virus [[7]McMullan L.K. Flint M. Chakrabarti A. Guerrero L. Lo M.K. Porter D. et al.Characterisation of infectious Ebola virus from the ongoing outbreak to guide response activities in the Democratic Republic of the Congo: a phylogenetic and in vitro analysis.Lancet Infect Dis. 2019; 19: 1023-1032https://doi.org/10.1016/S1473-3099(19)30291-9Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. siRNAs redesigned to match the outbreak sequence were named TKM-130803; 14 patients enrolled to receive a 7-dose regimen. After 14 days, a conservative dose of TKM-Ebola provided no survival benefit, the trial was terminated, and researchers concluded that advanced EBOV disease was not susceptible to TKM-Ebola therapy. This failure to provide therapeutic benefit was attributed to several potential factors. Most strikingly, trial patients’ viral RNA levels at the time of enrollment were several logs greater than those tested in pre-clinical animal studies. Questions remained if TKM-Ebola siRNAs were present in adequate levels during treatment. Here, Janet Scott et al. reevaluated clinical samples from the TKM-Ebola trial, developed and applied a new test to count the siRNA molecules and relate the amount to EBOV RNA in patient blood [[8]Scott J.T. Sharma R. Meredith L.W. Dunning J. Moore C.E. Sahr F. et al.RAPIDE-TKM trial teamPharmacokinetics of TKM-130803 in Ebola virus disease in Sierra Leonean: patients showed plasma concentrations which exceeded target levels, with accumulation of drug in patients with most severe disease.EBioMed. 2020; https://doi.org/10.1016/j.ebiom.2019.102601Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. Previous animal studies measured the activity of circulating siRNAs and in macrophage target cells, and had found TKM-Ebola to provide survival if delivered within 3 days of infection [[6]Thi E.P. Mire C.E. Lee A.C.H. Geisbert J.B. Zhou J.Z. Agans K.N. et al.Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates.Nature. 2015; 521: 362-365https://doi.org/10.1038/nature14442Crossref PubMed Scopus (204) Google Scholar]. Scott et al. found a molar excess of TKM-Ebola siRNA molecules relative to virus RNA [[8]Scott J.T. Sharma R. Meredith L.W. Dunning J. Moore C.E. Sahr F. et al.RAPIDE-TKM trial teamPharmacokinetics of TKM-130803 in Ebola virus disease in Sierra Leonean: patients showed plasma concentrations which exceeded target levels, with accumulation of drug in patients with most severe disease.EBioMed. 2020; https://doi.org/10.1016/j.ebiom.2019.102601Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. However, the patients had much higher initial viral load and were in the later stages of EBOV infection. The authors next performed a pharmacokinetic model of dosing regimens and conclude the drug was delivered in abundance relative to virus in circulation, yet patients with severe Ebola infection had sustained TKM-Ebola levels, and thus were failing to clear the drug. This has implications for other LNP-based siRNA therapies where the siRNAs may not reach the intracellular targets, and thus be ineffective in patients with compromised organ function. This follow-up study of the TKM-Ebola clinical trial revisits and highlights how initial experiences conducting research in an outbreak are necessary to advance clinical care to Ebola patients [[8]Scott J.T. Sharma R. Meredith L.W. Dunning J. Moore C.E. Sahr F. et al.RAPIDE-TKM trial teamPharmacokinetics of TKM-130803 in Ebola virus disease in Sierra Leonean: patients showed plasma concentrations which exceeded target levels, with accumulation of drug in patients with most severe disease.EBioMed. 2020; https://doi.org/10.1016/j.ebiom.2019.102601Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. They successfully worked with industry, academic, humanitarian and government agencies following newly developed regulations and protocols. They gained the trust of the local community to enroll patients under proper ethical guidelines. They delivered the investigational treatment within the extreme conditions of an Ebola treatment center. Results and limitations were presented to the scientific community [[3]Rojek A. Horby P. Dunning J. Insights from clinical research completed during the west Africa Ebola virus disease epidemic.Lancet Infect Dis. 2017; 17: e280-e292https://doi.org/10.1016/S1473-3099(17)30234-7Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar,[5]Dunning J. Sahr F. Rojek A. Gannon F. Carson G. Idriss B. et al.Experimental treatment of Ebola virus disease with TKM-130803: a single-arm phase 2 clinical trial.PLoS Med. 2016; 13e1001997https://doi.org/10.1371/journal.pmed.1001997Crossref Scopus (122) Google Scholar]. Precious Ebola patient samples were collected, shared with enhanced laboratories with biosecurity allowing additional research to be performed and knowledge gained. Lessons learned in West Africa are being applied in the current Ebola outbreak in the eastern provinces of DRC, now the second largest with over 3300 cases. A four-arm, multi centered, phase 2 clinical trial was initiated to evaluate efficacy of the nucleotide analogue prodrug remdesivir (GS-5734), the monoclonal antibody mAb114, and cocktail REGN-EB3 with Zmapp as the control [[9]EbolaWHO R&D blueprint – ad-hoc expert consultation on clinical trials for Ebola therapeutics. WHO, 2019https://www.who.int/ebola/drc-2018/treatments-approved-for-compassionate-use-update/en/Google Scholar]. Using same lab assays ensured comparable results and multiple trial locations allowed sufficient enrollment (681 patients) to conclude that REGN-EB3 and mAb114 were 89% and 90% effective, respectfully, promoting survival in patients with low viral loads, and should therefore continue to be administered for the duration of the outbreak [[10]Mulangu S. Dodd L. PALM Consortium Study Team. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.New England Journal of Medicine. 2019; https://doi.org/10.1056/NEJMoa1910993Crossref Scopus (931) Google Scholar]. Scientifically proven, effective treatments can dramatically change future EBOV outbreaks, encouraging patients to seek care in treatment centers, lowering viral loads and quelling person-to-person transmission, and saving lives. With proper treatment, Ebola can be cured. The author declared no conflicts of interest. The conclusions, findings, and opinions expressed by the author contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, or the Centers for Disease Control and Prevention. Pharmacokinetics of TKM-130803 in Sierra Leonean patients with Ebola virus disease: plasma concentrations exceed target levels, with drug accumulation in the most severe patientsTKM-130803 was circulating in molar excess of circulating virus; a level considered needed for efficacy. Given extremely high viral loads it seems likely that the patients died because they were physiologically beyond the point of no return. Subjects who died exhibited some indication of impaired drug clearance, justifying caution in dosing strategies for such patients. This analysis has given a useful insight into the pharmacokinetics of the siRNA in the disease state and illustrates the value of designing PKPD studies into future clinical trials in epidemic situations. Full-Text PDF Open Access