Emerging treatments

REGN-EB3

REGN-EB3 (also known as REGN3470-3471-3479) is an antibody cocktail consisting of three fully human monoclonal antibodies targeted at three non-overlapping Zaire ebolavirus glycoprotein epitopes. An interim analysis of a randomised controlled trial found that REGN-EB3 was associated with a higher likelihood of survival compared to ZMapp and remdesivir. Approximately 6% of patients who received REGN-EB3 died, compared to 24% of patients who received ZMapp and 33% of patients who received remdesivir.[143] REGN-EB3 has received orphan drug designation from both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and is administered as a single intravenous dose. It is being used on a compassionate use basis as one of the two treatments of choice in the current outbreak in the Democratic Republic of the Congo.

mAb114

A human IgG1 monoclonal antibody targeted to the Zaire ebolavirus glycoprotein. It was isolated from a human survivor of the 1995 outbreak in Kikwit (Democratic Republic of the Congo), and developed by the National Institutes of Health in the US. Interim analysis of a randomised controlled trial found that mAb114 was associated with a higher likelihood of survival compared to ZMapp and remdesivir. Approximately 11% of patients who received mAb114 died, compared to 24% of patients who received ZMapp and 33% of patients who received remdesivir.[143]mAb114 has received orphan drug designation from the FDA, and is administered as a single intravenous dose. It is being used on a compassionate use basis as one of the two treatments of choice in the current outbreak in the Democratic Republic of the Congo.

ZMapp

An experimental combination of 3 humanised monoclonal antibodies targeted at 3 Ebola virus glycoprotein epitopes, engineered for expression in tobacco plants.[150][151][152] ZMapp had been found to be protective when administered to non-human primates 24 to 48 hours after infection. Another study showed that the drug was able to rescue non-human primates when treatment is initiated up to 5 days after infection.[153] A randomised, controlled trial in 72 patients in sites in Liberia, Sierra Leone, Guinea, and the US found that, although the use of ZMapp plus the current standard of care appeared to be beneficial compared with current standard care alone, results did not meet the pre-specified statistical threshold for efficacy and further research is required.[154] No major safety concerns were noted in this trial, and only one serious adverse effect (hypertension) was found to be related to the infusion itself. It is being used on a compassionate use basis in the current outbreak in the Democratic Republic of the Congo.

Remdesivir

A prodrug of adenine nucleotide analogue that has potent activity against a variety of filoviruses in primate cell infection models. Initial studies have demonstrated excellent effectiveness as a treatment in non-human primates infected with Ebola virus.[155] It was used in the UK for a case of late Ebola virus relapse with meningoencephalitis. The patient recovered after being treated with a 14-day course given in combination with a high-dose corticosteroid. It is being used on a compassionate use basis in the current outbreak in the Democratic Republic of the Congo.

Favipiravir

Formerly known as T-705, favipiravir is an experimental antiviral drug that selectively inhibits viral RNA-dependent RNA polymerase. It is active against influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus, as well as other flaviviruses, arenaviruses, bunyaviruses, and alphaviruses. The drug is currently approved in Japan for influenza pandemics, but has been found to be effective against Ebola virus in mouse models.[156] Human phase II trials in Guinea used a higher dose than that used for influenza. The JIKI trial, a multi-centre non-randomised trial undertaken in Guinea in 2014-2015, suggested good tolerability at a higher dose in a low-resource setting, as well as a potential benefit in patients with low viral loads.[157] It is being used on a compassionate use basis in the current outbreak in the Democratic Republic of the Congo.

rVSV-ZEBOV vaccine (Ervebo®)

The rVSV-ZEBOV vaccine (also known as rVSV-ZEBOV-GP or V920) is a live attenuated vesicular stomatitis virus with 1 of its genes replaced by an Ebola virus gene. Phase I trials have confirmed the safety of this vaccine, although joint pain seems to be a common, self-limiting adverse effect.[158][159][160][161] The STRIVE (Sierra Leone Trial to Introduce a Vaccine against Ebola) trial, a combined phase II and III clinical trial to assess the safety and efficacy of rVSV-ZEBOV, found that no cases of Ebola were reported in the 7998 participants who were vaccinated.[162] An open-label, cluster-randomised, ring vaccination trial in which contacts of a suspected Ebola case were vaccinated with a single intramuscular dose of rVSV-ZEBOV was conducted in Guinea. Patients in the treatment arm received the vaccine immediately, while vaccination was delayed by 21 days in the control arm. The study found that rVSV-ZEBOV has a high protective efficacy. No patients who received the vaccine developed Ebola virus infection 10 days or more after randomisation in the immediate-treatment arm; however, cases occurred in unvaccinated patients in the comparison group.[163] The World Health Organization's Strategic Advisory Group of Experts (SAGE) on immunization recommends a ring vaccination strategy and vaccination of health care workers and other frontline workers with rVSV-ZEBOV for the prevention of Ebola virus infection, and it is being used in the current outbreak in the Democratic Republic of the Congo. World Health Organization: interim recommendations on vaccination against Ebola virus disease (EVD) external link opens in a new windowPreliminary results on the efficacy of rVSV-ZEBOV using a ring vaccination strategy in the current outbreak found the vaccine to be more than 97% effective.[164]The US Food and Drug Administration has approved the vaccine for the prevention of Ebola in adults. A conditional marketing authorisation has been granted in the European Union for active immunisation of adults at risk of infection with Ebola. WHO have prequalified the vaccine, a step that helps to speed up its licensing, access, and roll out in countries most at risk of Ebola outbreaks.

Ad26.ZEBOV/MVA-BN-Filo vaccine

A vaccine candidate which uses a prime-boost strategy to enhance immunogenicity and involves the use of 2 distinct viral vectors that are administered as different doses. The Ad26.ZEBOV component of the regimen is a monovalent vaccine based on adenovirus serotype 26 vector (Ad26) expressing the EBOV glycoprotein, and is designed to provide active specific acquired immunity to the Zaire ebolavirus. The MVA-BN-Filo component of the regimen is a multivalent vaccine based on modified vaccinia Ankara (MVA) vector expressing EBOV, Sudan virus, and Marburg virus glycoproteins and Tai Forest virus nucleoprotein, and is designed to provide immunity to the Sudan ebolavirus, Zaire ebolavirus, Tai Forest ebolavirus, and the Marburg virus. The vaccine is as a 2-dose heterologous course, given 56 days apart. It is currently undergoing phase III trials, and it is being used in the current outbreak in the Democratic Republic of the Congo.[165]

ChAd3-ZEBOV vaccine

ChAd3-ZEBOV is a chimpanzee-derived adenovirus vector with an Ebola virus gene inserted. A randomised, placebo-controlled phase II trial found that an antibody response to vaccination with ChAd3-ZEBOV or rVSV-ZEBOV was observed in 71% to 84% of active-vaccine recipients versus 3% of placebo recipients by 1 month. Responses were largely maintained at 12 months.[166]

TKM-100802 (siRNA)

Also known as TKM-Ebola. Consists of a combination of small interfering RNAs that target Ebola virus RNA polymerase-L, formulated with lipid nanoparticle technology. Has been shown to be protective in non-human primates, and is effective against Marburg virus in guinea pigs and monkeys.[151][167][168][169] The FDA granted expanded access use of this drug under an Investigational New Drug application (IND). Using emergency protocols, it was administered to a small number of patients.[137][150] However, a phase II single-arm trial started in Sierra Leone in March 2015 was discontinued in June 2015, after 19 patients were enrolled, due to a lack of clinical benefit.[170]

ZMab

An experimental product composed of 3 monoclonal antibodies directed against the envelope glycoproteins of the Ebola virus, developed by the National Microbiology Laboratory (Winnipeg, Canada), through the Public Health Agency of Canada. Not made to good manufacturing practice (GMP) standards, it has been used in some patients on a compassionate basis. Concerns have been raised by reports of the rapid emergence of resistant Ebola virus mutants in primates with delayed death after treatment with monoclonal antibody preparations, emphasising the importance of detailed monitoring of any patients treated with these products.[171]

MIL-77

Contains 3 monoclonal antibodies prepared in China in mammalian Chinese hamster ovary (CHO) cell-line cultures. This experimental preparation has been used on a compassionate basis in two British patients who both survived.[172]

BCX-4430

An experimental adenosine analogue found to be active against Ebola virus in rodents. Its mechanism of action is thought to be due to the inhibition of viral RNA-dependent RNA polymerase. It is active against flaviviruses, bunyaviruses, arenaviruses, and paramyxoviruses. The drug has been shown to be protective in non-human primates and rodents, even when administered 48 hours after infection.[173] A phase I safety trial is under way.

FX06

One severely unwell patient in Germany was successfully given 3 doses of FX06, a fibrin-derived peptide, in addition to renal replacement therapy and high-quality intensive care.[114] This drug is currently being evaluated as a potential adjunctive treatment for sepsis with vascular leak syndrome in animal models. It has also been evaluated in humans as a potential treatment for preventing reperfusion injury after cardiac revascularisation with no major negative adverse effects.[174][175] It has been given on a compassionate-use basis to 2 patients; however, no conclusions can be drawn yet.

AVI-7537

A drug consisting of antisense phosphorodiamidate morpholino oligomers (PMOs) that target the Ebola virus VP24 gene. It has been shown to confer a survival benefit to infected non-human primates.[176] AVI-6002 is an experimental drug that consists of 2 PMOs (AV-7537, and AV-7539, which targets the VP35 gene). AV-6002 has undergone phase I clinical studies.[137][150][177]

Interferons

Interferons have been used in the past but have unproven efficacy.[137] A phase II study is under way with limited patient enrolment to date.

Brincidofovir

Formerly known as CMX-001, brincidofovir is an experimental antiviral drug currently undergoing phase III trials for the treatment of cytomegalovirus and adenovirus. It also shows activity against Ebola virus in vitro.[137][150][178] The manufacturer announced that it would no longer participate in clinical trials of the drug for the treatment of Ebola owing to the decline of new cases of infection in Liberia, and the drug has been deprioritised for use in Ebola treatment.[179]

Other drugs

Therapeutic agents used for other diseases, such as clomifene, and chloroquine, inhibit Ebola virus interactions with human cells in models, but no trials are currently registered. Amiodarone has been shown to inhibit filovirus cell entry, and has been used compassionately in one treatment facility in Sierra Leone.[180][181][182] Atorvastatin plus irbesartan with or without clomifene has been used to treat some patients in Sierra Leone; however, no clinical data are available. Aptamers (DNA or RNA molecules selected in vitro and capable of binding a wide range of nucleic and non-nucleic acid molecules with high affinity and specificity) are being studied for the treatment of Ebola virus infection.[183] Small molecule inhibitors of Ebola virus infection are also being studied.[184] The World Health Organization has prioritised the antimalarial drug amodiaquine for testing in non-human primates. A specifically configured, experimental RNA compound, rintatolimod, has shown positive results against Ebola in an animal model.

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