New Ebola Drugs Signal End for Deadly Virus

A major milestone in drug discovery and development was achieved in the summer of 2019. Two drug candidates developed to combat the Ebola epidemic in Africa – REGN-EB3 and mAb114 – produced remarkable results in clinical trials, effectively neutralizing the virus overnight. Years of research culminated in an understanding of the ebolavirus and the development of effective drugs against it. But their work isn’t over, as many challenges stand in the way of a full cure to the deadly virus.

What is Ebola Disease?

Origins of the Ebolavirus

Despite the sudden influx of Ebola news coverage in recent years, the virus—thought to originate in bats—first manifested itself in Africa in 1976. Infection by the ebolavirus is characterized by hemorrhagic fever: flu-like symptoms coupled with uncontrollable bleeding (both internal and external), leading to the quick onset of death. In some cases of Ebola infection, the time between the first symptoms and death was less than one week.

Consecutive outbreaks of the then-unidentified deadly virus in Sudan and Zaire caused the region to fall into a state of panic, but quarantine measures managed to contain its spread. The ebolavirus was subsequently studied by researchers all over the world, with its name coming from the close proximity of its origin to the Ebola river.

Since 1995, small outbreaks of Ebola have popped up consistently throughout the African continent. In March 2014 however, the virus popped up in Guinea, quickly spreading to nearby Sierra Leone and Liberia, in what became the largest ever recorded Ebola outbreak and the first in West Africa.

Soon after, international coverage took off as the first individual from outside of the African continent contracted Ebola and died from it. Meanwhile, the disease continued to spread throughout Africa, with the most recent epidemic in the Democratic Republic of Congo (DRC) ongoing since 2018.

The Race for a Cure

At the height of the Ebola epidemic of September 2014, those infected by the virus had, on average, a 50% chance of survival. In some regions of Africa with accessibility issues and inadequate medical facilities, this number increased to as high as 90%. The fear of contracting the deadly virus with no known cure led to many healthcare workers fleeing their stations, causing the situation to further deteriorate into an enormous medical crisis.

Even treatment options for patients were primarily supportive, treating symptoms such as fever and pain. Existing antimalarial therapies, antibiotics as well as drug candidates were also used in desperate attempts to slow or stop the effects of the infection. None showed significant efficacy against the Ebola virus. In the background, researchers and medical professionals ramped up their efforts to come up with a cure that would stop the disease in its tracks.

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Drug Discovery and Development

Targeting Virus Mechanisms

In order to design a cure for Ebola, an understanding of the virus’s life cycle is crucial. Viruses like ebola break hijack the host cell’s machinery to make copies of themselves, then bud off the host cell to infect other cells. Ebola’s genetic code is completely encapsulated by just seven genes, which it uses to create proteins that enable it to enter host cells and replicate. Based on its life cycle, several antiviral targets have been studied: targeting the virus entry into the host cell, the RNA synthesis machinery, and the budding/cell exit process.

Blocking the ebolavirus’ entry into the host cell is a well-studied process, with hundreds of thousands of compounds screened for activity and several even progressing to clinical trials². Entry inhibitors can either target the initial attachment of the virus onto the cell surface or the transport into the cell (also known as macropinocytosis).

RNA synthesis is a key part of Ebola’s life cycle, with the virus taking over the host’s cell machinery to do so. Drugs can, therefore, target either the virus or the cell’s machinery to stop this process. Several candidates under this category made it as far as phase II clinical trials, but could not show conclusive evidence for their effectiveness.

Finally, the last and least studied target is the budding process in which copies of the virus exit the host cell. Strategies have been proposed to stop the viruses from reaching the outer membrane of the cell, while others target the budding process after the virus has reached the cell’s surface. Better knowledge of the mechanisms means more targets can potentially be exploited, which is important for the development of more therapies, increasing efficiency and reducing the risk of drug resistance.

REGN-EB3 and mAb114

In August 2019, a paper published results from Ebola clinical trials, with two biologic drugs—REGN-EB3 and mAb114—showing extremely promising results². Preliminary data from the study showed that patients treated with REGN-EB3 had a mortality rate of 29%, while those treated with mAb114 had a 34% mortality rate. In contrast, those who did not receive any treatment had a 75% mortality rate.

Further analysis of the data showed even better outcomes for those treated early after infection. Such patients showed a mortality rate of just 6% with REGN-EB3 and 11% with mAb114. The study was conducted in the Democratic Republic of Congo (DRC), in the midst of the most recent Ebola epidemic. These results were enough for the entire trial to be stopped, with all the remaining patients put onto courses with REGN-EB3 and mAb114.

From now on, we will no longer say that Ebola is incurable. People think that if you enter a treatment center, you’ll leave in a coffin. We have a great message: a treatment center is a place where you can recover and that you leave alive.

Jean-Jacques Muyembe-Tamfum, director of the DRC’s Institut National de Recherche Biomedicale, which oversaw the trial.

Both REGN-EB3 and mAb114 are monoclonal antibodies targeting the ebolavirus’ entry process. REGN-EB3 is being developed by Regeneron Pharmaceuticals and mAb114 by Ridgeback Therapeutics, with support from the US National Institute of Allergy and Infectious Diseases. The versatility and effectiveness of monoclonal antibodies as therapeutics are well established, with many on the market and an even greater number in the pipeline for the treatment of a wide range of diseases.

UPDATE (11 Aug 2022): Both REGN-EB3 (now sold under Regeneron’s brand name Inmazeb) and mAb114 (now sold under Ridgeback Pharmaceutical’s brand name Ebanga) were approved by the U.S. FDA in late 2020. Both were granted orphan drug status.

Mechanisms of Action

REGN-EB3 is a cocktail of three fully-human monoclonal antibodies, which were extracted from mice exposed to the virus. The genetically engineered mice meant that their immune systems could produce human strains of antibodies. Mice antibodies from ordinary mice are generally not well-received by our own immune systems, hence this approach works best. Developed by Regeneron, the trio of antibodies inhibits several virus entry processes.

mAb114 is a single monoclonal antibody treatment, having been initially extracted from the blood of a survivor of the 1995 Ebola outbreak. It works through a different mechanism compared to REGN-EB3. By binding to a region of the ebolavirus surface, it inhibits a key interaction with another region of the virus. This, in turn, prevents its entry into the host cell.

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Future of Ebola Medicine

Despite the overwhelming success of the two new treatments, it would be foolish to regard them as full cures to the ebolavirus. The efficacy of the drugs has yet to be tested on other strains of Ebola present in neighboring regions, which could react differently. Further research and funding are necessary to ensure more options to treat Ebola are available, with an added focus on making the treatments and trials accessible. In these regions especially, not enough people have access to treatments, even if they exist.

In addition, proper monitoring of the virus will enable us to control and predict further outbreaks. Educating communities about the symptoms of Ebola and how to handle infections, including vaccination and treatment options, is another important challenge facing us. Vaccination remains an important strategy to contain and control the spread of the ebolavirus, with several vaccines under development. A promising vaccine drug candidate in advanced clinical trials is based on a recombinant vesicular stomatitis virus (rVSV), showing a 97% effectiveness in protecting individuals from Ebola¹.

There is also the lingering concern that too little attention is paid to diseases in Africa and other less developed areas. Pharmaceutical companies simply do not have the incentives to divert their resources to combat diseases that are prevalent only in these regions. The costs of developing a drug go up into the billions of dollars, and by targeting diseases outside of Western countries, they run the risk of not being able to recoup this amount.

While the Food and Drug Administration (FDA) in the United States has programs in place to incentivize research into cures for these so-called ‘orphan’ or ‘tropical’ diseases, many continue to go under the radar. It is clear that the discovery and development of these new treatments signal the start, not the end, of the cure for Ebola.

Reference

1. Hoenen, T., Groseth, A., & Feldmann, H. (2019). Therapeutic strategies to target the Ebola virus life cycle. Nature Reviews Microbiology, 1.
2. Dyer, O. (2019). Two Ebola treatments halve deaths in trial in DRC outbreak. BMJ, 366:l5140