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EIDD-2801 enters clinical trials

Scientists at the Emory Institute of Drug Development (EIDD) at Emory University in Atlanta have developed an antiviral drug they called EIDD-2801. This drug is well absorbed when taken orally and is active against many viruses. EIDD-2801 is an analogue of the nucleoside cytidine. This is a building block of RNA molecules. In lab experiments with cells, EIDD-2801 has antiviral activity against certain RNA viruses, including ones that cause influenza A and B, Ebola and coronaviruses such as the following:

  • SARS-CoV-1 – this causes severe acute respiratory syndrome (SARS)
  • MERS-CoV – this causes Middle East respiratory syndrome (MERS)
  • SARS-CoV-2 – this causes COVID-19

EIDD-2801 appears to work by causing extensive changes, or mutations, in copies of the target virus. By inducing a high degree of mutations in copies of a virus, EIDD-2801 causes many copies of a virus to become non-infectious.

Experiments with mice suggest that EIDD-2801 can prevent disease caused by SARS-CoV-1 if taken as little as two hours prior to experimental exposure.

When EIDD-2801 was given to mice after infection with this virus, the drug reduced the amount of SARS-CoV-1 produced in the lungs. Autopsies of the mice found that the drug reduced the degree of lung injury caused by this virus. As with all antiviral drugs, benefit from EIDD-2801 was greatest if given shortly after infection.

A compressed timeline

Note that coronavirus disease in mice caused by SARS-CoV-1 is accelerated compared to what happens in humans. For instance, in the case of infection with SARS-CoV-1, peak virus levels in the lungs of mice occur on the first or second day after infection. In contrast, in people, virus levels may not peak until seven to 10 days after symptoms have appeared.

About mutations

EIDD-2801 works by causing mutations to appear in copies of coronaviruses made by infected cells. In general, cells infected by viruses tend to have a shortened lifespan. It is plausible that cells not infected by viruses could, in theory, incorporate EIDD-2801 into their regular development and develop mutations. Such mutations in theory have the ability to cause changes to the functioning of cells and perhaps cause abnormal development in such cells. However, according to publicly available documents, such mutations have not been found in lab experiments with EIDD-2801. Still, further experiments and studies in animals are needed to confirm the safety of EIDD-2801.

Another approved broad-spectrum antiviral drug is ribavirin. It works by causing extensive mutations in copies of viruses made by infected cells. However, ribavirin has the potential to cause mutations in uninfected cells. The prescribing information for ribavirin cautions against its use in pregnant women and advises that people planning to conceive children should wait until a certain period of time has passed after cessation of ribavirin.

Historically, ribavirin has been taken for months as part of combination therapy by people with chronic hepatitis C virus. In contrast, treatment with EIDD-2801, if it is eventually approved by regulatory authorities, is likely to be for a shorter period—probably one or two weeks. This reduced exposure should contribute to EIDD-2801’s long-term safety.

Resistant virus

If all goes well, another broad-spectrum antiviral drug, remdesivir, is likely to be approved for use as a treatment for people with COVID-19. It is plausible that one day SARS-CoV-2 could mutate, as many viruses do, and develop reduced susceptibility to remdesivir. Based on research with coronaviruses that infect mice, EIDD-2801 is able to treat mouse coronaviruses that are resistant to remdesivir. These experiments need to be repeated with SARS-CoV-2.

Clinical development

Unpublished data suggest that EIDD-2801 is generally safe in a phase I clinical trial. The pharmaceutical company Merck, called MSD outside of Canada and the U.S., will be developing EIDD-2801.

The broad antiviral activity of EIDD-2801 suggests that it has potential for being tested in clinical trials against seasonal and pandemic influenza and coronaviruses.

—Sean R. Hosein

REFERENCES:

  1. Sheahan TP, Sims AC, Zhou S, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Science Translational Medicine. 2020;12(541):eabb5883.
  2. Merck. Merck and Ridgeback Bio collaborate to advance development of novel antiviral candidate, EIDD-2801. Press Release. 26 May 2020.