Dr. Timothy Sheahan in 2017 works in a lab at the UNC-Chapel Hill Gillings School of Global Public Health. [Photo Courtesy of Mary Lide Parker]

Clinical studies evaluating an antiviral drug that is in development against SARS-CoV-2 are expected to begin later this spring. Scientists working to develop the drug, which is called EIDD-2801, suggest that if trials are successful, the drug could not only be used to limit the spread of SARS-CoV-2, but could also control future outbreaks of other emerging coronaviruses. EIDD-2801 is an orally available form of the antiviral compound EIDD-1931, which has shown promise in reducing lung damage in animal models.

Researchers at the University of North Carolina (UNC) at Chapel Hill Gillings School of Global Public Health are playing a key role in the development and testing of EIDD-2801. The team, together with U.S. collaborators, has now reported on results from tests evaluating the drug in cultured human lung cells infected with SARS-CoV-2, as well as in mice infected with the related coronaviruses SARS-CoV (severe acute respiratory syndrome-coronavirus) and MERS-CoV (Middle East respiratory syndrome coronavirus). Their results showed that, when used prophylactically, or administered early following infection, EIDD-2801 can prevent severe lung injury in infected animals.

Virologists in the lab of Ralph Baric, PhD, the William R. Kenan Jr., distinguished professor of epidemiology, are working with colleagues in the lab of Mark Denison, PhD, the Edward Claiborne Stahlman professor of pediatrics at Vanderbilt University Medical Center (VUMC), and with George Painter, PhD, CEO of the nonprofit DRIVE (Drug Innovation Ventures at Emory) and director of the Emory Institute for Drug Development (EIDD), where EIDD-2801 was discovered. Their results are reported in Science Translational Medicine, in a paper titled, “An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.”

Three new human coronaviruses have emerged in the past 20 years; SARS-CoV in 2002, MERS-CoV in 2012, and SARS-CoV-2 in 2019, the authors wrote. There are currently no antiviral drugs approved to treat SARS-CoV-2 or any human CoV. In fact, all human coronaviruses are thought to have emerged as zoonoses, the researchers pointed out. Zoonotic diseases are those that have made the species jump from animals into humans. “More alarmingly,” they further noted, there are many SARS-like and MERS-like coronaviruses circulating in bat reservoir species that can use human receptors and replicate efficiently in primary human lung cells, without adaptation. “The group 2b SARS-like CoV represent an existential and future threat to global health as evidenced by the emergence of SARS-CoV and SARS-CoV-2,” they wrote. “The presence of these ‘pre-epidemic’ zoonotic strains foreshadow the emergence and epidemic potential of additional SARS-like and MERS-like viruses in the future. Given the diversity of CoV strains in zoonotic reservoirs and a penchant for emergence, broadly active antivirals are clearly needed for rapid response to new CoV outbreaks in humans and domesticated animals.”

β-D-N4-hydroxycytidine (NHC, EIDD-1931) is an orally bioavailable ribonucleoside analog that has been shown to have broad-spectrum antiviral activity against various unrelated RNA viruses, including influenza, Ebola, CoV, and Venezuelan equine encephalitis virus (VEEV). For their reported studies, the UNC-led team first tested NHC against SARS-CoV-2, MERS-CoV and SARS-CoV in human lung cell cultures. Following what they described as the “promising antiviral activity of NHC in vitro, the team then tested the in vivo efficacy of an orally bioavailable prodrug of NHC, β-D-N4-hydroxycytidine-5’-iso propyl ester, or EIDD-2801, which had been designed or optimized bioavailability in humans and non-human primates.

Their results in mice showed that when given as a treatment 12 or 24 hours after the start of infection, EIDD-2801 reduced the degree of lung damage and weight loss in mice infected with SARS-CoV or MERS-CoV. And while the therapeutic window of opportunity for treatment in mice was quite narrow, it is expected that this treatment window will be longer in humans—possibly spanning the first week of symptoms—because it takes longer for the disease to progress in humans than it does in mice. “Although the improvement in both SARS- and MERS-CoV outcomes diminished with the delay of treatment initiation time, it is important to note that the kinetics of disease in mice are compressed as compared to that in humans,” the team wrote. Mice will show peak lung titers within a couple of days, in parallel with the onset of clinical signs and lung damage, whereas in humans this typically occurs 7–10 days after the onset of symptoms. “… early intervention with an antiviral like EIDD-2801 is likely to provide the most clinical benefit although there may opportunities in severe patients where the duration of virus replication may be extended,” the scientists stated.

Compared with other potential COVID-19 treatments that must be administered intravenously, EIDD-2801 can be delivered orally. In addition to ease of treatment, this offers a potential advantage for treating patients who are less unwell, or potentially for prophylaxis, for example, in a nursing home where many people have been exposed but are not yet sick. And as Baric further stated, “This new drug not only has high potential for treating COVID-19 patients, but also appears effective for the treatment of other serious coronavirus infections.” The researchers concluded, “The potency of NHC/EIDD-2801 against multiple coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses … Together, our data support the continued development of EIDD-2801 as a potent broad spectrum antiviral that could be useful in treating contemporary, newly emerged, and emerging coronavirus infections of the future.”

The authors acknowledged that their study does have limitations, and the drug candidate wasn’t tested against SARS-CoV-2 directly mice because there aren’t yet any robust mouse models that recapitulate SARS-CoV-2 pathogenesis in humans. This is due to the “virus spike glycoprotein and mouse ACE2 receptor incompatibility complicating the evaluation of medical countermeasures,” they pointed out. And because a mouse model for SARS-CoV-2 doesn’t exist, testing of EIDD-2801 may circumvent some steps, suggested first author Timothy Sheahan, PhD, a Gillings assistant professor of epidemiology and a collaborator in the Baric Lab. “… in normal times, testing in nonhuman primates would be the obvious next step on the road to human testing. Since these are not normal times, this could be skipped and evaluated under compassionate use and established clinical trials in people. The goal is to directly attack the virus, lessen symptoms, decrease pathogenesis, and save lives.”

Andrea Pruijssers, the lead antiviral scientist in the Denison Lab at VUMC, further stated, “We are amazed at the ability of EIDD-1931 and -2801 to inhibit all tested coronaviruses and the potential for oral treatment of COVID-19. This work shows the importance of ongoing National Institutes of Health (NIH) support for collaborative research to develop antivirals for all pandemic viruses, not just coronaviruses.” Denison was senior author of a December 2019 study that first reported that EIDD-1931 blocked the replication of a broad spectrum of coronaviruses.

The interinstitutional collaborators, supported by an NIH grant through the University of Alabama at Birmingham, also performed the preclinical development of remdesivir, another antiviral drug that is currently in clinical trials of patients with COVID-19. In the Science Translational Medicine paper, Maria Agostini, PhD, a postdoctoral fellow in the Denison lab, demonstrated that viruses that show resistance to remdesivir experienced higher inhibition from EIDD-1931. “Viruses that carry remdesivir resistance mutations are actually more susceptible to EIDD-1931 and vice versa, suggesting that the two drugs could be combined for greater efficacy and to prevent the emergence of resistance,” said Painter.

And EIDD-2801 may offer several therapeutic advantages over remdesivir, the authors further suggested. Unlike remdesivir, which must be administered intravenously, “EIDD-2801 is an oral drug that could be administered at home, early after diagnosis,” continued Sheahan. “This has the potential to be as ubiquitous as Tamiflu in the future, as long as it proves to be safe and effective in people … With three novel human coronaviruses emerging in the past 20 years, it is likely that we will continue to see more. EIDD-2801 holds promise to not only treat COVID-19 patients today, but to treat new coronaviruses that may emerge in the future.”

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