Story by Defense Threat Reduction Agency’s Chemical and Biological Technologies Department
What if one antiviral pill could counter several biological threat agents? While broad-spectrum antibiotics have existed for almost one hundred years, broad-spectrum antivirals are relatively new and few in number. With aid from the Defense Threat Reduction Agency’s (DTRA) Chemical and Biological Technologies Department, in its role as the Joint Science and Technology Office (JSTO), a new broad-spectrum antiviral may soon become a reality to support the warfighter. The search for the antiviral began with two collaborators, but grew to include many more, and became relevant in the fight against COVID-19 — and may become relevant in countering diseases caused by other enveloped RNA viruses, such as chikungunya and influenza.
In 2013, DTRA-JSTO awarded Emory University a contract to create a therapeutic for the Venezuelan equine encephalitis virus and other viruses that cause swelling of the brain. The Venezuelan equine encephalitis virus invades the central nervous system and can cause long-term neurological damage, and it is also a biological threat agent; the former Soviet Union weaponized metric tons of the virus after World War II. There is no medicine approved by the Food and Drug Administration for the virus.
DTRA-JSTO had a long list of requirements for the broad-spectrum antiviral. The medicine should be in pill form, easy to manufacture, effective, safe, fast-acting, hard to gain resistance against, and able to reach and heal tissues in the body most hurt by the infection. Given its many conditions, DTRA-JSTO anticipated trade-offs during drug development. Fortunately, the antiviral candidate — EIDD-2801 — has exceeded DTRA-JSTO’s expectations.
To appreciate the potential of EIDD-2801 requires an understanding of the antiviral candidate’s active ingredient: EIDD-1931, which is a ribonucleoside molecule that prevents the RNA virus from replicating, or making copies of itself. This inhibition mechanism is significant because an enveloped RNA virus, like other types of viruses, must replicate inside a person to cause illness. Enveloped RNA viruses include Ebola; the Venezuelan equine encephalitis virus; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19; chikungunya; and influenza. These viruses cause common or uncommon infections, and EIDD-1931 has the potential to stop these viruses from causing disease. Additionally, through the literature, EIDD-1931 is known to reach tissues throughout the body, including the central nervous system. Therefore, DTRA-JSTO had already considered it to counter encephalitic alphaviruses.
However, EIDD-1931 was only effective when administered intravenously, which is not a preferred method of medicine delivery on the battlefield. A pill would be a better method, but the oral form of the compound struggled in leaving the gastrointestinal tract to enter the bloodstream. Researchers needed to reformulate EIDD-1931 so that it could reach the bloodstream and breach the blood-brain barrier to become effective against the Venezuelan equine encephalitis virus and other encephalitic alphaviruses. The blood-brain barrier prevents harmful molecules from entering the central nervous system, which, unfortunately, also limits the penetration of drugs to treat diseases of the central nervous system, such as the Venezuelan equine encephalitis virus.
Because of EIDD-1931’s potential to curb the replication of enveloped RNA viruses, interagency government partners of DTRA-JSTO and the Department of Defense (DoD), including the Department of Health and Human Services (HHS), were interested in the compound’s ability to counter chikungunya and influenza viruses. Once researchers at Emory University had successfully synthesized the oral EIDD-2801 —and demonstrated that the candidate antiviral is able to cross from the gut into the bloodstream and cross the blood-brain barrier — DTRA-JSTO and DoD collaborated with HHS to successfully advance EIDD-2801 through small animal research. The success of the small animal research was a feat unachieved by other candidate compounds for encephalitic alphaviruses.
The next step was to test the candidate antiviral in a large animal model, but no model was available.
Around the time that DTRA-JSTO began its search for a broad-spectrum antiviral pill, the Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) awarded the University of Pittsburgh a grant to develop a nonhuman primate animal model for encephalitic alphaviruses. DTRA-JSTO’s and JPEO-CBRND’s research efforts aligned in November 2019 to evaluate EIDD-2801 in nonhuman primates. A month later, through a peer-reviewed publication in the Journal of Virology,1 researchers announced the compound displayed superior preclinical, broad-spectrum activity against the Venezuelan equine encephalitis virus and other encephalitic alphaviruses — and coronaviruses (Middle East respiratory syndrome and severe acute respiratory syndrome, or MERS and SARS).
In January 2020, the ongoing development of EIDD-2801 gained interest from the pharmaceutical industry. Because EIDD-2801 had displayed antiviral efficacy against coronaviruses, it was potentially useful in curbing the pandemic. One pharmaceutical company sponsored clinical trials in the United Kingdom to test the new compound’s safety and ability to fight COVID-19. The evaluation is now led by another pharmaceutical company, and the company changed the name of the antiviral compound to MK-4482. DTRA-JSTO positioned its resources and acquisition processes to support advanced clinical development of MK-4482 for COVID-19. Data from the evaluation of MK-4482 against COVID-19 may also benefit the warfighter.
Meanwhile, safety and efficacy studies of the antiviral pill to counter the Venezuelan equine encephalitis virus continue in nonhuman primates. These data, and data from studies sponsored by pharmaceutical companies to test the utility of the therapeutic against COVID-19, are forthcoming. If the new antiviral pill is proven to be safe and effective against the Venezuelan equine encephalitis virus in animal models, then DTRA-JSTO will have helped produce the first therapeutic against encephalitic alphaviruses. If the pill is also proven to be safe and effective against COVID-19 and, down the road, against influenza and chikungunya viruses, then DTRA-JSTO will have helped achieve a medical milestone: the development of a broad-spectrum antiviral pill that will be widely available to the warfighter. The promise of the new antiviral pill, one which can counter common and rare diseases, is something the warfighter and the nation can look forward to.
1. Agostini ML, Pruijssers AJ, Chappell JD, et al. 2019. Small-molecule antiviral β-d-N4-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance. Journal of Virology. 93(24). Doi: 10.1128/JVI.01348-19.
POC: Michael A. Johnson, michael.a.johnson138.civ@mail.mil