The Joint Program Executive Office for Chemical,
Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum
antiviral countermeasure against deliberate use of high-consequence
viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of
Ebola virus disease (EVD).
Remdesivir (
GS-5734,
Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort.
Remdesivir is an inhibitor of
RNA-dependent RNA polymerase, a viral
enzyme that is essential for viral replication. Its robust potency and broad-spectrum
antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing
Coronavirus Disease 2019 (COVID-19) pandemic today.
Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of
COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute
viral infections for patients afflicted with both EVD and
COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination
therapy that joins
therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear
drug and
biological product development pathway for
therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example,
remdesivir's clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for
remdesivir is likely to be the exception rather than the rule. The current regulatory licensure pathway for
therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA's established Animal Rule (21 CFR 314.600-650 for drugs; 21 CFR 601.90-95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the
drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include
aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the
therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of
remdesivir as illustrative of the effort that will be needed to field future
therapeutics against highly lethal, infectious agents.