A CETR-based partnership accelerator for rapid drug development targeting SARS-CoV-2 and pan-CoVs

Summary: The unprecedented COVID-19 global health crisis is fueled by the absence of an effective vaccine and no specificantiviral drugs. Consequently, major research efforts have focused on identifying efficacious therapies. The mosteffective short-term solution is repurposing and repositioning of approved drugs or clinical-stage drug candidates,as this approach shortens the time to the clinic. Furthermore, as there are no drugs against any zoonoticcoronaviruses associated with human respiratory infections, pan-coronavirus drug regimens are vital to counterfuture outbreaks. To best address this urgency, a drug development Accelerator has been established as aformal partnership between our NIH Center of Excellence in Translational Research (CETR) and Merck andCo., Inc., a global leader in the discovery and development of antiviral drugs. The CETR program, which isfocused on novel and repositioned drugs against high-threat bacterial infections, provides a comprehensiveplatform for drug discovery. Merck brings a full complement of approved antiviral drugs and advanced candidatesfor repurposing and repositioning, with an emphasis on novel nucleoside and protease inhibitors. Firstly, smallmolecule compounds representing both FDA approved drugs and clinical stage drug candidates discoveredagainst other viruses will be evaluated in viral cytopathic and neutralization assays to assess inhibition of SARS-CoV-2. Lead candidates will be assessed for EC50/90/CC50 values, ADME pharmacokinetics, and safety todetermine their potential for immediate use in therapy. If data supports a robust therapeutic window, thenrepurposed compound(s) will be submitted for an IND under FDA EUA. A rodent model utilizing SARS-CoV-2infection will be used to assess in vivo PK/PD parameters supporting clinical dose ranging and safety margins.Secondly, a pan-coronavirus drug development candidate will be identified from either drug repositioning or fromMerck's focused compound libraries for existing antiviral classes discovered against other conserved viraltargets, as well as new lead series to host and viral targets representing >65 mechanisms of action. Thesecompounds will be screened in a high throughput virus challenge assay. SAR will benefit from the multi-millioncompound Merck sample collection via in silico substructure and similarity searches. Lead compounds will beassessed for robust in vivo therapeutic efficacy against SARS-CoV-2; metabolic stability, toxicity, ADME,rodent tolerability; pharmacologic properties consistent with QD or BID dosing, and acceptable safetymargins supportive of initiation of first in human clinical studies. The ultimate goal is the identification ofdevelopment candidates that can enter preclinical IND enabling safety derisking studies. This is anunprecedented public-private partnership for drug discovery The goal of this drug Accelerator is to identify arepurposed compound(s) that can treat COVID-19 patients within 4-6 months and by the end of Year 2, identifycandidates with pan-coronavirus efficacy that can enter preclinical IND-enabling and derisking studies.