(T1530-05-31) Exposure Response Assessment of a Novel, Directly Acting Antiviral, BDGR-251, in EEEV Infected Mice

Purpose: BDGR-251 is a novel, directly acting antiviral with outstanding in vivo efficacy in both pre-exposure prophylaxis and post-exposure therapy in murine infection models of Eastern Equine Encephalitis Virus (EEEV). Here, we report on the exposure-response relationship of BDGR-251 in both scenarios.

Methods: BALB/c mice were intranasally infected with plasmid derived EEEV V105. In the prophylactic studies, intraperitoneal drug treatment was started 2 hours prior to infection and continued for 5 days while in therapeutic studies, treatment was delayed for 48 hours post infection. Groups of animals (n=3) were sacrificed at up to 13 predefined time points within 5 days after initiation, plasma and brain tissue were harvested, and BDGR-251 concentrations (via LC-MS/MS) and viral load (via plaque assay) were quantified.

Results: Drug exposure in plasma and brain was found to be dose proportional. The viral load in brain of untreated animals increased exponentially and peaked at 72 hours post infection, followed by death of all animals. In the prophylactic scenario, 24 mg /kg given once daily (QD) completely prevented detectable viral load, while dosing 12 mg/kg twice daily (BID) suppressed detectable viral load until 96 hours. Lower doses of 6 mg/kg QD and 3 mg/kg BID were only able to suppress detectable viral load for 48 h and 72 h, respectively. In the therapeutic scenario, 24 mg/kg QD resulted in complete viral load suppression after 2.5 days of dosing (from 10⁸ to < 10¹ pfu/g brain), while 12 mg/kg BID did not consistently suppress viral load in the brain.

Conclusion: In conclusion, we were able to establish that the compound BDGR251 has drug concentration-dependent viral killing of the tested EEEV strain. The 24 mg/kg drug dose eradicated detectable virus in both prophylactic and therapeutic scenarios.

References: 1. Eastern equine encephalitis virus neuroinvasive disease cases reported by year, 2010–2019. ArboNET, Arboviral Disease Branch, Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Vector-Borne Diseases; cdc.gov [accessed 13 August 2021].
2. E. Reichert, A. Clase, A. Bacetty, J. Larsen, Alphavirus antiviral drug development: Scientific gap analysis and prospective research areas. Biosecur. Bioterror. 7, 413–427 (2009).
3. Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models, Xufeng Cao, Dong Yang , Jyothi Parvathareddy, Yong-Kyu Chu, Eun Jung Kim, Jhewelle N Fitz-Henley, Xiaoyu Li, Pradeep B Lukka, Keyur R Parmar, Zaid H Temrikar, Priya Dhole, Robert Scott Adcock, Jon Gabbard, Shruti Bansal, Jasper Lee, Lillian Zalduondo, Ernestine Hayes, Jennifer Stabenow, Bernd Meibohm, Elizabeth A Fitzpatrick, Kevin Bailey, Rafael K Campos, Justin G Julander, Shannan L Rossi, Donghoon Chung, Colleen B Jonsson, Jennifer E Golden, Sci Transl Med. 2023.

Acknowledgements: This work has been supported by NIH grant 1U19AI171292-01 through the Rapidly Emerging Antiviral Drug Development Initiative - AViDD Center (READDI-AC) at the University of North Carolina. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. The authors are thankful to the staff of the University of Tennessee Health Science Center Department of Pharmaceutical Sciences and Regional Biocontainment Lab for their support provided in the presented studies. This is an Encore presentation.


Treatment and sample schedule in Prophylactic and Therapeutic scenario


Pharmacokinetic profile of BDGR251


Viral Load in different dosing regimen