CERSI Collaborators: University of Maryland, Baltimore MD: James Polli, PhD

FDA Collaborators: National Center for Toxicological Research: Vasily N Dobrovolsky, PhD, Page McKinzie, PhD; Center for Drug Evaluation and Research: Zheng Li, PhD

Project Start Date: November 2, 2022

Regulatory Science Challenge

COVID-19, the respiratory disease caused by SARS-CoV-2 coronavirus infection, has impacted the health of many people in the United States (US) and the world. Early in the pandemic, effective treatment options were limited, which posed challenges for pandemic response. One of the drugs authorized for emergency use for treating COVID-19 infection was Molnupiravir (MOV), a novel drug compound which has also been studied under experimental trials. FDA issued an emergency use authorization (EUA) for MOV, for treatment of mild-to-moderate COVID-19 in adults who are at high-risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative treatment options approved or authorized by FDA are not accessible or clinically appropriate. Since then, many COVID-19 patients have received MOV therapy in the US alone.

Research conducted on the safety of MOV indicated that MOV is an in vitro mutagen (i.e., capable of altering the sequence of DNA) in assays conducted with bacteria and cultured mammalian cells. While such findings indicate that MOV has the potential to cause cancer and genetic diseases, mutagenicity studies conducted in animals (rodents) were largely negative. These animal studies were interpreted as indicating that MOV has little risk of inducing mutations (and causing cancer) in treated patients. To clarify the properties of MOV when administered to humans, researchers aim to determine whether a course of antiviral therapy with MOV results in mutations in white blood cells (WBCs) of COVID-19 patients. For detecting potential mutations, researchers will reveal the genetic makeup of the patient’s WBCs using error-corrected whole genome sequencing (WGS) methods specifically designed to identify rare DNA sequence changes (i.e., mutations). The results of this study will further characterize the MOV safety profile in WBCs, and potentially inform MOV risk in patients.

Project Description and Goals

Researchers will determine whether the current regimen of anti SARS-CoV-2 MOV therapy, i.e., 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days, can induce mutations in WBC DNA of treated patients. Researchers will recruit approximately 20 former COVID-19 patients who received MOV therapy and 20 age-matched former COVID-19 patient control subjects who did not receive MOV therapy. The recruited subjects will provide ~6ml of blood from their cephalic vein via standard venipuncture collection. Patient recruitment and blood collection will be performed by collaborators from M-CERSI. Blood processing and detection of mutations will be performed by the FDA/National Center for Toxicological Research (NCTR) collaborators. Researchers will isolate WBCs from the collected blood, extract genetic material, i.e., endogenous genomic DNA from these WBCs, and perform WGS on the DNA using two different methods. WGS generates enormous volumes of data, and computer assisted analysis will be used to identify mutations, calculate mutation frequencies, and determine mutational signatures (collections of different types of mutations) for each blood sample. Statistical analyses will be used to compare mutational data from the MOV-treated patient and control samples in order to determine if MOV-treated patients show increased frequencies of mutations. Also, researchers will determine if mutational signatures (i.e., the types and locations of mutations in the DNA) in the MOV-treated group are different from the signatures in the control group, and if the mutational signatures in COVID patients (potentially associated with MOV administration) are consistent with mutational signatures established previously for in vitro cultures of mammalian cells treated with MOV. Results from this study have the potential to add to the literature on the effects and potential risks of MOV on WBCs in patients.