Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice

Ju Hwan Jeong; Santosh Chokkakula; Seong Cheol Min; Beom Kyu Kim; Won-Suk Choi; Sol Oh; Yu Soo Yun; Da Hyeon Kang; Ok-Jun Lee; Eung-Gook Kim; Jang-Hoon Choi; Joo-Yeon Lee; Young Ki Choi; Yun Hee Baek; Min-Suk Song

doi:10.1016/j.antiviral.2022.105430

Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice

Antiviral Res. 2022 Dec:208:105430. doi: 10.1016/j.antiviral.2022.105430. Epub 2022 Oct 6.

Authors

Affiliations

¹ Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Chungbuk, 28644, South Korea.
² Department of Pathology, Chungbuk National University Hospital, Cheongju, South Korea.
³ Department of Biochemistry, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Chungbuk, 28644, South Korea.
⁴ Division of Acute Viral Disease, Center for Emerging Virus Research, National Institute of Infectious Diseases, Korea National Institute of Health, Cheongju, 28159, South Korea.
⁵ Center for Emerging Virus Research, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju-si, South Korea.
⁶ Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Chungbuk, 28644, South Korea; Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, 34126, South Korea.
⁷ Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Chungbuk, 28644, South Korea. Electronic address: songminsuk@chungbuk.ac.kr.

Abstract

As the SARS-CoV-2 pandemic remains uncontrolled owing to the continuous emergence of variants of concern, there is an immediate need to implement the most effective antiviral treatment strategies, especially for risk groups. Here, we evaluated the therapeutic potency of nirmatrelvir, remdesivir and molnupiravir, and their combinations in SARS-CoV-2 infected K18-hACE2 transgenic mice. Systemic treatment of mice with each drug (20 mg/kg) resulted in slightly enhanced antiviral efficacy and yielded an increased life expectancy of only about 20-40% survival. However, combination therapy with nirmatrelvir (20 mg/kg) and molnupiravir (20 mg/kg) in lethally infected mice showed profound inhibition of SARS-CoV-2 replication in both the lung and brain and synergistically improved survival rates up to 80% compared to those with nirmatrelvir (36%, P < 0.001) and molnupiravir (43%, P < 0.001) administered alone. This combination therapy effectively reduced clinical severity score, virus-induced tissue damage, and viral distribution compared to those in animals treated with these monotherapies. Furthermore, all these assessments associated with this combination were also significantly higher than that of mice receiving remdesivir monotherapy (P < 0.001) and the nirmatrelvir (20 mg/kg) and remdesivir (20 mg/kg) combination (P < 0.001), underscored the clinical significance of this combination. By contrast, the nirmatrelvir and remdesivir combination showed less antiviral efficacy, with lower survival compared to nirmatrelvir monotherapy due to the insufficient plasma exposure of the remdesivir, demonstrating the inefficient therapeutic effect of this combination in the mouse model. The combination therapy with nirmatrelvir and molnupiravir contributes to alleviated morbidity and mortality, which can serve as a basis for the design of clinical studies of this combination in the treatment of COVID-19 patients.

Keywords: Combination therapy; In vivo; Molnupiravir; Nirmatrelvir; Remdesivir; SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology
COVID-19 Drug Treatment*
Mice
Mice, Transgenic
SARS-CoV-2*

Substances

molnupiravir
Antiviral Agents