Despite the invention and distribution of COVID-19 vaccines, new infections in the US still rose to above a hundred thousand per day in recent months [1]. Immuno-suppressed people, as well as people exposed to variants, could still experience severe effects from infection, including death [2]. Along with vaccinations, the medical community must have access to effective, versatile anti-viral drugs to treat infections [2]. One candidate for such a drug is molnupiravir, which was originally developed to treat influenza [3]. Molnupiravir is currently in phase 3 clinical trials for COVID-19 [3].

 

RdRp is an enzyme that assists the bodily spread of SARS-CoV-2 by producing mutated RNA copies for the virus [3]. Scientists believe that molnupiravir operates via a two-step process [3]. First, molnupiravir is converted to EIDD-1931, which, through phosphorylation, becomes EIDD-1931-triphosphate [3]. This triphosphate competes with the RdRp enzyme to procure RNA copies for SARS-CoV-2 [3]. The RNA copies that molnupiravir produces have increased amounts of G-to-A and C-to-U transition mutations, which ultimately promote antiviral activity [4]. This hypothesis has been corroborated by the biochemical and structural data from two studies, one of which also indicated that molnupiravir does not induce viral-resistance mutations and that it is resistant to coronaviruses’ proofreading exoribonucleases [5]. Altogether, these findings suggest that molnupiravir might be the versatile anti-viral drug needed to properly treat patients infected with SARS-CoV-2.

 

During a phase 1 study to determine the safety and pharmokinetic profile of molnupiravirconducted by Painter and colleagues, researchers administered both single and multiple ascending doses to patients in a randomized, double-blind, placebo-controlled experimental setting [2]. They found that EIDD-1931 levels rapidly appeared in subjects’ plasma and reached their maximum levels at around 1 to 1.75 hours [2]. Following that peak, EIDD-1931 plasma concentrations decreased with a half-life of about an hour [2]. Considering that pronounced EIDD-1931 levels are associated with reduced viral potency, these results were very promising.

 

Along with reducing viral activity, phase 1 trials also revealed that molnupiravir is well-tolerated by humans [2]. In one trial, fewer than half of the subjects involved reported an adverse event [2]. Among both the single- and multiple-dose groups, the placebo group experienced more adverse events than the molnupiravir group [6]. Overall, patients reported no severe adverse events, and only two experienced moderate adverse events [6]. One patient in the single ascending dose subgroup experienced headache, while the patient in the other group reported pain in an extremity, influenza-like illness, and oropharyngeal pain [6]. Only one patient discontinued participation early, due to the development of a rash [2]. In terms of safety, the researchers did not uncover any clinically significant findings related to hematological parameters, vital signs, clinical laboratory results, or electrocardiogram data [6]. Phase 2 trial data is not currently available to the public [3].

 

Albeit ongoing, reports from phase 3 trials have shown promising, preliminary evidence on molnupiravir’s efficacy, safety profile, and tolerance by human subjects. Recently, Merck Sharp and Dohme published the results of their phase III trial [7]. They found that molnupiravir reduced patients’ risk of hospital admission or death by 50% in the study population [7]. This population consisted of at-risk adults suffering from mild to moderate COVID-19 who had not been hospitalized [7]. Only 7.3% of patients who took the drug were hospitalized or had died by day 29 of the study, compared with 14.1% of patients in the placebo group [7]. Furthermore, molnupiravir was effective regardless of patients’ varying type, risk factors, or date of symptom onset [7].

 

Ultimately, molnupiravir appears to be a promising means of treating COVID-19. If more phase 3 trials continue to demonstrate similarly positive results, the drug could be approved by the FDA and act as another needed tool in fighting the pandemic.

 

References

 

[1] The New York Times, “Coronavirus in the U.S.: Latest Map and Case Count,” The New York Times, Updated October 22, 2021. [Online]. Available: https://www.nytimes.com/interactive/2021/us/covid-cases.html.

 

[2] G. R. Painter et al., “Developing a direct acting, orally available antiviral agent in a pandemic: the evolution of molnupiravir as a potential treatment for COVID-19,” Current Opinion in Virology, vol. 50, p. 17-22, October 2021. [Online]. Available: https://doi.org/10.1016/j.coviro.2021.06.003.

 

[3] M. Imran et al., “Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19,” Molecules, vol. 26, no. 19, p. 1-18, September 2021. [Online]. Available: https://doi.org/10.3390/molecules26195795.

 

[4] C. J. Gordon et al., “Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template,” Journal of Biological Chemistry, vol. 297, no. 1, p. 1-8, July 2021. [Online]. Available: https://doi.org/10.1016/j.jbc.2021.100770.

 

[5] B. Malone and E. A. Campbell, “Molnupiravir: coding for catastrophe,” Nature Structural & Molecular Biology, vol. 28, no. 9, p. 706-708, September 2021. [Online]. Available: https://doi.org/10.1038/s41594-021-00657-8.

 

[6] W. P. Painter et al., “Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2,” Antimicrobial Agents and Chemotherapy, vol. 65, no. 5, p. 1-14, May 2021. [Online]. Available: https://doi.org/10.1128/AAC.02428-20.

 

[7] E. Mahase, “Covid-19: Molnupiravir reduces risk of hospital admission or death by 50% in patients at risk, MSD reports,” BMJ, Updated October 4, 2021. [Online]. Available: https://doi.org/10.1136/bmj.n2422.