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Molnupiravir: A Prospective Oral Antiviral for Treatment of COVID-19  

By: Justin Budz, PharmD Candidate c/o 2023

             On January 19th, 2020, a 35-year-old man in an urgent care clinic in Snohomish County, Washington was the first to be confirmed by the Centers for Disease Control and Prevention (CDC) to be infected with Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 As of March 10, 2022, the United States (US) has accumulated 79,248,406 total cases, with 961,260 of those cases resulting in deaths. Two years after the first case, the US has made great progress towards curbing infection of COVID-19. This is largely due to vaccination efforts; as of March 10, 2022, over 216.4 million Americans (65.2% of the US population) have been fully vaccinated, over 254 million Americans (76.6%) have received at least one dose, and over 95 million Americans (44.2%) have received an additional booster dose. Even with these impressive vaccination rates, new variants of COVID-19 are still causing on average 78.3 weekly cases of COVID-19 per 100,000 US citizens.2

Transmission of COVID-19 mainly occurs via inhalation of airborne droplets and particles containing the virus. Once inside the body, the virus utilizes surface spike protein to bind to Angiotensin-Converting Enzyme 2 (ACE2) receptors present on pneumocytes in the alveoli of the lungs. Once bound to ACE2, the virus enters the host cell via either membrane fusion or endocytosis.3 Inside the cell, viral RNA is translated into polyproteins which aid in the replication and transcription of viral proteins. These proteins are packaged in the Golgi apparatus and are eventually assembled into new viruses that can exit the cell via exocytosis to infect new cells.4 COVID-19 operates mainly as a respiratory disease. As infection persists, the patient will commonly present with dry cough, fever, and shortness of breath.5

Current Proposed Treatment Strategies for COVID-19

With better understanding of COVID-19’s replication process, RNA-Dependent RNA-Polymerase (RdRp) became a drug target of interest. RdRp plays a crucial role in the replication of COVID-19 and remains present in different variants of coronaviruses. Upon translation of mRNA, RdRp acts to replicate the viral genome. If the function of RdRp is inhibited, it would prevent the release of the virion from the host cell.6 A large benefit of using RdRp as a target is that there is no known equivalent of RdRp in humans, therefore greatly reducing the risk of RdRp inhibitors damaging regular host cells.6

Remdesivir (Veklury®) is one of few antiviral drugs authorized for the treatment of hospitalized adult and pediatric patients with COVID-19. Remdesivir is an RdRp inhibitor. It is formulated as an adenosine nucleotide prodrug that is first metabolized to a nucleoside monophosphate via carboxyesterase 1 or cathepsin A. The nucleoside monophosphate is then phosphorylated by cellular kinases to form the pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and has high selectivity over natural ATP for incorporation into nascent RNA chains of RdRp, resulting in delayed chain termination during replication of viral RNA. Remdesivir exhibits antiviral activity against COVID-19 in primary human airway epithelial cells with a 50% effective concentration (EC50) of 9.9 nM after 48 hours of treatment. After 72 hours of treatment, remdesivir inhibits the replication of COVID-19 in continuous human lung epithelial cells with an EC50 value of 280 nM.7

Although remdesivir is a successful treatment option for hospitalized COVID-19 patients, its largest setback is that it can only be administered as an IV injection, limiting its accessibility to patients within a hospital or inpatient acute care setting. Common side effects (incidences occurring ≥ 5%) observed with remdesivir are nausea and increased alanine and aspartate transaminase (ALT/AST) concentrations.7 Even with the development of remdesivir, there is still a substantial demand for medications that are safe, tolerable, and orally effective against COVID-19. Current RdRp inhibitors that have been under investigation for use against COVID-19 include molnupiravir, galidesivir, ribavirin, sofosbuvir, and tenofovir disoproxil fumarate. Molnupiravir stands out from the prospective RdRp inhibitors not only due to its success in clinical trials but because it can be administered as an oral dosage form for the treatment of non-hospitalized COVID-19 patients.

Molnupiravir: Overview

Molnupiravir was originally developed by scientists at Emory University in Atlanta, Georgia for the treatment of alphavirus infections.8 Prior to the COVID-19 pandemic, it was in pre-clinical testing for seasonal influenza. Molnupiravir demonstrated anti-influenza activity and good oral bioavailability in mice, ferrets, and nonhuman primates. Additionally, these early studies showed that molnupiravir was orally effective against coronaviruses, including SARS-CoV and middle east respiratory syndrome coronavirus (MERS-CoV).8 As the COVID-19 pandemic began to develop, the pre-clinical studies began to shift and an agreement to develop molnupiravir as an oral treatment for non-hospitalized COVID-19 patients was signed between Emory University, Ridgeback Biotherapeutics, Wayne & Wendy Holman, and Merck.12 Molnupiravir became a drug of promise as new pre-clinical studies showed that molnupiravir proved effective at reducing COVID-19 infection by blocking transmission in ferrets.12

Molnupiravir is formulated as a ribonucleoside analog that is first converted to n-hydroxycitidine (NHC) and then phosphorylated by host kinases to create the active form NHC-triphosphate. NHC-triphosphate acts as a competitive substrate for RdRp in COVID-19.9 Upon binding to RdRp, molnupiravir disrupts normal RdRp function, causing low-frequency mutations across the viral genome. Predominant mutations were observed as transitional substitutions in nucleotides; changing cytosine to uracil and guanine to adenine. As a result, RdRp generates mutated RNA copies which will eventually lead to a viral error catastrophe, or the accumulation of mutations above a tolerable threshold, resulting in severe impairment or complete loss of viral replication.10

Molnupiravir: Completed Clinical Trials

Molnupiravir progressed to Phase 1 clinical trials sponsored by Ridgeback Biotherapeutics. The study was conducted using 130 participants (109 male, 21 female) ages 19-60 years old. Most participants were White (n =122), followed by Black/African American (n = 4). The average BMI of participants was 24.8 kg/m².11 The phase 1 clinical trials evaluated molnupiravir using single and multiple-dose administrations in a randomized, double-blinded, and placebo-controlled study. Administration of doses ranging from 50 – 1600 mg produced a mean Cmax value of 13.2 ng/mL with a tmax between 0.25 – 0.75 hours. Half-life elimination was about 7 hours. The Cmax and AUC increased in a dose-proportional manner with no accumulation following multiple doses. Absorption of molnupiravir was 36% lower when administered with a meal.12

Primary outcomes of this phase 1 clinical trial focused on accounting for the number of participants with treatment emergent adverse events.12 The main observed adverse effects included headache, diarrhea, and rash. Molnupiravir did not exhibit any negative effects on vital functions or hematological parameters. Doses were well tolerated between 50 – 800 mg given twice daily and 50 – 1600 mg given once daily for a duration of 5 days. Based on the results of this phase 1 clinical trial, molnupiravir exhibits a quick onset of action, a wide therapeutic window, and a safety profile with good patient tolerance.12

Exposure-response analyses from phase 2 clinical trials proved that an 800 mg dose of molnupiravir was the most appropriate for further investigation into phase 3 of the MOVe-OUT trial funded by Merck Sharp and Dohme.13,14  MOVe-OUT is a phase 2/3, double-blind, parallel-group, randomized, placebo-controlled trial evaluating the safety and efficacy of molnupiravir in non-hospitalized adults with COVID-19.14 The study was conducted on 1433 participants (698 male, 735 female) who were 18-90 years of age. Participant races included White (n = 813), Black/African American (n = 75), and Asian (n = 49). A total of 1,424 (99.4%) participants had at least 1 risk factor, the majority being obesity (73.7%), followed by age over 60 years (17.2%), diabetes mellitus (15.9%), and a serious heart condition (11.7%). Participants were randomly assigned in a 1:1 ratio using a centralized, interactive-response technology system to receive either four 200-mg capsules of molnupiravir or identical placebo, administered by mouth twice daily for 5 days. Participants were followed for 29 days.14

Inclusion criteria included laboratory confirmed SARS-CoV-2 infection, onset of signs or symptoms of COVID-19 within 5 days, and at least 1 risk factor for development of severe illness from COVID-19.14 Exclusion criteria included an anticipated need for hospitalization within the first 48 hours, dialysis or estimated glomerular filtration rate less than 30 mL per minute, pregnancy, unwillingness to use contraception during the intervention period and for at least 4 days after completion of the regimen, severe neutropenia, platelet count below 100,000 per microliter, and SARS-CoV-2 vaccination. The use of any therapies intended as COVID-19 treatments were prohibited through day 29.14 The primary endpoint was the incidence of hospitalization for more than 24 hours or death through day 29.14

The primary endpoint was the incidence of hospitalization for more than 24 hours or death through day 29.14 Results concluded that participants receiving molnupiravir had a lower risk of hospitalization or death through day 29. In the molnupiravir group, 6.8% (48/709) of participants were hospitalized as compared to 9.7% (68/699) of participants in the placebo group (95% CI, −5.9 to −0.1).14 The trial also reported 1 death (0.1%) in the molnupiravir group and 9 deaths (1.3%) in the placebo group. The risk of death decreased by 89% (95% CI, 14 – 99) when using molnupiravir compared to placebo.14

Results concluded that participants receiving molnupiravir had a lower risk of hospitalization or death through day 29. In the molnupiravir group, 6.8% (48/709) of participants were hospitalized as compared to 9.7% (68/699) of participants in the placebo group (95% CI, −5.9 to −0.1).14 The trial also reported 1 death (0.1%) in the molnupiravir group and 9 deaths (1.3%) in the placebo group. The risk of death decreased by 89% (95% CI, 14 – 99) when using molnupiravir compared to placebo.14

The secondary endpoint was based on the World Health Organization (WHO) 11-point Clinical Progression Scale and on COVID-19 symptoms reported by patients through day 29.14 In regard of the WHO Clinical Progression Scale, participants in the molnupiravir group showed improved outcomes by day 5 in comparison to the placebo group, with increasing differences observed by days 10 and 15.14 In regard to COVID-19 signs and symptoms, resolution of symptoms was more likely in the molnupiravir group than in the placebo group; 30.4% of participants in the molnupiravir group experienced at least 1 adverse event compared to 33% in the placebo group. The most frequently reported adverse events in the molnupiravir and placebo groups were COVID-19 pneumonia (6.3% vs 9.6%, respectively), diarrhea (2.3% vs. 3.0%, respectively), and bacterial pneumonia (2.0% vs. 1.6%, respectively).14

FDA Issues Emergency Use Authorization

Data from the MOVe-OUT trial supported the claim that oral molnupiravir is an effective treatment for COVID-19. As a result, on December 23rd, 2021, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for Merck’s molnupiravir for the treatment of mild-to-moderate COVID-19 in adults positive for SARS-CoV-2 and who are at high risk for progression to severe COVID-19, including hospitalization or death.15 Molnupiravir is only recommended as an alternative when COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate. It is administered as four 200 milligram capsules taken by mouth every 12 hours for 5 days, for a total of 40 capsules. Molnupiravir should be initiated within 5 days of COVID-19 symptom onset. It is not authorized for pre- or post-exposure prevention of COVID-19 or for initiation of treatment in patients already hospitalized. Molnupiravir should be avoided in patients younger than 18 years of age as it may affect bone and cartilage growth. Molnupiravir should also be avoided during pregnancy as findings from animal reproduction studies show that molnupiravir may cause fetal harm. Females of childbearing age are advised to use a reliable form of birth control during treatment and for 4 days after the final dose. Males of reproductive age are advised to use a reliable form of birth control during treatment and for 3 months after the final dose.15

Many patients infected with COVID-19 can fully recover from the infection with minimal medical intervention.16 However, upon progression to severe disease, both harm to patient health and strains on healthcare systems can be of result. Vaccination remains the most important intervention to lower the risks of hospitalization and death from COVID-19.17 However, new variants of COVID-19 continue to jeopardize high-risk patients, making early treatment options ever so more important. Treatments such as remdesivir and monoclonal antibodies are currently authorized for at-risk outpatients with COVID-19.18 Both agents require administration via infusion or injection in a hospital or inpatient acute care settings. The concurrent FDA issued EUA of nirmatrelvir/ritonavir (Paxlovid ®) and molnupiravir provides patients with multiple oral treatment options that can be easily administered by the patient at home within a shorter time frame of the onset of symptoms and for less of a cost.


As access to new treatments such as molnupiravir emerge, not only does the world become more prepared against new variants of COVID-19 but it also comes closer to shutting the doors of the pandemic. It is essential that pharmacist and other health care practitioners alike stay cognizant of COVID-19 updates so that patients receive the best care possible.


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