The COVID-19 pandemic, caused by SARS-CoV-2, had resulted in significant increase in mortality and morbidity globally. The clinical profile of COVID-19 ranges from asymptomatic to life-threatening events. Early intervention in asymptomatic and mild COVID-19 patients in high-risk category would reduce the further progress of disease. When there is a high level of viral RNA in the blood, there will be more chances of severe infection, transmission and hospitalization. Therefore, an effective oral antiviral drug is required to combat this. Currently, remdesivir is the only antiviral drug that is approved by the US-FDA for the treatment of SARS-CoV-2 infection. Some of the antiviral drugs used off label are favipiravir, lopinavir, oseltamivir, among others. Recently, many drugs received emergency use authorization (EUA) by the US-FDA for COVID-19 including the combination of nirmatrelvir and ritonavir, Molnupiravir, and anti-SARS CoV-2 antibodies.


Molnupiravir is one of the oral antiviral drugs under consideration for COVID-19. This oral agent was developed by Drug Innovation Ventures at Emory University, Atlanta, GA and later was acquired by Ridgeback therapeutics in partnership with Merck and Co, USA. Previously, it was developed for the treatment of influenza viruses and encephalitic alpha viruses like Venezuelan, Eastern and Western equine encephalitic viruses with its significant inhibitory effect in cell cultures [1, 2]. 

Pharmacokinetic studies showed that the twice daily administration of Molnupiravir will provide sufficient drug concentration in the respiratory tissues [3]. The dose used was 800 mg orally twice daily for 5 days, with or without food, within 5 days of symptom onset. It is available as a 200-mg capsule [4]. The clinical trials in other viral infections showed that it was well absorbed orally, and the rate of absorption significantly decreased but not the extent of absorption when given with food. Mutagenicity, reported during the use of this drug through in vitro studies, is a major drawback for not inclusion of this drug in COVID-19 treatment guidelines [5]. The commonly observed adverse effects (AE) were nausea, diarrhea and headache. Other AEs reported were back pain, hot flushes, influenza-like syndrome, pain in extremity and rhinorrhea [4,5,6]. It has been reported that this drug affects cartilage and bone growth and causes fetal growth retardation in preclinical studies, hence not recommended in children and pregnant woman [4, 7].

In in vitro study, addition of Molnupiravir to human airway epithelial cell culture against SARS-CoV-2, improved the air way cell function and decreased the viral titer [8]. Molnupiravir reduced the SARS-CoV-2 replication in human lung-only mice (LoM) [9] and in the Syrian hamster model [10]. Decrease in the viral RNA load was demonstrated in in vivo studies by Abdelnabi et al. In this study, Molnupiravir was studied in combination with favipiravir [11]. Molnupiravir acts by increasing the mutation rate in the SARS-CoV-2 genome which is lethal to the virus and causes death of virus [3, 8, 12, 13]. The detailed mechanism of action of Molnupiravir in COVID-19 is depicted in Fig. 1. Based on the available data in other viral infections and preclinical studies, clinical trials were conducted with Molnupiravir for SARS-COV-2 infections.

Fig. 1
figure 1

Mechanism of action of Molnupiravir in COVID-19. Molnupiravir is a prodrug, converted to an active nucleoside b-D-N4-hydroxycytidine (NHC) by the host esterases present in the plasma. This active compound is converted to its triphosphate (NHC triphosphate). RNA-directed RNA polymerase (RdRp) uses NHC triphosphate as its substrate in place of cytidine and uridine forming stable complexes and forms mutated RNA. This escapes from proofreading. Molnupiravir increases the mutation rate in the viral genome which exceeds biologically tolerable threshold (“error catastrophe”). This mutation is lethal to the virus and finally leads to death of virus [12, 13]

Fig. 2
figure 2

PRISMA flow chart

The present systematic review was conducted with the aim to find out the evidence on efficacy and safety of Molnupiravir in COVID-19 through clinical studies.


Search strategy

Literature search was carried out by two authors (KRM and ME) in PubMed, MedRxiv, BioRxiv, FDA, ClinicalTrials.Gov, and Google Scholar and also by cross-referencing the articles. Keywords used for the purpose of this review included “Molnupiravir”, “MK-4482”, “Oral antiviral pill”, EIDD-2801”, “COVID-19”, “SARS-CoV-2″, “Efficacy”, “Safety” and “Clinical Trial”. The literature search was done for the articles published from January 2021 to March 2022. The search strategy is depicted in Fig. 2.

Selection criteria

Intervention studies, original research mainly Randomized Controlled Trials (RCTs) and interim reports of unpublished RCTs were included in this review.

Articles were screened by examining the titles and abstracts. Articles with inaccessible full text, preclinical studies, review and duplicated articles, commentaries, editorials, perspectives and conference papers were excluded.

An additional search was done in the and for ongoing clinical trials with Molnupiravir in COVID-19. The details of the ongoing trials data was collected from CTRI India and clinical

Data extraction

For eligible articles, full text was accessed and read for the purpose of this review. Data extraction was done for original research studies of published and unpublished with interim reports. The data extraction sheet was used to extract details such as study title, author name, year of publication, objectives, study participants (inclusion and exclusion criteria), interventions, outcomes (both safety and efficacy).

For ongoing studies, the trial registration number, type and phase of study, sample size, arm details, inclusion and exclusion and outcomes were noted.


Outcome parameters to assess safety and efficacy of Molnupiravir were categorized as below:

  • Efficacy

    • Incidence of hospitalization or death at day 29

    • Mean viral load

    • RT-PCR negativity

    • Isolation of infectious virus from nasopharyngeal swabs

    • Clinical improvement and progression of COVID-19

  • Safety: Reported adverse events (AEs)/SAEs (serious adverse events)/death


A total of 100 articles were collected. After initial screening, 30 articles were included. After full text review, 4 RCTs and 2 unpublished RCTs with interim reports were included for this review. The data of 18 ongoing trials was also collected.

Published clinical studies

Out of the 4 studies with Molnupiravir, the phase I study was done on healthy volunteers (n = 130) to find out the safety and dosing range of Molnupiravir. It was found safe and well tolerated. There was no decrease in absorption in the fed state. The tested dose ranges from 50 to 800 mg (single dose up to 1600 mg) two times a day for 5 and half days. The incidence of adverse events in placebo group was higher compared to Molnupiravir group; it was 43.8% vs. 35.4%, with single dose and 50.0% vs. 42.9%, multiple ascending doses, respectively (Table 1). The most commonly reported adverse event was headache in single ascending dose study and diarrhea in multiple ascending dose study [4].

Table 1 Safety data of Phase I and Phase II studies on Molnupiravir

The second study was AGILE trial which was a Phase Ib/IIa dose escalation study conducted in eighteen COVID-19 patients. Patients within 5 days of symptom onset were recruited and randomly allocated to three sequential dose cohorts (300, 600 and 800 mg) of 6 participants in each group. The results showed that 25% of patients who received 800 mg and 83% of standard of care had mild adverse events. Molnupiravir 800 mg twice daily was considered safe and well tolerated, with a plasma concentration within the target range [14]. Other details of Phase I and Phase II clinical trials on Molnupiravir are shown in Table 1.

The Phase IIa study was conducted in 202 unvaccinated adults with 200, 400, and 800 mg of Molnupiravir in RT-PCR positive SARS-CoV-2 infection. The baseline antibodies status was higher (35%) compared to placebo (18%) group. Results showed that the time to viral clearance was significantly decreased in the Molnupiravir 800 mg arm compared to the placebo arm (log-rank p value < 0.013, median: 14 days vs. 15 days) but not with 200 mg and 400 mg of Molnupiravir. This was highly significant in sero-negative patients (median: 14 days vs. 27 days; p value < 0.01). On day 28, the viral clearance was 92.5%, 91.3%, 78.7% and 80.3% with 800 mg, 400, 200 mg of Molnupiravir and placebo, respectively.

The isolation of virus from nasopharyngeal swabs was significantly less in Molnupiravir group compared to placebo group, and it was 1.9% vs. 16.7% and 0% vs. 11.1% on day 3 and day 5, respectively. The significant difference was observed between the doses of 400 and 800 mg of Molnupiravir.

The median time to resolution of COVID-19 symptoms was 8 days (95% CI, 6.0 to 12.0) vs. 8.5 days (95% CI, 7.0 to 11.0) in Molnupiravir 800 mg and placebo, respectively. Adverse events and other primary outcomes are mentioned in Table 2 [15].

Table 2 Efficacy and safety outcomes of published studies on Molnupiravir in COVID-19

Phase III clinical trial (MOVe-OUT trial) was conducted in non-hospitalized patients with mild-to-moderate disease and with at least one risk factor for progression to severe illness. It has been reported that, in the intention-to-treat population, the risk of hospitalization for any cause or had died through day 29 was lower with Molnupiravir (7.3% [28 of 385 participants]) compared to placebo (14.1% [53 of 377 participants]). The difference reported was −6.8 percentage (95% confidence interval [CI], −11.3 to −2.4; p = 0.001). The absolute risk difference of −5.4 (95% confidence interval, −9.9, −1.0) was observed on high viral load (> 106 copies/mL) at baseline.

A pre-specified supporting analysis showed that only 6.3% vs 9.2% of COVID-19–related hospitalizations or deaths occurred in the Molnupiravir group compared to the placebo group (difference, −2.8 percentage points; 95% CI, −5.7 to 0.0).

One death was reported in the Molnupiravir group, and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants in the Molnupiravir group and 231 of 701 in the placebo group. At baseline, quantifiable RNA was confirmed in 77.6% nasopharyngeal samples. The mean change of SARS-CoV-2 nasopharyngeal RNA titer from baseline over time was −0.33 (95% CI, −0.50, −0.16) [16].The efficacy and safety outcome details are shown in Table 2.

Unpublished studies with interim reports

The unpublished studies whose interim reports/data were given in the press release have been summarized in Table 3. These studies were Phase III studies conducted by Hetero Pharma [17] and Optimus Pharma companies [18] in India. For review of the data, the information was obtained from the press release information by Hetero Pharma Company and through email communication from the Optimus Pharma Company. Incidence of hospitalization was very less on day 14 in Phase III conducted Optimus Pharma. The clinical improvement based on a 2-point decrease in WHO clinical progression scale was significant on day 5, and the difference was nearly 40% in the Hetero Pharma study and not significant in the Optimus Pharma trial. Significantly increased RT-PCR negativity was observed from Day 5 to Day 14 in case of Hetero Pharma trial results and Day 5 to Day 10 in Optimus Pharma trial. Median time to clinical improvement was significantly reduced in the Hetero Pharma trial but not in the Optimus Pharma trial. Discontinuation of treatment due to drug-related AEs was reported in around 0.3% in the Optimus Pharma trial.

Table 3 Efficacy and safety outcomes of Molnupiravir in COVID-19 unpublished studies

Ongoing clinical trials

There are nearly 18 ongoing trials with Molnupiravir registered with CTRI and In these trials, Molnupiravir at 800 mg twice daily plus standard of care is comparing with standard of care alone. Most of the studies are testing this drug in mild COVID-19 patients. Six trials are registered in clinical and remaining in CTRI India. Four studies are testing Molnupiravir in moderate cases of COVID-19. One trial (MOVe-AHEAD) is being conducted in the prevention of COVID-19. Details of the sample size and outcome parameters to be measured are shown in Table 4 [19,20,21,22,23].

Table 4 Ongoing clinical trials with Molnupiravir in COVID-19

Approval status by regulatory authorities of various countries

Medicines and Healthcare products Regulatory Agency (MHRA) of the UK authorized Molnupiravir on November 4, 2021, based on interim analysis of MOVe-OUT study. Molnupiravir from Ridgeback/Merck had received EUA by the US-FDA on December 23, 2021 for non-hospitalized adult patients with mild-to-moderate COVID-19. Additionally, Molnupiravir had also received restricted use authorization (RUA) from the Central Drugs Standard Control Organization (CDSCO), India on December 28, 2021 [24].


Globally 575,887,049 confirmed cases of COVID-19 including 6,398,412 deaths have been reported to WHO as of 2 August 2022 [25]. Infection with SARS-CoV-2 virus can cause a range of clinical manifestations, from no symptoms to critical illness. Based on the severity of illness, they grouped into asymptomatic, mild, moderate and severe illness. It has been reported that mild COVID-19 disease patients with underlying co-morbidities are at high risk for progressing to severe COVID-19 [26].

A comparative risk analysis study from USA reported that nearly two-thirds of COVID-19 hospitalizations could be ascribed to diabetes, obesity, hypertension and heart failure [27].

For these high-risk people to treat mild to moderate COVID-19, US-FDA has authorized antiviral medications such as Nirmatrelvir with Ritonavir combination, Molnupiravir and monoclonal antibodies (Ab) such as Cock tail Ab, bemlaninivimab, and etesivimab and bebtelovimab.

Molnupiravir, a direct oral antiviral drug, was initially developed for the treatment of influenza viral infection. This drug has shown potent antiviral activity against SARS-CoV-2. Antiviral drugs could be used to keep viral burden down in order to minimize transmission and to suppress the development of more virulent strains. Molnupiravir has received EUA in 3 countries for treatment of mild-moderate COVID-19 in certain adults who are at high risk for progression to severe COVID-19, including hospitalization or death.

It is the first oral antiviral drug to be included in the WHO treatment guidelines for COVID-19. WHO recommended this drug based on the largest data of six randomized controlled trials involving 4796 patients [28].

Molnupiravir is available as oral tablet, and four tablets (total 800 mg) should be given twice daily for 5 days within 5 days of symptom onset. It has been reported that use of this drug as early as possible after infection can help prevent hospitalization.

The NIH COVID-19 treatment guideline panel recommends use of Molnupiravir ONLY when ritonavir-boosted nirmatrelvir or remdesivir cannot be used [29].

Till now, there is no data available on the Molnupiravir combination with antiviral drugs for the treatment of mild COVID-19 patients, and further studies are required to find out if combination therapy will have beneficial effects.

Molnupiravir acts through inhibition of RdRp enzyme (RNA replicase). This enzyme catalyzes the replication of RNA from an RNA template and is one of the 16 non-structural proteins (nsp) coded by the gene. Other antivirals which inhibit this enzyme are ribavarin, sofosbuvir, remdesivir and favipiravir. The last two drugs were repurposed in COVID-19. Remdesivir has already received approval by the US-FDA for use in hospitalized COVID-19 patients. This drug is given through the parenteral route. The oral antiviral drug which gained popularity during the first wave of COVID-19 was favipiravir; however, it was not approved by US-FDA. The various features of these antiviral drugs are mentioned in Table 5.

Table 5 Comparison of pharmacokinetics and pharmacodynamics of various antiviral drugs

The main concern of Molnupiravir is mutagenicity which is more closely explained with the drug’s basic mechanism of action against COVID-19. Molnupiravir is a cytidine nucleoside analogue and enters the virus RNA and causes mutations that prevent it from replication. It has been reported through animal cell culture that Molnupiravir causes mutations in human DNA.

Merck has conducted assays such as Big Blue and PIG-a for assessing the mutagenicity or genotoxicity of Molnupiravir in in vivo mammalian systems. Molnupiravir, at higher and longer doses (mg/kg), gave equivocal results in in vivo PIG-a mutagenicity assay and negative results in in vivo Big Blue model [30, 31].

FDA reviewed the genotoxicity and clinical study (treatment with Molnupiravir for 5-day) data and concluded that Molnupiravir has a low risk for genotoxicity [32].

Because of the safety concern, ICMR had not included this drug in the national COVID-19 treatment protocol in spite of its approval by CDSCO under restricted emergency use category.

From the phase I and II trials, it was reported that Molnupiravir (800 mg) was safe and well tolerated with no serious adverse events. The MOVe-OUT was a large multicentric Phase 3 clinical trial conducted in 1433 mild COVID-19 patients who are at high risk for progression to severe disease. The incidence of hospitalization is lower in the Molnupiravir-treated group, and on average it was 8% from the published reports.

During the pandemic, many drugs failed to show response against COVID-19, but Molnupiravir showed good results by decreasing hospitalization; hence, researchers considered this drug as magic pill.

The other oral antiviral drug Paxlovid, a combination of nirmatrelvir and ritonavir, has received EUA by US-FDA at the same time of Molnupiravir approval. This is based on the clinical trial conducted on 2246 participants who are at risk of progression to severe disease. When this drug was administered within 3 days of symptom onset, the incidence of COVID-19–related hospitalization or death by day 28 was 0.72% and 6.45% in nirmatrelvir group and placebo group, respectively. The difference −5.81% (95% CI, −7.78 to −3.84) was statistically significant (p < 0.001), and 88.9% relative risk reduction was recorded during the study. There were no deaths in nirmatrelvir group compared to 9 deaths in placebo group [33].

The above results showed the higher efficacy of nirmatrelvir and ritonavir combination compared to Molnupiravir.

Even with the indication, duration of treatment is same for both drugs; the disadvantage of Molnupiravir is that it should be given as 4 tablets twice daily compared to 3 tablets twice daily with Paxlovid (Table 5).

The adverse events reported in the published studies were around 30%, but the interim analysis of the studies conducted by Hetero and Optimus Pharma showed very less (4–6%) adverse events. Commonly reported adverse events of Molnupiravir were headache, dizziness and GI symptoms.

The results of 12 ongoing trials in India will help to make appropriate decisions on Molnupiravir use in COVID-19. Only one prophylactic study is ongoing, and results of this first prevention trial of Molnupiravir (move-Ahead trial) are much awaited.

Recent systematic review and meta-analysis by Kamal L et al. reported that evidence available from preclinical and clinical studies confirms the efficacy and safety of Molnupiravir as an antiviral therapy to treat mild-to-moderate COVID-19 infections in high-risk patients. [34]

Both the published RCTs were conducted in non-vaccinated participants. At present, no data is available for use of Molnupiravir in vaccinated patients. This data is vital as a good proportion of population worldwide is currently vaccinated. Further, there are no studies on the role of Molnupiravir in breakthrough infections following vaccination.

The important challenges with Molnupiravir use in COVID-19 are as follows:

  1. 1.

    Mutagenicity reported in preclinical studies and long-term safety

  2. 2.

    Use of this drug within 5 days from symptom onset

  3. 3.

    Role in asymptomatic patients–when to start treatment?

  4. 4.

    Role of this drug in vaccinated COVID-19 patients

  5. 5.

    Role in immune compromised patients

  6. 6.

    Cost and accessibility

  7. 7.

    Interaction with co-administered specific anti-SARS-CoV-2 drugs

  8. 8.

    Comparative effectiveness and safety with other oral antivirals (like nirmatrelvir + ritonavir [Paxlovid])

  9. 9.

    Medication adherence (compliance)–considering the faster and less eventful convalescence occurring currently

  10. 10.

    Antiviral resistance–particularly with the novel strains


From the available evidence from clinical studies, it can be concluded that Molnupiravir at 800 mg twice daily for 5 days within 5 days of symptom onset is safe and effective in high-risk patients with mild-to-moderate COVID-19 infection. It delays the disease progression by reducing hospitalization and/or death.

The previous studies were conducted in unvaccinated patients. Presently, most of the mild cases of COVID-19 are self-limiting who generally recover uneventfully without any specific COVID-19 treatment.

For confirmative use of this drug in mild-to-moderate COVID-19 disease, further studies are required in vaccinated COVID-19 patients and in patients with various emerging SARS-CoV-2 variants and studies on comparative effectiveness with other antiviral drugs.