Molnupiravir – 2024

RECOMMENDATION: Molnupiravir should not be used routinely for treatment of COVID-19. It may be considered as an option when remdesivir or nirmatrelvir-ritonavir (Paxlovid) are not available or appropriate, for patients with mild to moderate COVID-19 illness of less than 5 days’ duration, in patients with risk factors for severe disease (see Justification).

DATE OF RECOMMENDATION:

We recommend against use of molnupiravir in patients with COVID-19 and no risk factors for severe disease (strong recommendation, low certainty evidence)

Definition of mild:

•  Symptomatic (any acute COVID-19 related symptoms)
•  AND respiratory rate <24/min
•  WITHOUT pneumonia or hypoxia

Definition of moderate illness:

•  Pneumonia (clinical or radiological) OR hypoxia (SpO2 <94% in adults with no underlying lung disease)
•  AND respiratory rate ≤30/min
•  AND SpO2 ≥90% on room air

Definition of Severe illness

Pneumonia with ANY ONE of the following:

•  severe respiratory distress or respiratory rate >30/min
•  SpO2 <90% on room air
•  NO invasive or non-invasive respiratory support needed

Definition of critical:

•  Requirement for high-level respiratory support: noninvasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
•  OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
•  OR sepsis
•  OR shock

We recommend against routine use of molnupiravir in patients with mild to moderate COVID-19 with risk factors for severe disease when other options are available (conditional recommendation, low certainty evidence)

A conditional recommendation is one for which the desirable effects probably outweigh the undesirable effects (weak recommendation FOR an intervention) or undesirable effects probably outweigh the desirable effects (weak recommendation AGAINST an intervention) but appreciable uncertainty exists. This implies that not all will be best served by this recommendation and decisions can be made by the patient and caregiver based on patient values, resources and setting with a clear understanding of the ensuing harms and benefits.

Definition of mild:

•  Symptomatic (any acute COVID-19 related symptoms)
•  AND respiratory rate <24/min
•  WITHOUT pneumonia or hypoxia

Definition of moderate illness:

•  Pneumonia (clinical or radiological) OR hypoxia (SpO2 <94% in adults with no underlying lung disease)
•  AND respiratory rate ≤30/min
•  AND SpO2 ≥90% on room air

Definition of Severe illness

Pneumonia with ANY ONE of the following:

•  severe respiratory distress or respiratory rate >30/min
•  SpO2 <90% on room air
•  NO invasive or non-invasive respiratory support needed

Definition of critical:

•  Requirement for high-level respiratory support: noninvasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
•  OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
•  OR sepsis
•  OR shock

Justification

Low certainty evidence from randomised controlled trial data suggests that Molnupiravir may have a marginal benefit if at all in reducing hospitalisation or death (low certainty evidence). Low certainty evidence also suggests that it may not lead to a quicker negative PCR for SARS-CoV-2, and it may not speed up clinical improvement. Remdesivir and Nirmatrelvir/ritonavir are antivirals with stronger evidence for efficacy and safety. Putting this together with uncertainties about safety and the risk of resistance, Molnupiravir should not be used as a first-line option for patients even at a high risk of hospitalisation, and not at all for patients at low risk of hospitalisation. However, for patients at high risk of hospitalisation, where Remdesivir and Nirmatrelvir/ritonavir are not available (which is common in India), or cannot be used due to drug-drug interactions, or intravenous therapy is deemed inappropriate, Molnupiravir may be an alternative option. Risk factors for hospitalisation include immunocompromise, obesity, diabetes and/or chronic cardiopulmonary disease, chronic kidney or liver disease, active cancer, those with disabilities, and people who have not been vaccinated against SARS-CoV-2.1

Evidence Summary

Date of latest search: 01st March 2023

Date of completion & presentation to the Expert Working Group: 25th January 2024

Date of planned review:

Evidence Synthesis Team: Hanna Alexander, Jane Miracline, Hana Nazim, Naveena Gracelin Princy Z, Priscilla Rupali

Summary of findings table

Explanations:

a.  Bernal, Bulter C, Caraco Yosef, Khoo, Thippabotta

b. Downgraded by one level for serious indirectness as the study population includes unvaccinated participants which does not reflect the current scenario

c.  Downgraded by one level for serious imprecision as the lower bound of the 95% CI includes appreciable benefit and the upper limit includes harm

d.  Aribas, Bernal, Bulter C, Caraco Yosef, Fischer

e.  Downgraded by one level for serious imprecision because the OIS criteria not met and event is very rare.

f.  Bernal, Bulter C, Fischer, Khoo, Thippabotta, Zou R

g.  Downgraded by one level for inconsistency as we identified substantial heterogeneity (I2=63%)

h.  Bernal

i.  Downgraded by one level for serious imprecision: lower confidence interval, bound represents a mild benefit from Molnupiravir whereas the upper bound includes harm

j.  Aribas, Bernal, Caraco Yosef, Fischer, Khoo, Thippabotta, Zou R

k.  Aribas, Bernal, Buter C, Caraco Yosef, Fischer, Khoo, Kumarasamy, Thippabotta, Zou R

Background

Molnupiravir was the first oral antiviral treatment developed specifically for COVID-19 developed by Merck, Sharp and Dohme and Ridgeback Therapeutics. Molnupiravir is a newer orally bioavailable prodrug of Emory Institute of Drug Development-2801 [EIDD-2801]/MK-4482), which is the synthetic ribonucleoside derivative N4-hydroxycytidine and ribonucleoside analog, with potential antiviral activity against a variety of RNA viruses recently been tested for COVID-19. The TP form of EIDD-1931 is incorporated into RNA and inhibits the action of viral RNA-dependent RNA polymerase. This results in the termination of RNA transcription decreases viral RNA production, and viral RNA replication2. In November 2021, the UK authorised Molnupiravir for use in people who have mild to moderate COVID-19 and at least one risk factor (such as obesity, older age, diabetes mellitus or heart disease) for developing severe illness3. The FDA granted emergency use authorization for the treatment of mild COVID-19 infection in December 20214. With the advent of different covid variants, the monoclonal antibodies which were useful antivirals in mildly symptomatic or asymptomatic individuals who were at high risk of severe COVID-19 infection rapidly became ineffective5. Hence oral options like molnupiravir and Nirmatrelvir/ritonavir became attractive options.

However, controversy remains regarding the utility of Molnupiravir with widespread vaccination globally thus reducing risk of severe disease in high risk patients. The drug though invented at Emory University was later acquired by Ridgeback therapeutics in partnership with Merck & Co, USA. Molnupiravir was initially developed as a possible treatment for influenza viruses, encephalitic alphaviruses like Venezuelan, Eastern and Western equine encephalitic viruses due to its significant inhibitory effect in cell cultures6. On December 23rd 2021 FDA gave emergency use authorization for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults (>18yrs) with who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options were are not accessible or clinically appropriate. An in-vitro study by Zhou et al has suggested that the drug, though intended to disrupt only viral RNA, could also incorporate into and cause mutations in human DNA and potentially “contribute to the development of cancer”. Molnupiravir metabolite the ribonucleoside analog β-D-N4 -hydroxycytidine (NHC), is a potent mutagen.

However, with advent of new strains with immune escape, Molnupiravir retains its activity against the VOCs Alpha, GHB-03021/2020* and Omicron, making this a possible therapeutic option. This review aims to update the evidence from randomized clinical trials of Molnupiravir for treatment of COVID-19, for any duration, which could guide clinicians and researchers regarding the appropriate use of this drug.

Methods

We searched PubMed, Epistemonikos, and the COVID‐19‐specific resource www.covid‐nma.com, for studies of any publication status and in any language. We also reviewed reference lists of systematic reviews and included studies. We performed all searches up to 01st March 2023.

We searched the above databases and found 25 records. After removing duplicates and excluding studies that did not match our PICO question, 9 RCTs were included in the review.

We extracted data for the following outcomes, pre-defined by the Expert Working Group:

PICO:

Two reviewers independently assessed eligibility of studies from the search results using the online Rayyan tool. Data extraction was performed by one reviewer, and checked by another, using a piloted data extraction tool. Risk of bias (RoB) was assessed using the Cochrane RoB v2.0 tool, with review by a second reviewer and compared with covid.nma database. If there was a difference in more than one domain it was assessed by a third independent author. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs). We performed a meta-analysis if outcomes were measured and reported in a similar way for the populations in each trial using random-effects models with the assumption of substantial clinical heterogeneity and the I2 test to calculate residual statistical heterogeneity, using Review Manager (RevMan) v5.4. Evidence would then be synthesized and reviewed by the Methodology Committee. We considered use of fixed effects model if we found that adequate weightage was not given to bigger trials on advice from the methodology committee. We used GRADE methodology to prepare summary of findings tables on GRADEPro GDT.

Results

We found 9 RCTs that matched the PICO question as pre-defined by the expert working group.

Apart from the 3 trials we included in the previous recommendation, we have included 6 more trials for the evidence update. The trials included a total of 29725 participants, all of whom were adults. Three trials were a multicenter trials involving many countries like Brazil, Chile, Colombia, France, Israel, Mexico, Philippines, Poland, Russia, South Africa, and South Korea. Two trials reported from UK, one from India and one from china. Four trials included unvaccinated patients and three trials had 50-60% of population, vaccinated. One trial had 99% of its population vaccinated. Four trials compared Molnupiravir with placebo whereas the other five trials compared Molnupiravir with standard of care.

Each trial and its results are described below, characteristics of the trials are summarized in the Summary of characteristics of included trials table. Risk of bias for each outcome as per domain in each trial is displayed alongside the forest plots below. The following comparisons were investigated in the trials (we compared outcomes for arms randomized to Molnupiravir vs. standard of care or placebo).

  • Four trials compared Molnupiravir with placebo (2117 participants).
  • Five trials compared Molnupiravir with standard of care (27608 participants).

Our expert working group classified the following outcomes as critical - hospitalization or death in 28 days, time to progression of each targeted COVID-19 sign/symptom, clinical improvement –as defined by 2-point decrease in the WHO clinical progression and mortality (all-cause), time to clinical improvement, time to viral clearance, Adverse events: all and serious as important outcomes.

Critical (primary) Outcomes

As presented in the ‘Summary of findings’ table, the evidence is of low certainty about the effect of Molnupiravir on mortality, hospitalized or death in 28 days, incidence of viral negative PCR by D7, clinical improvement, adverse events and serious adverse events

a. Hospitalized or death in 28 days: Low certainty evidence in 5 trials with 28766 patients revealed that Molnupiravir has little to no effect on hospitalization or death in 28 days compared to standard of care or placebo. However, there was a wide confidence interval, ranging from important benefit to important harm (RR 0.80; 95% CI 0.56 to 1.15, I2=41%).

b. All-cause mortality: Low certainty evidence in 5 trials with 27697 patients suggested that Molnupiravir may reduce all-cause mortality compared to placebo or standard of care. We used a fixed effect model for this meta-analysis to give appropriate weightage to the larger trials thus a narrow confidence interval emerged, suggesting benefit (RR 0.37; 95% CI 0.16 to 0.87, I2=22%)

c. Negative SARS-CoV-2 PCR at day 7: Low certainty evidence in 6 small trials with 3134 patients revealed that Molnupiravir may not lead to a negative SARS-CoV-2 PCR at day 7 (RR 1.13; 95% CI 1.01 to1.27, I2=63%).

d. Clinical improvement by WHO progression scale 1-3 to 0: Low certainty evidence in one trial with 1295 patients suggested that Molnupiravir may make little to no difference to clinical improvement by day 28 (RR 1; 95% CI 0.89 to1.12, I2=0%).

e. Adverse events: Low certainty evidence in 7 trials with 3384 patients suggested that Molnupiravir had little to no risk of adverse events compared to those receiving placebo or standard of care. (RR 0.97; 95% CI 0.89 to1.07, I2=0%)

f. Serious Adverse events: Low certainty evidence in 9 trials with 27795 patients revealed that Molnupiravir had no increased risk of adverse events as compared to those receiving placebo or standard of care. (RR 1.09; 95% CI 0.79 to 1.49, I2=0%)

Summary of characteristics of included trials

Forest Plots

1.Hospitalization or death by day 28

Sugroup - Severity

2. All-cause mortality D28

Sensitivity - Fixed Effect Analysis

Subgroup - Severity

3. Negative SARS-CoV-2 PCR at Day 7

4.Clinical improvement scale 1-3 to 0 at Day 29

5. Adverse events

Sensitivity - Fixed Effect Analysis

6.Serious adverse events

Evidence to Decision

The Expert Working Group met on 25th January 2024 to update the recommendation for Molnupiravir as a treatment for COVID-19. Conflict of interest declarations were reviewed by the Steering Committee; none were found to be relevant to Molnupiravir.

Summary of Judgments

Problem

COVID-19 pandemic caused by the SARS-COV2 virus has significantly impacted India’s health structure by increasing the morbidity and mortality. Even though around 75% of the population is currently fully or partially vaccinated, limited antivirals are available for appropriate treatment. The group judged the problem to be of the utmost priority. This antiviral acts on RdRp, but differs from remdesivir. While remdesivir causes chain termination of SARS-CoV-2 virus, Molnupiravir causes mutagenesis of the virus or ‘error catastrophe’ during transcription, thus killing the virus.

Desirable effects

Low certainty evidence from studies revealed that Molnupiravir made little no difference on hospitalization or death at 28 days RR 0.80 (95% CI 0.56 to 1.15) and may reduce all-cause mortality RR 0.37 (95% CI 0.16 to 0.87) with no significant effect on conversion to negative PCR at Day 7 RR 1.13 (95% CI 1.01 to 1.27). The group voted that the overall desirable effects as trivial.

Undesirable effects

According to the data from studies, Molnupiravir had little to no effect on adverse events RR 0.97 (95% CI 0.89 to 1.12) or serious adverse events RR 1.09 (95% CI 0.79 to 1.49). The group felt that the pooled data suggested that Molnupiravir was associated with little to no significant impact on adverse events, including serious adverse events. The group voted that the overall undesirable effects as small.

Certainty of Evidence

Using GRADE methodology, the evidence synthesis team rated the certainty of evidence as low for hospitalisation or death at Day 28, all-cause mortality D28, Clinical improvement scale 1-3 to 0 Day 29, Incidence of PCR negativity by D7, serious adverse events and adverse events. The expert working agreed with these judgements and rated the overall certainty of evidence as low.

Values

The panel discussed the following points when concluding that there is probably no important uncertainty or variability.

Balance of effects

Earlier, since the studies have looked at unvaccinated population with mild to moderate disease across the studies, the panel felt that it is not representative of the current scenario. But in this review studies included vaccinated populations like Zou, Butler, and Khoo. The group had varying opinions and felt that the balance of effects varies as it depended on the circulating variant and vaccination status of the patients and the attendant risk of severe disease.

Resources required

The group felt that the costs were moderate to deliver this intervention as this is an oral pill and the total costs for a single course would amount to around 1400Rs.

Certainty of evidence of required resources

No studies reporting this were reviewed by the group but the clinicians in the group were aware of the cost and hence felt that there was high certainty of evidence for required resources to implement this intervention.

Cost effectiveness

The panel discussed and agreed that there was no research evidence that evaluated cost of Molnupiravir in an Indian context, when other oral options were available.

Equity

At this point in time this intervention would probably reduces equity if found suitable and efficacious in Indian settings as cost are low and there is no need for hospitalization

Acceptability

The group felt that this intervention is likely to have wide acceptance by all the relevant stakeholders (policy-makers, patients and clinicians) as it is an oral drug and can be administered easily. Since it is an oral drug, monitoring the adherence of the patients is important to achieve desired effect. The group discussed that this should only be considered as an alternative as other efficacious options exist and are available and accessible. It could be safely used in older patients as they are less likely to be affected by teratogenicity concerns, though less evidence for benefit exists in this subgroup.

Feasibility

This is a feasible intervention if found efficacious as it is of low cost and can easily be delivered in a short course of 5 days.

Implementation considerations

Molnupiravir is an alternate oral antiviral to be given within 5 days of symptom onset in mild to moderate COVID-19. As a relatively affordable oral drug, and one of few available for mild to moderate COVID-19, it should be reserved for those at high risk of progression to severe disease. Due to risk of teratogenicity and predisposition to malignancies, Molnupiravir should be avoided as far as possible to women of child bearing age (avoid in partners and spouses as well) or in children.  Clinicians, hospitals and policymakers should consider how to put appropriate measures in place to ensure patient safety. Additionally, as Molnupiravir is a new drug, caution should be taken to follow patients up closely, at least clinically, to allow rarer or unknown adverse effects to be detected.

Subgroup considerations

In the randomized trial the study and control groups were unvaccinated adults.  The benefits that were seen were only in obese individuals with a BMI > 30. There was no significant difference in the other sub-groups studied.

It is not clear how beneficial the drug is in a vaccinated population on the basis of the published data.

Monitoring and Evaluation

Molnupiravir is an antiviral with an advantage of being an oral drug and thus can result in misuse. The current evidence reveals a small benefit in mild disease in those who are unvaccinated and risk factors. At present the pooled data does not suggest significant short-term or long term adverse events. This recommendation against the use of Molnupiravir will be reviewed as and when, any new evidence emerges.

Research Priorities

The MOVE-out study recruited unvaccinated patients prior to the emergence of Omicron variant. Further research is needed for

1.  Assessing treatment efficacy/effectiveness in fully vaccinated patients with mild illness and risk factors for progression

2.  Assessing genotoxicity in more in-vitro and in-vivo models

3.  Assessing the impact of Molnupiravir on inducing viral mutations that may have phenotypic consequences especially in immunocompromised individuals

4.  Assessing the in-vitro activity of Molnupiravir against the constantly emerging Omicron variants.

References
  1. World Health Organization. Therapeutics and COVID-19: Living guideline, 10 November 2023. World Health Organization, Geneva. 2023. Available from: https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-therapeutics-2023.2.
  2. EIDD-2801 [Internet]. [cited 2022 Jan 13]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/145996610
  3. First oral antiviral for COVID-19, Lagevrio (molnupiravir), approved by MHRA [Internet]. GOV.UK. [cited 2022 Feb 7]. Available from: https://www.gov.uk/government/news/first-oral-antiviral-for-covid-19-lagevrio-molnupiravir-approved-by-mhra
  4. Commissioner O of the. Coronavirus (COVID-19) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 in Certain Adults [Internet]. FDA. FDA; 2021 [cited 2022 Feb 7]. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-oral-antiviral-treatment-covid-19-certain
  5. Preliminary data indicate COVID-19 vaccines remain effective against severe disease and hospitalisation caused by the Omicron variant [Internet]. European Medicines Agency. 2022 [cited 2022 Feb 7]. Available from: https://www.ema.europa.eu/en/news/preliminary-data-indicate-covid-19-vaccines-remain-effective-against-severe-disease-hospitalisation
  6. Molnupiravir and Drug Development at Emory | Emory University | Atlanta GA [Internet]. [cited 2022 Jan 13]. Available from: https://news.emory.edu/tags/topic/molnupiravir/index.html
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