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17th June 2022
The clinical benefits of molnupiravir may not just be restricted to a reduction in either hospitalisation or death, according to the results of a secondary analysis of data from the MOVe-OUT trial by an international group of researchers in collaboration with the manufacturer, Merck and Co.
Molnupiravir is a small-molecule ribonucleoside prodrug of N-hydroxycytidine (NHC) and was studied in MOVe-OUT a phase 3, double-blind, randomised, placebo-controlled trial. The aim of the trial was to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in non-hospitalised, unvaccinated adults with mild-to-moderate, COVID-19 and at least one risk factor for severe COVID-19 illness. The findings of the study indicated that the drug, given at a dose of 800 mg every 12 hours for 5 days, was able to reduce the risk of hospitalisation or death when given within 5 days of the onset of COVID-19 symptoms.
While molnupiravir was clearly effective, researchers wondered if there were any further clinical benefits attributable to the drug and therefore decided to perform a secondary analysis of data generated in the trial. In particular, the researchers focused on the need for respiratory interventions, COVID-19-related acute care visits and changes in the level of inflammatory markers such as C-reactive protein (CRP). The reported outcomes were assessed in terms of the relative risk reduction (RRR).
Additional clinical benefits of molnupiravir
The trial randomised 1433 participants to either molnupiravir or placebo. A reduction in CRP levels was noted as early as day 3 and this was greater than for the placebo group (-1.44 vs 1.92, molnupiravir vs placebo, p value not stated) and in fact, CRP levels in the placebo group did not reduce until day 10.
Fewer patients given molnupiravir required any respiratory interventions (RRR = 34.3%, 95% CI 4.3% – 54.9%), in particular noninvasive mechanical ventilation (RRR = 75.4%). In addition, among the subgroup of patients who became hospitalised, fewer treated with molnupiravir required any form of respiratory intervention (RRR = 21.3%).
There was also difference in the proportion of molnupiravir patients requiring either an acute care visit (RRR = 32.1%) or a COVID-19-related acute care visit (RRR = 33.8%) compared to those taking placebo.
While there were apparent improvements in numerical changes in CRP values, the authors did not report the associated statistics for the change and it is therefore unclear whether the observed differences between the outcomes examined were statistically significant. It is also unclear if these differences were clinically meaningful. A further limitation recognised by the authors was that the data were derived from patients who were unvaccinated against COVID-19 and so the generalisability of the findings to patients already vaccinated are not clear.
Despite these limitations, the authors concluded that their findings suggested added clinical benefits from the use of molnupiravir in the treatment of non-hospitalised adults with mild to moderate COVID-19.
Johnson MG et al. Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19. A Randomized, Placebo-Controlled Trial Ann Intern Med 2022
20th December 2021
The use of oral molnupiravir treatment within 5 days of COVID-19 symptom onset, led to a 50% reduction in the risk of hospitalisation for any cause of death among unvaccinated patients. This was the main finding of a study by the MOVe-OUT group which was supported by the manufacturer of the drug, Merck Sharp and Dohme.
Molnupiravir is a small-molecule ribonucleoside pro-drug of N-hydroxycytidine (NHC) and which has been shown to inhibit the influenza virus and is phosphorylated in vivo and incorporated into viral RNA, rendering the virus non-infectious. Early trial data suggested that the drug was efficacious and safe in patients infected with COVID-19 which formed the basis for the current MOVe-OUT trial.
For the Phase II-III trial, non-hospitalised patients with mild or moderate, laboratory confirmed COVID-19, symptom onset of no more than 5 days and at least one risk factor for more severe disease, were enrolled in the study. Risk factors included age (> 60 years), active cancer, chronic kidney disease, COPD, obesity, diabetes or serious heart conditions such as heart failure and coronary artery disease. Patients were excluded where there was an anticipated need for hospitalisation (due to COVID-19) within the next 48 hours.
Those enrolled were randomised 1:1 to molnupiravir treatment (800 mg) twice daily for five days or identical placebo. The primary efficacy endpoint was the incidence of hospitalisation for any cause, which the researchers defined as > 24 hours of acute hospital care or death through to day 29. The researchers also included a primary safety outcome as the incidence of adverse events.
A total of 1433 participants with a median age of 42 (53.6% female) were assigned to molnupiravir treatment (716) or placebo. Overall, 99.4% of these individuals had at least one risk factor for severe COVID-19, most commonly obesity (73.7%), age > 60 (17.2%) and diabetes (15.9%) with disease severity classed as mild in more than half (55.2%) of all cases.
The percentage of patients meeting the primary endpoint was 7.3% (molnupiravir) and 14.1% (placebo), a treatment difference of 6.8% (95% CI -11.3 to – 2.4, p = 0.001). Patients receiving molnupiravir had a lower risk of hospitalisation or death through to day 29 (6.8% vs 9.7%). There was one death reported in the molnupiravir group and 9 in the placebo group, all of which were considered to be COVID-19-related.
In terms of safety, 30.4% vs 33% of participants in the molnupiravir treatment arm vs placebo, experienced > 1 adverse event including diarrhoea, nausea and dizziness.
Since the trial was undertaken among unvaccinated participants, the potential value of the drug in preventing breakthrough infections could not be evaluated. Nevertheless, authors concluded that molnupiravir treatment was effective for the treatment of COVID-19 and that it did not appear to have any major safety concerns.
Bernal AJ et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients N Engl J Med 2021
5th November 2021
The MHRA has given approval to Lagevrio (molnupiravir) for patients with mild to moderate symptoms of COVID-19, to reduce their risk of hospitalisation and death. Although the results of the Phase III clinical trial, MOVe-OUT, are yet to be published, the manufacturer, Merck and Ridgeback, posted interim results in a press release at the beginning of October 2021.
The interim analysis showed that among patients taking lagevrio, 7.3% were hospitalised compared to 14.1% assigned to placebo (risk difference = 6.8, p = 0.0012). In addition, through to day 29 after randomisation, there were no reported deaths among those taking lagevrio compared with 8 in the placebo arm.
The MHRA says that it has undertaken a “rigorous review of its safety, quality and effectiveness” adding that “Lagevrio is most effective when taken during the early stages of infection” hence the MHRA recommends its use as soon as possible following a positive COVID-19 test and within five days of symptoms onset.
According to the Summary of Product Characteristics of the drug, Lagevrio is indicated “for treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults with a positive SARS-COV-2 diagnostic test and who have at least one risk factor for developing severe illness.” The recommended dose is four 200mg capsules taken every 12 hours for 5 days although the efficacy if taken over a longer period of time is yet to be established.
Commenting on the MHRA approval, its chief executive Dr June Crown said “Lagevrio is another therapeutic to add to our armoury against COVID-19. It is also the world’s first approved antiviral for this disease that can be taken by mouth rather than administered intravenously. This is important, because it means it can be administered outside of a hospital setting, before COVID-19 has progressed to a severe stage.”
6th October 2021
According to an interim analysis, Merck and Ridgeback’s investigational anti-viral drug, molnupiravir (MPV), halved the risk of hospitalisation in patients with mild-to-moderate COVID-19. MPV is a pro-drug that is incorporated by RNA polymerase into COVID-19 and which has been shown in preliminary studies, to reduce nasopharyngeal COVID-19 infectious virus and viral RNA.
The results come from the Phase III MOVe-OUT trial, designed to evaluate the safety, tolerability and efficacy of MPV in non-hospitalised patients with COVID-19. Enrolled patients had laboratory-confirmed mild-to-moderate COVID-19 and with an onset of symptoms within 5 days of study randomisation. In addition, all patients were required to have at least one risk factor associated with poor disease outcome. A second trial, examined the value of MPV in hospitalised patients although this was halted after it became apparent that molnupiravir was unlikely to demonstrate a clinical benefit in hospitalised patients.
MOVe-OUT is evaluating molnupiravir at a dose of 800mg twice daily and while the results are yet to be published, the interim analysis seems positive. According a joint press release from the companies, 7.3% (28/385) of patients receiving MPV were either hospitalised or died through to Day 29 following randomisation (28/385), compared with 14.1% (53/377) of placebo-treated (p=0.0012). In addition, after 29 days, there were no deaths were reported in patients who received MPV compared to 8 deaths in the placebo arm.
The incidence of drug-related adverse events was shown to be comparable (12% and 11% MPV vs placebo). Fewer subjects discontinued study therapy due to an adverse event in the molnupiravir group (1.3%) compared to the placebo group (3.4%).
Merck plans to submit an application for Emergency Use Authorisation (EUA) to the FDA as soon as possible and plans to submit marketing applications to other regulatory bodies worldwide.