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28th February 2023
Lagevrio was refused a marketing authorisation by the European Medicines Agency on the 23rd February 2023, for the treatment of adults with COVID-19. However, the manufacturer, Merck Sharp & Dohme B.V., may ask the EMA to re-examine its opinion within 15 days.
Data on lagevrio had initially revealed how treatment with the drug treatment led to a reduction in the risk of hospitalisation or death among unvaccinated individuals with at least one risk factor for more severe disease. However, with the introduction of widespread COVID-19 vaccination, the question of whether the drug would still offer benefit to at-risk and vaccinated patients, remained unanswered. Nevertheless, while there was some preliminary data which suggested that the drug retained anti-viral activity against several COVID-19 variants, even among those who had been vaccinated, more definitive data were required.
The PANORAMIC trial was designed to examine if the addition of lagevrio to usual care could reduce hospital admission and COVID-10-related mortality among patients who had been vaccinated against the virus. PANORAMIC was a huge, randomised trial, recruiting over 26,000 patients and assigning nearly 13,000 to lagevrio. The results clearly showed that lagevrio failed to reduce the frequency of COVID associated hospitalisations or deaths in high-risk, vaccinated individuals. In fact, the authors of the PANORAMIC trial went as far as to say that the observed avoidance of both hospitalisation and mortality due to COVID-19 were largely as a result of extensive vaccination.
In a letter explaining the decision, the EMA noted that after an evaluation of the data provided by the manufacturer, it was concluded that clinical benefits of the drug among patients who are not receiving supplemental oxygen but still at risk of developing severe COVID-19, could not be demonstrated. In fact, the EMA stated that ‘based on the totality of the data, it was not possible to conclude that Lagevrio can reduce the risk. of hospitalisation or death or shorten the duration of illness or time to recovery in adults at risk of severe disease.’ Adding that ‘it was not possible to identify a specific group of patients in whom a clinically relevant benefit of Lagevrio could be demonstrated.’
11th January 2023
Molnupiravir treatment in vaccinated, high-risk patients infected with COVID-19, failed to reduce both the rate of hospitalisation and death compared to usual care according to the results of a large, randomised trial by members of the PANORAMIC Trial collaborative group.
It is possible that the early treatment of COVID-19 infected patients with anti-viral agents, might prevent deterioration, speed up recovery and reduce the need for hospital admission. One such anti-viral is molnupiravir (EIDD-2801) and which was originally shown to be a potentially effective clinical candidate with high potential for monotherapy of seasonal and pandemic influenza virus infections.
Nevertheless, early molnupiravir treatment in patients infected with COVID-19 and at least one risk factor for severe illness, was subsequently shown to reduce the risk of hospitalisation or death in unvaccinated adults. But with millions of individuals now vaccinated against COVID-19, it remains uncertain whether molnupiravir treatment is still an effective option in such patients.
There is some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this is not conclusive. As a result, in the present study, researchers set out to establish the effectiveness of molnupiravir in vaccinated, high-risk, community patients at reducing hospital admission or death.
The study included community (i.e., non-hospitalised) patients aged 50 years and older, or 18 years and older with relevant comorbidities and who had COVID-19 symptoms within the previous 5 days, together with a positive PCR or rapid antigen test within the past 7 days. Eligible participants were randomly assigned (1:1) to receive molnupiravir 800 mg twice daily for 5 days plus usual care or usual care alone. The primary outcome was set as all-cause hospitalisation or death within 28 days of randomisation.
Molnupiravir treatment and adverse COVID-19 outcomes
A total of 25,783 individuals with a mean age of 56·6 years (58.5% female) were randomised to molnupiravir (12, 821) or usual care. Additionally, 69% of the whole cohort had comorbidities and 94% had received at least three doses of a COVID-19 vaccine.
Hospitalisations or deaths were recorded in 1% of both groups (adjusted odds ratio, aOR = 1·06, 95% CI 0·81 – 1·41, p = 0.33). Moreover, in subgroup analyses, there were no significant differences when assessed on several factors including the presence/absence of co-morbidities, age (< 65 vs > 65), or among those who were immunocompromised.
Despite no difference in the primary outcome, molnupiravir treatment was associated with a reduction in the median time from randomisation to first recovery (hazard ratio, HR = 1·36, 95% CI 1·32 – 1·40).
The authors concluded that in a highly vaccinated population at high risk of complications from COVID-19, the avoidance of hospitalisation and death was primarily achieved via extensive vaccination. They added that the benefits of molnupiravir in terms of a faster recovery time need to be considered in the context of several other relevant factors including the prevailing disease, burden on health-care services, drug-acquisition cost, social circumstances, cost-effectiveness, and opportunity costs.
Citation
Butler CC et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet 2022.
18th October 2022
In a 2019 study, it was reported that an anti-viral drug (EIDD-2801, molnupiravir)) was a clinical candidate with high potential for mono-therapy of seasonal and pandemic influenza virus infections. However, it was also recognised that the drug may have a role in the fight against COVID-19. In a phase 2a double-blind, placebo-controlled, randomised, multicentre clinical trial, molnupiravir treatment led to 92.5% of patients seeing viral RNA clearance compared to 80.3% of placebo recipients after 4 weeks. In fact, in this study, infectious virus was detected in swabs from 1.9% of the molnupiravir group compared with 16.7% of the placebo group after three days of treatment. Encouraged by these findings, a randomised trial in 1433 participants, found that molnupiravir treatment of unvaccinated patients who had at least one risk factor for severe COVID-19 illness, reduced the risk of hospitalisation or death.
But the value of molnupiravir among those who have been vaccinated was much less clear. As a result, for the present study, a team of UK researchers, the PANORAMIC Trial Collaborative Group, sought to determine the effectiveness of molnupiravir treatment at reducing all-cause, non-elective hospital admission and or death within 28 days among those with a higher risk of an adverse outcome following a breakthrough infection and who had been previously vaccinated against COVID-19. The study enrolled individuals 50 years of age and older or over 18 years but with co-morbidities and with COVID-19 symptoms with an onset of no longer than 5 days and a PCR positive COVID-19 test result. Participants were randomised 1:1 and stratified by age (< or > 50 years) and vaccination status (yes/no) to receive usual care and molnupiravir 800 mg twice daily for 5 days or usual care alone. Enrolled patients were then followed for 28 days after randomisation. In addition, there was a virology subgroup who provided daily nasopharyngeal swabs for the first 7 days and then on day 14. The primary outcome was all-cause hospital admission and or death within 28 days of randomisation. Secondary outcomes included the time to self-reported recovery (TTR) and the researchers also examined differences in the level of virus reported on day 7 and mean viral load for participants in the virology subgroup.
Molnupiravir treatment and COVID-19 outcomes
A total of 25,783 participants with a mean age of 56.6 years (58.6% female) were included and randomised to molnupiravir (12,962) or usual care. Overall, 68.9% of the cohort had co-morbidities and 98.9% had at least one dose of a COVID-19 vaccine and 93% had received three doses of a vaccine.
The primary outcome occurred in 0.8% of both groups (adjusted odds ratio, aOR = 1.06, 95% CI 0.80 – 1.40) and there were no differences in the subgroups.
The median time to first recovery from randomisation was 9 days in the molnupiravir group and 15 in the usual care group, giving an estimated benefit of 4.2 days (95% CI 3.8 – 4.6 days). Moreover, this effect was consistent across the subgroups.
In the virology cohort on day 7, COVID-19 was below the detection limit in 21% of those receiving molnupiravir and 3% in the usual care group (p = 0.039) and the mean viral load was also significantly lower (3.82 vs 4.93, p < 0.001).
The authors concluded that while molnupiravir treatment did not reduce the risk of hospitalisation or death (although this was already very low), the drug did result in a faster recovery time and a reduced viral detection and load.
Citation
Butler CC et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): preliminary analysis from the United Kingdom randomised, controlled open-label, platform adaptive trial SSRN preprint 2022
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.
Citation
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.
Findings
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.
Citation
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.
While approved for use in the UK, both the the FDA and the EMA are currently undertaking a review of the data on Lagevrio and will no doubt make an announcement in due course.
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.
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