The continued emergence of potentially threatening new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), most recently the highly infectious variant Omicron of concern (VOC), is evidence that the 2019 coronavirus disease pandemic ( COVID-19) is far from over, despite the massive deployment of vaccines.
As cases and hospitalizations continue to increase in many countries, new treatments are sought to stop the progression of the disease, prevent serious illness and death or disability. One of them is the small molecule molnupiravir, which is the subject of a new research paper.
Study: Molnupiravir for oral treatment of Covid-19 in outpatients. Image Credit: Banjerd Titawong / Shutterstock
Molnupiravir is a ribonucleoside prodrug that is metabolized to the active molecule N-hydroxycytidine (NHC), which inhibits SARS-CoV-2 and other viruses with a ribonucleic acid (RNA) genome. When taken orally, the drug gives rise to NHC, which travels through the bloodstream and enters cells. In cells, it is phosphorylated in its triphosphate form.
This is absorbed into the viral genome by the viral RNA polymerase enzyme, causing the uptake of the wrong nucleoside – whether adenosine or guanosine – during viral replication. The accumulation of many missense or deleterious mutations in the genome leads to non-productive infection because the virus is unable to replicate in the host cell.
Phase 1 and 2 trials have been completed for this prodrug, and 800 mg was selected as the test dosage for further studies. This document, published in The New England Journal of Medicine, reports the results of the MOVe-OUT trial in non-hospitalized at-risk adults who developed mild to moderate COVID-19 symptoms five days or less before treatment with molnupiravir.
This was a phase 2 to 3, double-blind, parallel-group, randomized, placebo-controlled trial in 15 countries at 107 centers.
The 1,400 patients enrolled had one or more risk factors for severe COVID-19, such as over age 60, active cancer, chronic kidney disease or obesity, chronic obstructive pulmonary disease, cardiovascular disease or diabetes . None were seriously ill or had near-end renal failure, severe neutropenia or low platelet count, and none had been vaccinated.
Almost 75% were obese, one in seven was elderly, and the same proportion had diabetes mellitus. Half had become symptomatic within 3 days of receiving the drug or placebo, and almost the same number had moderate symptoms. Genomic sequencing has so far been performed in more than half of the participants, showing that the most common strains are Delta, Mu and P.1.
Patients may be given anti-inflammatory drugs, glucocorticoids, or both, but not monoclonal antibodies or remdesivir. They were randomly given molnupiravir or placebo for five days.
What did the study show?
The results showed that 7% of patients in the treatment group were hospitalized or died within 29 days compared to 10% in the placebo group, a difference of 3 percentage points. If only events related to COVID-19 were included, the difference remained the same.
If only deaths were considered, the risk was 90% lower, with one death in the treatment group versus 9 in the placebo group (0.1% versus 1.3%, respectively). Compared using the WHO Clinical Progress Scale, they found that the improvement in the treatment group began to exceed that in the five-day placebo group, and the most significant differences were seen. on days 10 and 15.
Viral RNA was detectable in nasal swabs in 78% of patients, 88% of which were tested on day 5. Although testing is still ongoing, current data shows that the viral load was significantly lower with molnupiravir. on days 3, 5 and 10, compared to placebo.
On the security front, there was little choice between the two groups. About 8% in both groups developed adverse events related to the treatment regimen. COVID-19 pneumonia occurred in 6% and 10% of the treatment and control groups, respectively, with 2% in each group developing bacterial pneumonia. The progression of COVID-19 has occurred in 8% and 10%, respectively. Diarrhea, nausea, and dizziness were the most common, at less than 2% for most events, in both groups.
Additional deaths after day 20 occurred in 1 and 3 participants in the treatment and control groups, respectively. Overall, so far there have been 2 and 12 deaths in the two groups, respectively.
What are the implications?
These results should be weighed against a high-risk setting indicating that the trial took place in patients who may have developed progressive disease at a higher rate. With monoclonal antibody clinical trials, with similar high-risk outpatients with COVID-19, hospitalizations were reported in 3-7% of participants, compared to 10-14% in this study.
On day 29, the risk of hospitalization or death was reduced by 3 percentage points with molnupiravir for all viral variants based on available data. However, some groups did not show significant differences with treatment, including those who had previously been infected with SARS-CoV-2, those with a very low viral load, and diabetes mellitus.
The results were supported by an assessment using the WHO Clinical Progression Scale and changes in self-reported symptoms of this disease. The drug seems safe. The efficacy of the drug differed in the final analysis compared to the interim analysis, mainly due to the lower incidence of death or hospitalization in the placebo group at the second time point. This could be due to changes in the characteristics of the sample (such as a higher female representation, more patients who have already been infected with SARS-CoV-2 and more patients with a low viral load) or the characteristics of the patient. epidemic, or regional characteristics (newly enrolled countries may have had lower or higher hospitalization thresholds).
The ability of a drug to reduce the progression of the disease and thus ease the burden on hospitals is important in this rapidly spreading pandemic, while lowering the viral load to minimize the risk of transmission is also important. Compared to monoclonal antibodies, which must be given by injection in a medical setting, molnupiravir is one of many oral agents that are being studied for home administration.
Its wide efficacy against several variants is another advantage since its action does not depend on binding to spike proteins and is not affected by spike mutations. The drug therefore deserves a more in-depth evaluation to validate these results.