The continuing emergence of new and potentially threatening severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, most recently the very infectious Omicron variant of concern (VOC), is evidence that the coronavirus disease 2019 (COVID-19) pandemic is far from being over, despite the massive rollout of vaccines.
As cases and hospitalizations continue to rise in many countries, new treatments are being sought to arrest the progression of the disease, preventing severe illness and death or disability. One such is the small molecule molnupiravir, the focus of a new research paper.
Study: Molnupiravir for Oral Treatment of Covid-19 in Non-hospitalized Patients. 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 given orally, the drug gives rise to NHC, which travels in the bloodstream and enters the cells. Within the cells, it is phosphorylated to its triphosphate form.
This is taken up into the viral genome by the viral RNA polymerase enzyme, causing the uptake of the wrong nucleoside – either adenosine or guanosine – during viral replication. The accumulation of numerous missense or deleterious mutations in the genome leads to non-productive infection as the virus is unable to make replicating copies of itself within the host cell.
Phase 1 and 2 trials have been completed for this prodrug, and 800 mg was selected as the trial dosage for further studies. The current paper, published in The New England Journal of Medicine, reports the results of the MOVe-OUT trial in at-risk, non-hospitalized adults who developed symptoms of mild to moderate COVID-19 five or fewer days before treatment with molnupiravir.
This was a phase 2–3 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 60 years of age, active cancer, chronic kidney disease or obesity, chronic obstructive lung disease, cardiovascular disease, or diabetes. None were seriously ill, or had near-terminal kidney failure, severe neutropenia or low platelet counts, and none had been vaccinated.
Almost 75% were obese, one in seven were 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 was carried out in over half the participants so far, showing the most common strains to be Delta, Mu and P.1.
Patients could receive anti-inflammatory drugs, glucocorticoids, or both, but not monoclonal antibodies or remdesivir. They were randomly assigned 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 the next 29 days vs. 10% in the placebo group, amounting to a 3 percentage point difference. If only COVID-19-related events were included, the difference remained the same.
If only deaths were considered, the risk was lower by 90%, with one death in the treatment group vs. 9 in the placebo group (0.1% vs. 1.3%, respectively). When compared using the WHO Clinical Progression Scale, they found that the improvement in the treatment group began to exceed that in the placebo group by five days, and the most significant differences were seen by days 10 and 15.
Viral RNA was detectable in nasal swabs in 78% of patients, of which 88% were tested on day 5. Though testing is still going on, current data shows that the viral load was significantly lower with molnupiravir at days 3, 5, and 10, compared to placebo.
Safety-wise, there was little to choose 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 treatment and control groups, respectively, with 2% in each group developing bacterial pneumonia. Progression of COVID-19 occurred in 8% and 10%, respectively. Diarrhea, nausea, and dizziness were the most frequent, at less than 2% for most events, in either group.
Additional deaths after day 20 occurred in 1 and 3 participants in the treatment and control group, respectively. Overall, so far there have been 2 and 12 deaths in the two groups, respectively.
What Are the Implications?
These findings must be evaluated against a high-risk background indicating that the trial took place in patients who would have been expected to develop progressive disease at a higher rate. With clinical trials on monoclonal antibodies, with similar high-risk non-hospitalized patients with COVID-19, hospital admissions were reported to occur in 3% to 7% of participants, compared with 10% to 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 according to the data available. However, some groups did not show significant differences with treatment, including those with prior infection with SARS-CoV-2, those with very low viral loads, and diabetes mellitus.
The findings were supported by assessment using the WHO Clinical Progression Scale and changes in self-reported symptoms of this disease. The drug appears safe. The drug's efficacy differed in the final analysis compared to the interim analysis, mainly because of the lower incidence of death or hospitalization in the placebo group at the second time point. This could be due to shifts in the sample characteristics (such as higher female representation, more patients with prior SARS-CoV-2 infection, and more patients with a low viral load) or the outbreak characteristics, or regional characteristics (newly enrolled countries may have had lower or higher thresholds for hospitalization).
The ability of a drug to reduce the progression of the disease and thus relieve the load on hospitals is significant in this fast-spreading pandemic while lowering the viral load to minimize the chances of transmission is also important. Compared to monoclonal antibodies, which must be given by injection in a medical facility, molnupiravir is one of several oral agents that are being studied for at-home administration.
Its broad efficacy against several variants is another advantage since its action does not depend on spike protein binding and remains unaffected by spike mutations. The drug thus deserves further evaluation for validation of these results.