The continued emergence of novel and potentially threatened SARS-CoV-2 variants, the latest of which is the highly pathogenic Omicron variant (VOC), is evidence that the coronavirus 2019 (COVID-19) pandemic is far from over, although The massive spread of vaccines.
As cases and hospitalizations continue to rise in many countries, new treatments are being sought to halt disease progression, and prevent severe illness, death or disability. One such component is the small molecule molonoperavir, which is the focus of a new research paper.
Study: Molnupiravir for the 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 using the RNA genome. When the drug is given orally, it triggers the NHC, which travels in the bloodstream and enters cells. Within cells, it is phosphorylated to its triphosphate form.
This is taken up in the viral genome by the enzyme viral RNA polymerase, causing the uptake of the faulty nucleoside – either adenosine or guanosine – during viral replication. Accumulation of many false or harmful mutations in the genome leads to a non-productive infection because the virus is unable to make duplicate copies of itself within the host cell.
Phase I and II trials of this prodrug have been completed, and 800 mg was selected as a trial dose for further studies. The current paper published in The New England Journal of Medicine, reporting the results of the MOVe-OUT trial in at-risk, non-hospitalized adults who developed mild to moderate COVID-19 symptoms five or less days prior to treatment with molopiravir.
This phase was 2-3 double-blind, parallel-group, randomized, placebo-controlled in 15 countries in 107 centres.
1,400 registered patients had one or more risk factors for severe COVID-19, such as age over 60, active cancer, chronic kidney disease, obesity, chronic obstructive pulmonary disease, cardiovascular disease, or diabetes. None were seriously ill, had semi-final renal failure, severe neutropenia or low platelet count, and none had been vaccinated.
Nearly 75% are obese, one in seven is elderly, and the same percentage has diabetes. Half developed symptoms within 3 days of receiving the drug or placebo, and about the same number had moderate symptoms. Genomic sequencing has been performed in more than half of the participants so far, showing the most common strains to be delta, myo and p1.
Patients can receive anti-inflammatory drugs, glucocorticoids, or both, but not monoclonal antibodies or remdesivir. They were randomly assigned to 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 versus 10% in the placebo group, representing a difference of 3 percentage points. If only COVID-19 related events were included, the difference would remain.
If only deaths were taken into account, the risk was 90% lower, with 1 death in the treatment group versus 9 in the placebo group (0.1% versus 1.3%, respectively). When compared using the WHO Clinical Progress Scale, they found that improvement in the treatment group began to exceed that in the placebo group by five days, and the most significant differences appeared on days 10 and 15.
Viral RNA was detectable in nasal swabs in 78% of patients, of whom 88% were tested on day 5. Although testing was ongoing, the current data show that viral load was significantly lower with molonoperavir on days 3, 5 and 10, compared to placebo.
Regarding safety, there was not much 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 the treatment and control groups, respectively, with 2% in each group developing bacterial pneumonia. The development of COVID-19 occurred in 8% and 10%, respectively. Diarrhea, nausea, and dizziness were the most common, 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, there have so far been 2 and 12 deaths in the two groups, respectively.
What are the implications?
These results should be evaluated against a high-risk background indicating that the trial was conducted in patients who were expected to develop progressive disease at a higher rate. Through clinical trials of monoclonal antibodies, with similar non-hospitalized high-risk patients with COVID-19, hospital admissions were reported in 3% to 7% of participants, compared to 10% to 14% in this study.
On day 29, the risk of hospitalization or death was reduced by 3 percentage points with molonoperavir for all viral variants according to the available data. However, some groups did not show significant differences with treatment, including those with previous SARS-CoV-2 infection, those with very low viral loads, and diabetes.
The findings were supported by assessment using the WHO Clinical Progress Scale and changes in self-reported symptoms for this disease. The drug appears to be safe. Drug efficacy differed in the final analysis compared to the interim analysis, mainly due to the lower mortality or hospitalization in the placebo group at the second time point. This may be due to shifts in sample characteristics (eg higher female representation, more patients with previous SARS-CoV-2 infection, more patients with lower viral load) or outbreak characteristics, or regional characteristics (newly registered countries). They may have had lower or higher thresholds for hospitalization).
The ability of the drug to reduce disease progression and thus reduce the burden on hospitals is important in this rapidly spreading epidemic while reducing the viral load to reduce the chances of transmission is also important. Compared to monoclonal antibodies, which must be given by injection in a medical facility, molnopiravir is one of several oral agents being studied for home administration.
Its broad efficacy against many variants is another advantage since its action is not dependent on spike protein binding and remains unaffected by spike mutants. The drug therefore deserves further evaluation to validate these findings.