Multiple vaccines have been developed that have made substantial contributions to controlling the COVID-19 pandemic, but where are the antivirals? Only repurposed drugs have been used and not with much success. That situation seems about to change with the authorization of drugs that target the RNA polymerase (Molnupiravir) and a viral protease (Paxlovid).
Molnupiravir is an orally available pro-drug of the nucleoside analog N4-hydroxycytidine (NHC). The latter is a nucleoside analogue which is incorporated into RNA by the viral RNA-dependent RNA polymerase. Once incorporated into RNA, NHC is recognized as either C or U by the RNA polymerase. As a consequence, many mutations are introduced into the viral genome, causing lethal mutagenesis and inhibition of infectivity. NHC has been shown to block SARS-CoV-2 transmission in ferrets.
Interim results in 775 patients of a phase 3 clinical trial with molnupiravir show that the drug reduced hospitalization or death about 50% compared with placebo in patients with mild to moderate COVID-19: 7.3% of patients who received molnupiravir were either hospitalized or died through Day 29 (28/385), compared with 14.1% of placebo-treated patients (53/377). No deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo, through day 29. The trial required that all patients have laboratory-confirmed COVID-19 with symptom onset within 5 days of assignment to control or drug group. Patients were recruited from multiple countries and included those with risk factors for poor disease. Merck expects to produce 10 million doses of the drug in 2021 and has submitted an application for emergency use authorization (EUA).
Paxlovid is an inhibitor of the 3CL or main protease of SARS-CoV-2, an essential viral enzyme that is required to process precursor proteins into functional products. The drug works by binding to the active site of the protease. Such inhibitors have been successfully developed and are approved for the treatment of AIDS and hepatitis C. Paxlovid inhibits viral reproduction in cell culture and in virus-infected mice when given orally. In a phase I trial in 4 participants, the drug was safe and well tolerated and reached levels greater than needed to inhibit reproduction in cell culture.
Interim analysis of a phase 2/3 randomized, placebo-controlled study of Paxlovid showed that the drug reduced the risk of hospitalization or death by 89%. This study enrolled non-hospitalized patients with COVID-19 who were at risk for severe illness. The patients were treated with Paxlovid within 3 days of symptom onset. Of the patients who received the drug, 3/389 were hospitalized through day 28 (0.8%) compared with 27/385 in the placebo group hospitalized and 7 deaths (7%). Similar results were obtained in a group of patients treated within 5 days of symptom onset. Based on these results, Pfizer plans to submit an application for EUA.
The only antiviral repurposed for SARS-CoV-2 that had any efficacy is remdesivir, whose widespread adoption is limited by the need to administer the drug intravenously. Because they are taken orally, Molnupiravir and Paxlovid should have a far greater impact on the pandemic, especially for people who refuse to be vaccinated. If these drugs had been available before the pandemic – which was certainly possible – it might have been largely prevented.
Dominique Verdejo says
Just to understand: these tests are made on real people who are showing mild to moderate COVID symptoms.
Some people are treated and some people are left with placebo. Those who are given a placebo are consequently not treated.
How can that be ?
14% of these people die. Beside the extremely high death ratio, it is absolutely immoral to let these people die.
Can you explain this ?
Matt E. says
Well is this a surprise. It kind of makes Pfizer look like the money grabber it has been accused of all along and opens it up for a law suites of all kinds. I am sure lawyers world wide are licking their lips and ring their greedy little hands with great big smiles as money symbols dance threw their heads and plans of making millions and billions of Dollars, Pounds, Euros, Marks and so forth are made.
The saddest thing is forgotten in the media’s race for it’s money grab at ads money for best made up story about what was found here and that is the story of hundreds of thousand of lives lost because a drug company had could have stopped this and didn’t all because the same company that made it big back in 1911 wanted to cash in again and that is the owners of Pfizer the markers of Aspirin.
Matt M says
I would like to try to answer some of your questions and alleviate some of your concern. You are correct that these studies include real people who are suffering from COVID-19. However, the first thing that I want to be sure to relay to you is that, according to modern medical ethical guidelines, patients who receive a placebo rather than an investigational drug must also receive all standard medical care. I assure you that Merck and other pharma companies do not cruelly and intentionally allow people to die without ANY treatment. The investigational drug is the only therapy they are denied. This is also the main design factor of such studies because, until we treat people with the drug, we do not yet know if the drug is beneficial or not. Sometimes people who receive the study drug have worse outcomes than those who get placebos and this is also valuable scientific data. In a perfect study, the ONLY difference between the groups would be the drug vs placebo, like if we had 500 pairs of identical twins who got the exact same medical treatment for an infection except that one twin got the drug and the other got the placebo. The more alike the two groups are the more we can attribute any difference in outcome to the investigational drug.
Secondly, the 14.1% of placebo-treated patients includes those who were hospitalized OR died (53 out of 377 patients). According to the linked data, only 8 of those 53 placebo-treated patients had died through Study Day 29 (8/377 = 2.1%). Again, these patients would have received any standard care deemed medically necessary by their medical team and provided by the hospital (ie, oxygen, corticosteroids, mechanical ventilation, etc.) and, unfortunately, still died. One reassuring quality in many or most drug studies, including this one by Merck, is that when the results are good outcomes that dramatically favor the investigational drug, the study is often stopped earlier than planned because it would be unethical to continue giving some patients a placebo when it appears that the drug is very effective and doesn’t have a lot of significant side effects. Drug companies actually love this scenario because they can often get preliminary regulatory approval for the drug and begin selling it rather than continue the very expensive study where they only lose money.
I hope I was able to answer most of your questions and relieve some of your concerns!