What's the main controversy on first COVID-19 oral drug Molnupiravir?

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What’s the main controversy on first COVID-19 oral drug Molnupiravir?

What’s the main controversy on first COVID-19 oral drug Molnupiravir? Experts analyze the breakthrough significance of the first COVID-19 oral drug Molnupiravir.

COVID-19 Drug Molnupiravir Found to Be Associated with SARS-CoV-2 Virus Unusual Mutations

The first COVID-19 oral antiviral drug

The only new coronavirus drugs on the market that can reduce the risk of severe illness after infection are antibody drugs, but as protein preparations, these drugs are all injected, which is inconvenient to use.

COVID-19 treatment has always lacked a drug that can be taken orally and used in the early stages of infection to reduce the risk of severe illness.

On October 1, Merck announced that the oral COVID-19 antiviral molnupiravir developed by it and Ridgeback has significantly reduced the risk of severe illness or death in a phase III clinical trial, and it will apply to the FDA for emergency use authorization.

If the application is successful, it will be the first to enter the practical and proven effective oral COVID-19 drug.

This drug targets the process of copying its own RNA genome, which is essential in the replication process of the COVID-19, and has similarities with Gilead’s Remdesivir. However, unlike Remdesivir, which directly inhibits the RNA replicase of the virus, molnupiravir allows the virus to introduce wrong bases during the process of RNA replication.

Like remdesivir, molnupiravir was previously developed as an antiviral drug for other viruses. Remdesivir has been developed as a hepatitis C drug and Ebola virus drug. Molnupiravir was developed as a flu medicine.

As with Radixivir, molnupiravir’s previous development journey was not smooth. BARDA (Biomedical Advanced Research and Development Authority, Biomedical Advanced Research and Development Authority) has provided funding for the research and development of this drug.

But the former director of BARDA had accused Ridgeback, which introduced molnupiravir from Emory, to exert pressure to force BARDA to provide funds.

The main point of controversy is the possibility of mutagenicity in similar drugs of Molnupiravir.

Pharmasset, which was acquired by Gilead after the development of a blockbuster hepatitis C drug, has evaluated the active ingredients of molnupiravir (molnupiravir is a prodrug, and the active ingredients that can play an antiviral effect are transformed and formed in the body), but also because of concerns about the possibility of mutagenesis. Give up the medicine.

Of course, the possibility of mutagenicity of similar drugs does not mean that molnupiravir is unsafe. Whether the potential side effects of a drug will actually occur, the actual dosage and duration of treatment must also be considered. In addition, we must also consider the targeted diseases and weigh the benefits and risks.

Like Remdesivir, molnupiravir has turned around in the COVID-19 epidemic. In July 2020, Merck announced that it will develop its role in the COVID-19 together with Ridgeback, which has rights in molnupiravi. Previously, this drug had been clinically tested in hospitalized severely ill patients, and it failed almost without suspense. As a drug that inhibits virus replication, the possibility of onset of effect for hospitalized patients who may have passed the peak of virus replication is naturally very low.

This time Merck announced a successful clinical trial aimed at patients with mild to moderate symptoms within 5 days of onset of symptoms, who have not been vaccinated, and then must have at least one factor that leads to an increased risk of severe illness (such as underlying diseases). The patient took 8 pills (800 mg) a day, the course of treatment was 5 days, and the follow-up observation was 29 days to compare whether there was a difference in the risk of hospitalization or death.

Originally planned to enroll 1,500 people, now it is close to recruiting the planned enrollment. Interim analysis of 775 subjects with data found that the drug had significant efficacy, so the trial was terminated under the recommendation of the independent data safety supervision committee. Of the 385 people in the drug group, 28 people were hospitalized without death, and 377 people in the control group had 53 people hospitalized, of which 8 people died. The proportion of hospitalization or death was 7.3% in the drug group and 14.1% in the control group. That is, molnupiravir can reduce the risk of hospitalization or death by about 50%.

40% of the patients had the viral genome sequenced, and 80% of them were found to be mutant strains of Gamma, Delta, and Mu. From the results, molnupiravi has been shown to be effective against these mutant strains. This is not surprising, molnupiravir is aimed at the viral gene replication process. These famous mutant strains, the mutation that is causing concern is the spike protein, which naturally does not affect the effectiveness of molnupiravir, an antiviral drug.

From the safety data of clinical trials, adverse drug reactions are not serious. 35% of people in the drug group reported adverse reactions, compared to 40% in the placebo group. If you look at the ratio, this seems to mean that there are many adverse reactions, but the placebo group has more than the drug group. The detailed data has not yet been released, and personal speculation is that most of these adverse reactions come from the COVID-19 disease. As a therapeutic drug, the participants in the trial are all patients. This is different from clinical trials of vaccines done by healthy people. Many reactions from the disease are recorded.

In terms of supply, it is easier for oral drugs to increase production than antibody drugs. Merck expects to produce 10 million treatment courses this year, 2021. The US government has purchased 1.7 million courses of treatment, and the unit price of a course of treatment is almost US$700, which is cheaper than the purchase price of antibody drugs. But in terms of cost, the cost of this small molecule chemical drug is much lower.

Merck mentioned that it will provide different pricing according to the economic income level of different countries. It will also provide technology transfer support for generic drug companies targeting the market in low- and middle-income countries. This is very necessary and should be. In the Phase III clinical trial of molnupiravir, only 10% of patients were from the United States, 23% were from Europe, 55% were from Latin America, and 15% were from Africa. Many patients in low- and middle-income countries have played a vital role in the success of this clinical trial, and the supply of drugs in these areas should also be guaranteed.

For long-term control of the epidemic, oral antiviral drugs such as molnupiravir are very important because they are convenient to use, and through such convenient drugs to reduce the risk of severe illness of infected persons, we can improve our adaptability to coexist with the COVID-19. The previous antibody drugs can also reduce the risk of severe illness, but they are inconvenient to use and small in output, making it difficult to popularize. However, even this kind of oral antiviral drugs does not replace vaccines, but is a supplement to existing vaccine-based epidemic prevention measures.

Why don’t people who have been vaccinated be recruited in this clinical trial? Because the ability of vaccines to prevent severe illness is so good, more than 90% of those recruited will not have enough severe cases to analyze. From another point of view, how can a 50% anti-severe medicine replace a 90% anti-severe vaccine? It can only be a supplement.

In addition, the potential mutagenicity just mentioned. Although this course of treatment is only 5 days, the trial excludes pregnant women. Even after approval, its applicable population is definitely smaller than the vaccine, and pregnant women and minors may be excluded. So for most people, the most critical and applicable is vaccination. This type of antiviral drug is a good supplement when it appears, but don’t think of it as the only means.