If you can't use Pfizer's P drug, can the newly launched Merck M drug be used?

I believe that everyone has a lot of understanding of Paxlovid (P medicine), but many people are complaining that this medicine is too difficult to buy, or the elderly at home have a disease, are taking a lot of medicine, check down and P drug conflict, or liver and kidney function is relatively poor can not use P drug. Everyone is asking, is there no other medicine besides P medicine? Just a few days ago, another new crown oral drug monolavir went on the market. What is the difference between this medicine and P medicine? Today I will talk about this monoravir.

1. What kind of medicine is monoravir?

The English name of monoravir is Molnupiravir, Chinese translation has several names, in addition to monoravir, there are also transliterations into monabigravir, monupiravir, monupivir, monuravir and so on, in fact, they all refer to the same drug. For the convenience of expression, we will collectively call it "monogravir", or simply "M drug".

Monoravir was approved for marketing in the UK in November 2021, and received emergency use authorization (EUA) from the US Food and Drug Administration (FDA) in December 2021 and emergency exception approval in Japan. On December 29, 2022, the State Food and Drug Administration conditionally approved the import registration of Merck's new coronavirus treatment monogravir capsules (trade name: Lizhuorui/LAGEVRIO). At present, this drug has been marketed in China.

From the mechanism of action, similar to Paxlovid, monoravir is also an oral small molecule antiviral. Monoravir is a prodrug that is metabolized to N4-hydroxycytidine (NHC), a ribonucleoside whose metabolites incorporate viral RNA, inducing the production of false mutations that inhibit viral replication.

Second, how effective is it?

Before introducing the efficacy of this drug, I will introduce you to the general pathological process of new crown infection. It is currently believed that the onset of the disease is related to two main processes. In the early clinical stage, the disease occurs mainly due to the replication of the virus, while in the later clinical stages of the disease, the main factor driving the development of the disease is the body's immune or inflammatory disorder, which can cause tissue damage.

Based on this understanding, treatment against the virus is expected to have the greatest clinical effect early in the disease. In the later stages of the disease, anti-inflammatory or immunosuppressive therapy is likely to benefit the patient.

Therefore, antiviral drugs, whether P drugs or M drugs, must be used in the early stages of the disease to exert maximum effect, not wait until they have developed to severe disease. Most of the clinical research on antiviral drugs has also been carried out in patients with mild to moderate new crown infection, but there is a high risk of progression to severe disease.

The Phase 3 clinical trial (MOVe-OUT study) of monoravir enrolled unvaccinated, non-hospitalized mild to moderate adult patients with mild to moderate COVID who were at high risk of progressing to severe COVID and enrolled within 5 days of symptom onset. One group of patients received monoravir 800 mg orally every 12 hours for 5 days, and the other group received a placebo. A total of 1433 patients were included in the final analysis. The study found that by day 29, the risk of hospitalisation or death was reduced by 31% with monoravir, with 48 (6.8%) patients hospitalized or dying in the monoravir group (709 in total) and 68 (9.7%) hospitalization or death in the placebo group (699 in total). There was one death in the monoravir group and nine deaths in the placebo group. Security is similar between the two groups. A secondary analysis of patients requiring hospitalisation during the trial showed a 21% reduction in the risk of using monoravir requiring respiratory intervention (conventional or high-flow oxygen therapy or non-invasive or invasive mechanical ventilation).

In contrast, Paxlovid's Phase 2-3 clinical trial results showed that P drug can reduce hospitalization rates and 88.9% risk of severe disease in mild and moderate adult COVID patients.

It should be noted that:

- This MOVe-OUT trial was conducted prior to the emergence of the Omicron variant and its subvariants. Although monoravir has also shown activity against the Omicron variant in vitro and animal studies, however, the PANORAMIC study published in Lancet in December 2022 suggests that monoravir appears to be less effective against the currently circulating Omicron.

- The PANORAMIC study found that monoravir did not reduce hospitalizations and deaths in COVID patients after vaccination. The large study, which enrolled 26,411 COVID patients, showed that 105 people were hospitalized or died in the standard-care group and 98 in the standard-care group, with no difference between the two groups (OR=1.06), and adverse events were comparable in both groups.

- Although there has not been a direct comparison of different COVID treatments in clinical trials, NIH guidelines recommend using monoravir only when Paxlovid and remdesivir are unavailable or unavailable, as monoravir appears to be less effective in preventing severe disease than Paxlovid and remdesivir.

3. Who is it suitable for?

Monoravir is indicated in essentially the same way as Paxlovid for the treatment of adults with mild to moderate COVID-19 patients with risk factors for progression to severe disease.

The so-called "risk factors for severe disease", according to its Chinese instructions, mainly include the following:

Factors at risk for progression to severe COVID-19 are considered to be associated with at least one of the following illnesses or conditions:

-Advanced age (e.g., ≥60 years)

- Obese or overweight (e.g., body mass index [BMI] ≥30 kg/m²)

- Chronic kidney disease

-diabetes

- Severe cardiovascular disease

- Chronic obstructive pulmonary disease

- Active cancer

Other medical conditions or factors may also put an individual patient at high risk of progressing to severe COVID-19, and the benefits and risks should be weighed against the risks of the individual patient.

NIH guidelines recommend the following sequence of antivirals for people at risk of progression to severe disease:

1. Paxlovid (oral): Emergency use authorization has been granted by the FDA for the treatment of the new crown. Import registration has been conditionally approved in China.

2. Remdesivir (intravenous): has been approved by the FDA for the treatment of the new crown. At present, it is not listed in China.

3. Monoravir (oral): has received emergency use authorization from the FDA for the treatment of the new crown. Import registration has been conditionally approved in China. If neither of the above drugs is available or available, it may be considered.

4. What are the side effects?

The most common adverse effects of monoravir are diarrhea, nausea, and dizziness.

▲ Adverse reactions found in the MOVe-OUT study

In addition, according to FDA opinion, a 5-day course of monoravir has a low risk of genotoxicity.

5. How to use it?

Monoravir is a prescription drug, be sure to follow your doctor's prescription and refer to the instructions for the drug to take it correctly.

Specific usage: 800 mg orally each time (a total of 4 capsules, each capsule contains 200 mg), once every 12 hours, for 5 consecutive days, should be started as soon as possible within 5 days after the onset of symptoms.

If the patient needs to be hospitalized before completing the 5-day course of this product, the full 5-day course of treatment can be completed according to the judgment of the medical staff. The safety and efficacy of dosing for more than 5 days is unclear.

Monoravir can be taken on an empty stomach or with a meal. If the patient finds that he missed a dose of this product within 10 hours of the usual time of taking the drug, he should make up the dose as soon as possible and resume the normal dosing schedule. If the patient misses a dose and more than 10 hours have passed since the usual dose, the patient should not retake the missed dose and should take the next dose at a regularly scheduled time. Patients should not double the dose to make up for missed doses.

6. What are the precautions?

 1. Reproductive toxicity: Theoretically, there is a risk that monoravir will be metabolized by human host cells and incorporated into host DNA, resulting in mutations. Reproductive toxicity has been reported in monoravir in animal studies. Therefore, monogravir is not recommended in pregnant patients unless there are no other options and clear indications for treatment, in which case the risks and benefits should be fully discussed with the physician. A pregnancy test is recommended before starting medication to rule out pregnancy.

For patients of childbearing potential, it is recommended that women should take reliable contraception during and within 4 days after taking monoravir. According to the FDA EUA product insert, it is also recommended that men of childbearing potential should use reliable contraception during and for at least 3 months after taking monoravir.

 2. Lactation: There is currently a lack of data on the use of monoravir in lactating populations, which may cause adverse effects in infants exposed to the drug through breastfeeding.

Therefore, lactating women should not breastfeed their infants during treatment with monoravir and for 4 days after the last dose, it is recommended to express and discard breast milk during this period to maintain milk secretion.

 3. Children: There is a lack of data on the use of monoravir in children under 18 years of age. Monoravir is not recommended for use

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 4. Drug Interactions: Neither monoravir nor its active metabolite is an inhibitor or inducer of a major drug-metabolizing enzyme or an inhibitor of a major drug transporter.

Therefore, monoravir is unlikely to interact with the co-medication. Therefore, in terms of drug conflicts, it has many advantages over P drugs.

Here, we have compared these two drugs for your reference.

Finally, I solemnly remind again: like P drug, this M drug is also a prescription drug, you can have a preliminary understanding of this new drug, see if you or your family belong to the applicable population, in case you need to use it, you must use the drug strictly according to the instructions under the guidance of the doctor.

As can be seen from the table above, there are many restrictions in the use of P drugs, especially in terms of drug interactions, which are not very friendly to people who are taking other drugs at the same time, so although M drugs seem to be slightly inferior to P drugs in preventing severe disease, if P drugs cannot be used, M drugs are also another good choice.

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