Another “myth” of preventing the new crown is broken, and American manufacturers are not working

Pfizer’s official website recently announced the main results of the PAXLOVID post-exposure prophylaxis study for the new coronavirus – compared with placebo, adult subjects who received 5-day and 10-day PAXLOVID treatment reduced the risk of infection by 32% and 37%, respectively.

This data is not statistically significant, that is to say, it fails to meet the primary endpoint of this study – reducing the risk of contracting the new coronavirus in people exposed to the virus.

Commenting on the results, Pfizer Chairman and Chief Executive Officer Albert Bourla said: “While we are disappointed by the results of this particular study, this does not affect what was observed in earlier trials for the treatment of high-risk patients with severe COVID-19. 19 patients with robust efficacy and safety data.”

Pfizer’s just-released report for the first quarter of 2022 showed that PAXLOVID’s sales were about $1.47 billion, a big gap from the previous forecast of $2.420 billion. Compared with Merck’s Molnupiravir sales of $3.2 billion in the first quarter, the gap is even more pronounced.

The failed attempt at post-exposure prophylaxis for the virus also makes its outlook even more bleak. And people’s expectations for preventive drugs have once again failed.

Ever since the outbreak began to spread, people have been looking for ways to prevent the new coronavirus. For this reason, there have also been a series of “Oolong” incidents such as queuing up to buy Banlangen and Shuanghuanglian.

As the new coronavirus spreads faster and faster, especially after Omicron becomes the mainstream strain, the R0 value has reached about 10, and the effectiveness of conventional anti-infection methods has weakened. If the booster shot is not given in time, even the protective effect of the vaccine is greatly reduced. All these make the mood of all parties to use some kind of drug to prevent the new crown virus more urgent.

In the past year, in the field of new crown virus prevention and treatment, in addition to vaccines, the global market size of new crown neutralizing antibodies has exceeded 10 billion US dollars, and post-exposure prophylaxis is its main purpose. Now this is also the direction that small molecule oral new crown drugs are trying to break through.

In order to “make up for the dead”, clinically, small molecule drugs such as PAXLOVID will be used preventively in the elderly who have not been vaccinated and have underlying diseases, so as to avoid serious illness and death. In a report by Health Times in early April, it was also mentioned that 8 medical staff used the drug for prevention after suspected accidental exposure.

From this perspective, the failure of Pfizer’s study will indeed disappoint many people.

What is more worth thinking about is, can small molecule oral drugs really prevent new coronary pneumonia? Can they change the “rules of the game” for new coronavirus prevention and treatment? What are the reasons behind it to be vigilant?

Can small molecule drugs prevent new crowns?

The study, which began in September 2021 and was completed at the height of the Omicron pandemic, enrolled a total of 2,957 subjects, according to trial details released by Pfizer. These individuals were all adults with negative rapid antigen test results, asymptomatic household contacts, individuals who had been in contact with an asymptomatic infected person within 96 hours or a person who had recently tested positive for COVID-19.

The researchers divided them into three groups and randomized them to receive “5 days of PAXLOVID followed by 5 days of placebo”, “10 days of PAXLOVID” or “10 days of placebo”.

It turned out that the infection profiles of the three groups were essentially the same, and PAXLOVID did not show better results. Although the full research data will not be released in the next few months, it is difficult to say what the specific reasons are, but in addition to disappointment, many industry experts are not surprised by the failure of PAXLOVID.

“This small molecule drug cannot prevent the new coronavirus from invading human cells.” Chang Rongshan, a virology expert, told Huxiu. In fact, small molecule antiviral drugs are difficult to play a preventive role. This is also determined by different mechanisms for preventing and treating infection.

Studies have shown that after the new coronavirus infects cells, its goal is to “hijack” the cells to complete gene expression and protein production, so as to replicate more viruses and infect more cells. In this process, various protein fragments are produced and then assembled together. The two essential and crucial ones are protease and RNA polymerase.

At present, Pfizer’s PAXLOVID and Merck’s Molnupiravir, two small-molecule specific drugs that have been authorized around the world, work by preventing these two substances.

This also means that these small-molecule antiviral drugs can only work when the virus starts to replicate.

Antibodies, on the other hand, prevent the virus from entering cells.

“This drug works relatively late in viral replication,” Dr. Paul Sacks, clinical director of the infectious disease department at Brigham and Women’s Hospital, said in an interview with medical industry media STAT: “Once the virus infects the cell, blocking protease It’s too late.”

In addition, some researchers compared the results of the PAXLOVID test with the results of the early neutralizing antibody drug test of the new crown epidemic, and believed that the reason for the difference between the two is that the products of companies such as Regeneron, Eli Lilly and AstraZeneca can be The 80% reduction in infection rate is likely due to the fact that the two work in different ways: PAXLOVID does not reach the site of infection faster, so it cannot block the virus in time.

With the continuous mutation of the new coronavirus, the preventive effect of neutralizing antibodies produced by natural infection is becoming more and more difficult to achieve.

“At present, it seems that it is difficult for neutralizing antibodies to play a major role. The neutralizing antibodies produced by different mutants have limited cross-protection effect and cannot be used for treatment to prevent severe death. The US FDA has urgently approved the serum of recovered patients for treatment. Severe cases, but the effect is getting worse and worse, so I have to cancel.” Chang Rongshan told Huxiu.

“The best way to prevent is to get vaccinated.” Jin Dongyan, a virologist at the University of Hong Kong, said bluntly to Huxiu, “Only when there is no vaccine, such as AIDS and certain influenza, antiviral drugs are used for prevention. Sometimes It will work. But at the end of the day, vaccines are fundamental, and antiviral drugs are just auxiliary means.”

Beware of more dangerous possibilities

In fact, the effectiveness of the widely used small-molecule new crown drugs still needs more research to verify.

According to Pfizer, since December 2021, PAXLOVID has been approved or authorized for conditional or emergency use in more than 60 countries around the world, mainly for the treatment of high-risk patients with new coronary pneumonia.

The Financial Associated Press reported that in the recent earnings conference call, Pfizer CEO Aberle revealed that the number of prescriptions for PAXLOVID is surging. In the week of April 22, 80,000 prescriptions were issued in the United States alone. This is the end of February. 10 times the prescribed amount.

However, in addition to the larger dosage, this drug has been frequently exposed to bad news recently, including “returning positive” after drug withdrawal, as well as the potential risk of promoting drug resistance and accelerating virus mutation.

“It can’t completely block virus replication, it can only inhibit it, which drives the new coronavirus to invade other organs and infect for a long time, such as the intestines.” Chang Rongshan told Huxiu. The long-term infection of these viruses in organs other than the lungs may lead to chronic infection, and the “Changyang” found can last for up to 500 days; after being cured and discharged from the hospital, the so-called “Fuyang” during the nucleic acid test review process may also be related to This is related.

In this regard, Pfizer has long been aware of it, and in its submission to the EU, it mentioned that “some subjects seem to have a rebound in the level of new coronavirus RNA around the 10th or 14th day”.

Further analysis found that 1% to 2% of patients in clinical trials had at least one re-positive nucleic acid test after 5 days of taking Paxlovid. The FDA is investigating the frequency and causes of this phenomenon.

In an interview with the media, the CEO of Pfizer also proposed to “take another round” in response to the rebound problem after completing the first course of treatment. According to the current FDA authorization, the drug can be taken for up to 5 days. The FDA indirectly refuted this suggestion through a data update.

To date, there is no data to support this claim, said Dr. John Farley, director of the FDA’s Office of Infectious Diseases. “We are continuing to review clinical trial data, but there is currently no evidence that a longer course of treatment is beneficial.”

However, the jury is still out on whether this rebound or re-infection can reinfect people. Chang Rongshan believes that the so-called Fuyang patients are only detected from nucleic acid fragments of the new coronavirus, or incomplete virus particles, and reinfection of people is rarely reported.

In this regard, Jin Dongyan also felt the same: “There is no evidence that patients with Fuyang are contagious. These people have high antibodies in their bodies, so there is generally no infection.”

The above-mentioned FDA data also show that these “Fuyang” patients have no symptoms, and the hospitalization rate and death rate have not increased.

Some other infectious disease experts are still worried that Fuyang patients are contagious, and have organized relevant research.

Another problem that worries researchers is that the “special medicine” that cannot completely “kill” the new coronavirus will train the virus to be stronger, which will lead to the problem of drug resistance. This is also related to the inability to completely remove the virus in the patient’s body during treatment. After drug intervention, the RNA of the new coronavirus is more prone to errors. In frequent combinations, it is very easy to produce new mutations that are resistant to drugs.

Jin Dongyan pointed out to Huxiu that, based on its mechanism of action, it is difficult for some oral drugs to develop drug resistance. Oral medicines help the body fight the virus to reduce it and stop replicating more quickly, reducing the chance of developing resistance. The above concerns may only arise in very specific populations, such as patients with impaired autoimmunity.

According to him, this situation is more common in HIV-infected patients whose disease is not under control, because patients with immunodeficiency will continue to be infected, and they will rebound after stopping the drug. “This group of people is really worth noting,” but don’t be overly concerned. Generally speaking, the new coronavirus is not a persistent infection. After the small molecule drugs and neutralizing antibodies help the human body fight the tough battle against the virus, the antibodies produced by the human body will completely control the virus and make the virus “unplayable”.

In any case, in the fight between humans and viruses, the virus will continue to mutate and evolve. As research continues, people will learn more and more about viruses and “weapons”, such as PAXLOVID and other special drugs.

From a global perspective, in the field of oral small-molecule drugs for COVID-19, in China alone, there are azvudine, which was originally used for AIDS treatment by real biology, proclutamide, which was originally used for cancer treatment by Kintor, and Junshi Bio’s oral drug. Nucleotide drug VV116, Hisun Pharmaceutical’s Favipiravir, and Ascletis, Simcere, WuXi AppTec and other companies are still in the preclinical stage of polymerase inhibitors and protease inhibitors.

It seems that mankind is getting closer to finding a small molecule drug that can really eliminate the new coronavirus in one fell swoop.

Before that, many experts suggested that it is still the first choice to vaccinate high-risk groups as soon as possible.

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