The end of the COVID-19 pandemic cannot be achieved by the power of drugs alone, but drugs are indispensable "sharp weapons" to extinguish the epidemic on many occasions.
Written by | Fang Jingyu
Source | "Medical Community" public account
After being included in the "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (Trial Ninth Edition)", the oral antiviral drug Paxlovid (nematvir tablets/ritonavir tablets) has attracted widespread attention.
The drug has received emergency conditional approval from the NmpaQ for the treatment of adults with mild to moderate coronavirus pneumonia (COVID-19) with a high risk factor for progression to severe illness. It replaces experimental antiviral drugs such as interferons in previous versions of the protocol.
On the evening of March 29, the Third People's Hospital of Shenzhen reported that small-scale clinical trials had initially shown that its efficacy was accurate.
The team of Professor Lu Hongzhou of the National Clinical Research Center for Infectious Diseases of the hospital used the drug in 24 cases of new crown patients. After 5 days of medication, the relevant indicators for the subjects were close to the discharge criteria.
As of now, Paxlovid has been approved in China for less than 2 months, but it has been put into use in many places.
On March 17, 21,200 boxes of Paxlovid were inspected and released by the customs of Shanghai Waigaoqiao Free Trade Zone, and all import customs clearance procedures were completed and shipped to the front line of the national fight against the epidemic.
Three days later, the Shanghai Public Health Clinical Center received 1,000 boxes of Paxlovid from Shanghai Pharmaceutical Holdings. This is the first time paxlovid has reached the frontline of the fight against the epidemic since it was approved. Since then, at the press conference on the prevention and control of the epidemic in Jilin Province, Zhang Li, deputy director of the Jilin Provincial Health Commission, said that 10,000 boxes of Paxlovids have been allocated by the state, in addition to 40% of the reserved reserves, all of which have been allocated to all parts of Jilin Province, and distributed to designated hospitals by cities and prefectures combined with the needs of local hospitals to ensure that the clinical treatment needs of various places are met to the greatest extent.
Today, when the epidemic rebounds in many places and the Omikeron BA.2 variant strain brings severe challenges to the national epidemic prevention work, the arrival of Paxlovid is undoubtedly a "timely rain".
"Ta" from 20 years ago
Looking back at Paxlovid's research and development history, we're going to set the timeline back 20 years.
In 2003, severe acute respiratory syndrome (SARS) outbreaks in several countries, including China, caused 8,096 infections and 774 deaths.
In June of the same year, a team of researchers at the University of Lübeck in Germany discovered a potential therapeutic target for SARS, the 3CL protease (3CLpro) of coronavirus.
In the life course of any virus, after the virus enters the cell, it will use the "resources" in the cell and its own genome to express the proteins it needs, and use them to promote the replication, assembly, release and other processes of the virus.
In many cases, host cells often express "conjoined baby" polypolymers based on the viral genome. Although these polymers are made up of functional proteins connected, they do not have any activity until they are segmented. As a result, many viruses carry proteases to segment polyproteins to obtain the functional non-structural proteins needed for their replication.
Structure of the coronavirus 3CL protease
Figure: Reference 5
The 3CL protease is such a protease: it can lyse the viral polymer proteins pp1a and pp1ab expressed by the host into non-structural proteins necessary for viral replication, so that the replication process of the virus is successfully completed.
The researchers hypothesized that if drugs were used to block the activity of 3CL proteases, would it be possible to interfere with viral replication by inhibiting the formation of functional non-structural proteins in the virus?
In 2004, the SARS outbreak ended. These drugs were sealed up until the COVID-19 pandemic in 2020.
The scientific community is once again looking for targets for replication of the new crown virus. Dafydd Owen, a chemist at Pfizer, also led the mission to "develop antiviral drugs for COVID-19."
Dafydd has always been known in the company for its expertise in discovering new drug targets. But this time, faced with an area he had never set foot in, Dafydd decided to "go the "unusual way" — to go through the data to find known targets, and then to develop new drugs by optimizing the design.
Soon, he flipped out the old antique PF-00835231 developed by the company. Unfortunately, PF-00835231 itself can only be administered intravenously. This seems "a bit slow" for the growing COVID-19 pandemic. The boss also told Dafydd that the company's goal is to develop an oral antiviral drug.
After several days of research, he decided to follow the company's arrangement, but also insisted on his target target, 3CL protease.
After 4 months of relentless research, Dafydd's lab synthesized PF-07321332. It theoretically satisfies the characteristics of effective and targeted oral administration. Since then, it has passed the basic in vitro antiviral research and animal pharmacokinetic research.
On March 23, 2021, Pfizer officially announced the phase I clinical trial of PF-07321332. This is only 12 months after Dafydd's 3CL protease inhibitor project was launched.
Subsequently, based on the study's data, on December 22 of that year, Paxlovid was granted an Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA). At this time, PF-07321332 finally had an official name - nirmatrelvir.
Paxlovid also has the name: Nematvir Tablets/Ritonavir Tablets.
Speaking by efficacy,
Paxlovid has won the favor of regulators in many countries
For a long time, the drugs used by countries around the world to treat COVID-19 have been mainly neutralizing antibodies to the new crown virus. These drugs are derived from the convalescent plasma of people infected with the new crown virus and are purified, modified and other steps.
Although they have shown a certain efficacy in the clinic, in the face of the impact of variants such as Delta and Omikerong, the drug resistance rate of neutralizing antibodies of the new crown virus has also increased significantly. In the United States, on January 24, 2022, the FDA suspended the use of two coronavirus neutralizing antibody "cocktails" in the United States due to rising rates of virus resistance monitored by the health department.
Other antiviral drugs that have been approved in some countries have been "questioned for efficacy". For example, remdesivir, which received EUA as early as May 1, 2020, was seen as "the hope of the people" in early clinical studies, but subsequent large-scale clinical studies confirmed little efficacy, slightly shortening the course of illness in non-critical patients, and having no effect on key indicators such as severe illness rate and mortality.
Another antiviral drug recognized by Japanese regulators and used on a large scale in the local area, favipiravir (also known as "favipiravir"), has also been repeatedly broken in clinical studies, and the idea of manufacturers to expand the drug market has been repeatedly shelved.
Paxlovid, under the attack of Delta and Omikeron, has been reliably cured in clinical trials for patients with COVID-19 who are at high risk of severe illness.
In the EPIC-HR study used by Pfizer when it submitted its listing application to regulatory authorities, Paxlovid reduced the likelihood of patients with severe high risk of progressing to severe COVID-19 or dying by 87.8% compared to placebo, when patients took the drug within 5 days of developing symptoms. If the patient takes the drug within 72 hours of the onset of symptoms, the probability of progression to severe illness or death is reduced by 88.9%. In addition, Paxlovid is a good safety profile, with adverse reaction characteristics similar to placebo.
Notably, in the EPIC-HR study, 98 percent of enrolled patients were infected with the Delta strain, an unprecedented proportion in clinical studies of antiviral drugs. Clinical studies of COVID-19 neutralizing antibodies rarely include people infected with the Delta strain. The molnupiravir study included only 58 percent of delta infected people. The efficacy of Paxlovid on the Delta strain in this study is also exactly the same as the results of the in vitro study that it is effective for most of the new coronavirus strains, including the Delta and Omiljung strains.
When patients take the drug within 5 days of the onset of symptoms, Paxlovid reduces the probability of progression to severe COVID-19 or death in high-risk patients by up to 87.8% relative to placebo Figure: Reference 6
Based on these clinical trial data, Paxlovid received EUA from U.S. and European regulatory authorities on December 22, 2021 and January 28, 2022, respectively, and was conditionally approved for marketing in China on February 11, 2022.
Because Paxlovid provided "timely rain" to European and American countries during the critical period of the epidemic, the drug regulatory authorities also praised Paxlovid.
EU Health Commissioner Stella Kyriakides described Paxlovid as the EU's "second line of defence after vaccines" and said that "Paxlovid is the first oral antiviral drug that we have approved for COVID-19 therapy that can be taken at home and could have a significant impact on patients at high risk of severe COVID-19".
Paxlovid's impact on the epidemic may not be limited to Europe and the United States. On November 16, 2021, Pfizer announced that it has signed an agreement with the Medicines Patent Pool (MPP) to temporarily grant drug patents to MPP licensed generic drug companies during the COVID-19 pandemic, and agreed to freely sell these generic drugs in 95 low- and middle-income countries and regions. After obtaining the approval of the mainstream regulatory authorities, MPP has also authorized a number of enterprises in China, including Fosun Pharma, Shanghai Disano, Huahai Pharmaceutical, Puluo Pharmaceutical, and Jiuzhou Pharmaceutical to produce oral preparations and/or APIs.
Will Paxlovid be the "savior" of the global pandemic?
The answer is beyond doubt.
First, the biggest beneficiaries of Paxlovid's application are those areas where the COVID-19 pandemic is out of control and has led to a severe run on medical resources, and normal medical work and even people's daily lives have been seriously affected.
In these areas, the widespread use of Paxlovid can greatly reduce the probability of high-risk groups progressing to severe illness, admission to the ICU or even death, alleviating the pressure of the epidemic on the medical system (especially critical care services), and avoiding the epidemic from having a greater impact on the normal social order.
Secondly, Paxlovid is conducting clinical studies on the Aomi Kerong variant, as well as clinical studies on post-exposure prevention of the new crown virus, which, once positive results, are undoubtedly great news for epidemic prevention and control.
With the global epidemic of the Olmikron variant gradually replacing the Delta strain, many antiviral drugs that have been effective against the original strain of the new crown virus or the Delta strain are facing serious drug resistance threats (as mentioned earlier, the application of neutralizing antibodies to the new crown virus has been deeply hit).
However, since the Aumi kerong variant does not have a new 3CL protease mutation and is also highly antivirally active against the Omiljun strain in in vitro studies, this means that Paxlovid will have a better chance of remaining effective against Omiljung infected people.
Since the inclusion of Paxlovid's key clinical studies is basically a Delta variant infection, and in vitro tests do not always predict the clinical situation, it will be critical to determine the efficacy of Paxlovid in the clinical setting for infected people with the Omitchon strain as soon as possible.
With Pfizer's announcement on September 27, 2021 of a Phase II/III clinical study (EPIC-PEP study) exploring Paxlovid's use for post-exposure prophylaxis of the new coronavirus, Paxlovid's role in post-exposure prophylaxis has also begun to be taken seriously by the medical community. In countries and regions that implement the "dynamic zero" policy (such as the mainland), the management of close contacts of new coronavirus infected people has always been a major problem, although the mainland has a strict and comprehensive medical observation arrangement for close contacts of new crown virus infection, but due to the risk of intra-family transmission during home isolation and internal transmission in isolation points during centralized isolation, simply taking medical observation measures cannot make us sit back and relax. If Paxlovid can make a breakthrough in clinical research on post-exposure prophylaxis, the use of drugs to prevent post-exposure prophylaxis in close contacts will be effective in blocking secondary transmission associated with close contacts and will also help prevent high-risk close contacts from developing symptomatic COVID-19. Of course, whether this use is feasible in reality will be closely related to the final results of the relevant clinical trials.
In summary, Paxlovid may indeed have some value in alleviating the run on medical institutions in some areas and alleviating the pressure of the epidemic in various countries, but it cannot be considered that Paxlovid is the "savior" of the global epidemic. After all, no human being has yet eliminated any infectious diseases by drugs alone.
Will the patent pool system affect Paxlovid?
For Pfizer, paxlovid's entry into the* patent pool has a negligible impact on the company's revenue. After paxlovid was listed, almost all of Pfizer's orders came from the centralized large-scale procurement of various national and regional governments, and for special products such as new crown antiviral drugs, these "pre-orders", especially orders from high-income countries, are often the real source of profitability for pharmaceutical companies. Moreover, without MPP's agreement, Paxlovid's inexpensive pricing is difficult for most residents in these low- and middle-income countries and regions to afford, and Pfizer can hardly say that it has a lot of profits in this part of the market.
What's more, many countries and regions have relevant laws and regulations on the "compulsory licensing of patents" for drug production in major public health events, that is, when major public health events occur, people's lives and property are greatly threatened, and urgently need drugs that are difficult to obtain due to patent barriers, the relevant departments may directly authorize drugs to specific enterprises for production and sales without the consent of the drug patentee.
In the 2001 "anthrax letter" terrorist attack in the United States, the U.S. government threatened to use a compulsory patent license for the company because the manufacturer of the anthrax treatment drug ciprofloxacin refused to reduce the price of the drug. The incident ended with concessions from the latter.
This shows that if Pfizer does not take measures such as MPP to give up Paxlovid's patent rights in specific markets, it is not impossible for Pfizer to get into trouble related to the compulsory licensing system in terms of the degree of development of the new crown epidemic. Therefore, for enterprises, "taking a step back from the sea and the sky", joining MPP is not a good thing for themselves.
Capacity problem, how to solve?
As early as the beginning of the new crown vaccine market, due to the serious shortage of mRNA vaccine and adenovirus vector vaccine, countries around the world have a fierce debate about the order of vaccine supply.
Thankfully, Paxlovid, as a chemical, has an inherent advantage in terms of capacity compared to biological products that are very demanding in production, quality control and transportation. Its production threshold is not highly complex, and there is no shortage of pharmaceutical companies with rich experience in chemical production worldwide. Theoretically, as long as Pfizer, which currently holds patents, allows, a large number of pharmaceutical companies will be able to carry out the production of Paxlovid in a relatively short period of time. The speed at which the patent pool is expanding is actually a reflection of the truth of this phenomenon.
Of course, Pfizer does not need to "go to great lengths" in order to expand production capacity. Because in the field of pharmaceutical production, the pharmaceutical custom research and development and production (CDMO) pharmaceutical companies with oem drugs as the only business (such as Patheon and Catalent in the United States and Delpharm in France) abound, and it is the norm for CDMO to entrust CDMO to produce drugs by R&D pharmaceutical companies, and CDMO often reserves sufficient production capacity in order to serve more customers. If one day Paxlovid encounters a capacity bottleneck, Pfizer's allocation of some pharmaceutical orders to CDMO production usually solves the problem.
Catalent, a famous AMERICAN CDMO company
图：Missouri Partnership
According to the "drug marketing authorization holder" system used in the mainland (and many other countries and regions), the procedures for simply replacing the production plant of drugs are relatively simple, and the impact of the transition period on the supply of drugs is relatively limited, which also provides policy guarantees for potentially urgently needed drugs, including Paxlovid, to a certain extent.
The end of the COVID-19 pandemic cannot be achieved by the power of drugs alone, but drugs are indispensable "weapons" to extinguish the epidemic on many occasions, which is true at home and abroad.
Reliable drugs can be adequately supplied, so with the cooperation of large-scale vaccination and non-drug epidemic prevention strategies, the possibility of winning the battle against the epidemic and insisting on maintaining "dynamic clearance" at the minimum cost will be greatly improved.
Time will be verified.
*The Medicines Patent Pool (MPP) system is an international system established to improve access to drugs for the treatment of diseases that seriously threaten public health, and the original research enterprise of the drug may voluntarily choose to add the drug to the patent pool, thereby authorizing specific pharmaceutical companies to produce generic drugs for the drug and sell them at low prices in the low-income countries and regions designated by the patent pool, but the list is determined by the organization. Before the COVID-19 pandemic, MPP mainly involved new drugs to treat infectious diseases such as AIDS, hepatitis C, and tuberculosis.
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