Does China still need new crown oral drugs?

The peak of severe disease is approaching, and it is difficult to find
a new crown oral medicine.

On the 26th, after verification and confirmation by a number of media, Beijing will soon distribute Paxlovid to various community health service centers, and supply it to residents after training by community
doctors.
Following the brief launch of Paxlovid on December 13, Internet hospitals such as JD Health and many branches of United Family have also begun to prescribe and sell drugs
.

On the 28th, an informed source confirmed to Tongjinyi that Paxlovid has been reduced from 2300 yuan a box to 1890 yuan a box, but the supply is extremely tight, and it is still giving priority to government orders and hospital orders
.

In a rapidly changing epidemic, a constant principle is that if any safe and effective oral medicine can save lives at this moment, it should be delivered to patients against all odds
.
If any drug does more harm than benefit to the patient, it should be stopped immediately
.

War in the group sense requires support and measurement
indicators in the group sense.
Any action with "one family" as a single family is particularly small and powerless in the face of the wave of infection with hundreds of millions, and the conservatism, lag, and stagnation of any link can only lead to a dead knot, and eventually lag far behind the needs of the real world, and when limited resources are concentrated on pseudo-demand without being stopped, then what is really wasted is the group's time, opportunities and even life
.

1 Specific drugs that are missing in the infection tsunami

In May 2021, before all oral drugs were available, Sarah, deputy director of the National Institute of Allergy and Infectious Diseases (NIAID).
Read once envisioned the role of coronavirus oral drugs in the pandemic: "What we really need is to give people a safe oral antiviral when they are detected to be infected with the virus, at the very early stages of the disease, start treatment immediately, prevent them from being hospitalized, prevent them from dying, and reduce the strain on the health system"
.

China was once considered the last piece of the new crown drug to fight for
.
A huge susceptible population, an immune barrier with 3 injections of inactivated vaccine and a peak vaccination for more than half a year, up to three years of new crown education, not rich medical resources, every factor can leverage the penetration rate
of a new crown product.

A month and a half ago, a small essay that did not distinguish between true and false could set off the ebb and flow of new crown special effect drug stocks in the secondary market, but today when the boots landed, an analyst told Tongjiyi, "(for domestic new crown special effect drugs) is no longer expecting"
.

The specific drugs that have not yet been marketed are about to miss the largest round of drug use in the last virgin land of the new crown in mankind: without large-scale interventions that flatten the curve, Omicron, with an R0 of more than 20, will cause more than 1 billion first-time infections in the next three or five months
, catalyzed by the winter and the upcoming Spring Festival homecoming and return to work.

The pessimism of the market is justified
.
Some analysts have estimated that people with no, mild and moderate diseases will reserve new crown drugs like flu drugs, and the penetration rate of 20% can support the tens of billions of tracks
.

But the imaginary tens of billions of market has finally become a phantom
under the reality of unprepared strategic shifts and symptomatic treatment.
A large number of non-high-risk asymptomatic, mild, and moderately ill people will be treated
with ibuprofen, acetaminophen and even Huaqingwen.

Medicine, people, diseases, the window period is fleeting, and China's new crown epidemic will change the world in a few months
.
After the current wave of infection, China's weak immune barrier will be strengthened due to group infection and the popularization of the fourth dose, and people who use drugs at home, such as asymptomatic/mild and moderate infections, who are afraid of asymptomatic/mild and moderate infections, will form OTC drug use habits after primary infection education; Population size and immunization status of high-risk populations following initial infection also change
.

In 2021, proclomide and Paxlovid entered phase III clinical trials at the same time or even earlier, but in China's most important first round of infection battle, although the front line has been under fire, more specific drugs are still stuck in
the quagmire of clinical self-certification.
According to incomplete statistics from the same freehand, there are still more than ten new crown drugs in China that are still in clinical trials
.

Paxlovid and azvudine remain the only two oral agents in the guidelines
.
The former is used for "pathogenesis 5 adults and adolescents with mild and ordinary forms within days with risk factors for progression to severe disease", the latter for "adult patients with common COVID-19", but their use was limited to very limited in-hospital settings
during the first wave of infections.

Tongxin consulted with many public hospitals in many places, each with different reserves of specific drugs, and the use of Paxlovid and azvudine in the hospital is not strictly differentiated according to the approved indications, but most hospitals cannot prescribe
to people outside the hospital.

In November before the release, in a certain cabin in Henan, a box of azvudine was "used for symptomatic common new crown infected people between the ages of 18-60.
.
.
.
.
.
.
5 tablets once daily on an empty stomach for 5 days per person, starting today"
.

Tongjiyi learned that before the positive home, infected people with higher anxiety levels in the cabin will also take
it to speed up the conversion to yin.

But after the outbreak of infection, when the peak of severe disease is approaching, at the moment when special drugs are most needed and should be used by special drugs, they are nowhere to be seen when high-risk people die
.

In the first 20 days of December, there were close to 248 million infections
nationwide.
On the evening of the 26th, the National Health Commission promulgated the "Overall Plan on the Implementation of "Class B and B Tube" for Novel Coronavirus Infection, requiring medical institutions at or above the county level to dynamically prepare new coronavirus infection-related traditional Chinese medicines, anti-new coronavirus small molecule drugs, antipyretic and cough treatment drugs according to the daily usage of three months.
.
.
.
.
.
.
Primary medical and health institutions should dynamically prepare traditional Chinese medicines, symptomatic treatment drugs and antigen detection reagents
related to new coronavirus infection according to 15-20% of the population served.

At present, Paxlovid is classified as Beijing Medical Insurance Class A Catalog, and the reimbursement ratio of different levels of medical institutions and different types of patients is different
.
However, in an eastern province, azvudine is classified as a local medical insurance category C and is a self-funded drug
.

In early December, the health commissions of many places issued a document requiring medical institutions at or above the county level to reserve new crown materials including but not limited to one withdrawal and two antibodies, and Chinese proprietary medicines for 3 months, but special drugs are still rare.

On December 9, Li Qing (pseudonym), a doctor at a health center in southwest China, received a notification
from Paxlovid and Azvudine.
This small city has been hit by several epidemics, and Li Qing felt that there was no need to use special drugs, so he reported 0
.

During the epidemic, the health center had a backlog of advent medicines, and only cold medicines were robbed
.
Before the rush of medicines, Li Qing had more than a dozen positive home-infected people on his hands, and the drugs equipped were Chinese medicine decoctions contributed by the local traditional Chinese medicine hospital, as well as Lianhua Qingwen and Double Huanglian oral liquid
.

On December 13, in the cries of experts "asymptomatic no medication" and "new crown only needs symptomatic treatment", Paxlovid and azvudine were once again tested on the net
.
As prescription drugs, they are repeatedly emphasized, toxic side effects, and should not be used
without medical advice.

However, in overseas countries that have undergone multiple rounds of repeated infections, new crown oral drugs for high-risk groups are essential
.

At the peak of infections at the beginning of the year, the South Korean government provided Paxlovid to more than 760,000 people and Merck's Molnupiravir
to more than 240,000.

In July this year, Australia expanded the eligibility of Paxlovid and Molnupiravir to provide antiviral drugs
after evaluation to those aged 70 and older (with or without symptoms), those over 50 with two risk factors, and those over 18 years of age with immunodeficiency.

In December, the Biden administration placed an additional order for 3.
7 million courses of Paxlovid after the United States had provided free antiviral drugs to nearly 6 million infected people who needed medication; On November 22, Shionogi Pharmaceutical Xocova was approved, and on December 13, the Japanese government ordered an additional 1 million copies of Xocova, and announced that it will expand the supply
to medical institutions and pharmacies in various regions from the 15th of this month.

Before and after the approval of marketing, Molnupiravir, Paxlovid and Xocova have reached agreements with MPP to improve the accessibility of new crown oral drugs in low- and middle-income countries through franchising, of which Xocova plans to cover 117 countries through this agreement, Paxlovid plans to cover 95 countries, and Molnupiravir that first signed a licensing agreement has 105 agreement authorizers
.

But what is puzzling is that there are still 245 million hypertensive patients, 226 million overweight and obese patients, 267 million elderly people over 60 years old, 330 million patients with cardiovascular and cerebrovascular diseases, and 100 million diabetic patients in China.
.
.
.
.
.
.
When the 120 hotline is burst, when infected people crowd hospital halls and corridors, do the many high-risk people who are lying at home, blocking the road, and crowding outside the hospital door really need to take special drugs?

In the cold winter when even the oxygen generator is out of stock, where is the Chinese new crown special medicine to prevent the return of severe illness?

2 If non-high-risk groups do not need specific drugs

So what are they developing?

Compared with his predecessors who are struggling in the phase III clinical trial of mild and moderate disease, Li Ming (pseudonym) has much less anxiety
.
The small molecule drug A he participated in the research and development will most likely not face the current dilemma of the pioneers, "now it is, or it is not on it, one by one, because as long as one pioneer obtains clinical indicators that can make both statistical differences and be recognized by Chinese regulators, everyone else can quickly follow up, the most important thing is that pathfinders must find that indicator", and when the new coolers go to phase III clinical trials, the controversy has been concluded
.

Although it is clear that the fact that this indicator cannot be made in the end does not mean that the compounds do not have antiviral effects, and the differences may not meet the real clinical drug needs, the significant symbolic meaning of the difference can allow these compounds to jump as quickly as azvudine, "This year's Paxlovid phase II/III clinical trial for standard risk groups (unvaccinated adults and vaccinated adults with one or more risk factors for progression to severe disease) failed , but can you say that it is ineffective for high-risk groups? Can you say that some drugs work, even if they are used on the first line? ”

That as-yet-to-be-verified indicator was still firmly designated as "improvement in clinical symptoms"
at a COVID conference in September this year.
Similar to the approved indications of Shionogi Xocova, but with stricter
requirements.

Li Ming does not think that the improvement of clinical symptoms raises the threshold, but various ineffective clinical trials do reflect the most helpless reality at that time: supervision and pharmaceutical companies cannot find a fulcrum to prove that an antiviral drug can be antiviral
.

Xocova and Paxlovid are both 3CL protease inhibitors, but when it comes to Omicron, Xocova, which was approved a year later, is no longer worthy of the title of "special drug"
.

During the epidemic period from the original strain to the alpha strain, the "people's hopes" were expected to "cure the new crown", such as replacing hormones to solve the cytokine storm; During the Delta epidemic, they were used for "mild to moderate COVID-19 with risk factors for severe disease.
" Patients' infection to reduce the rate of severe disease and mortality
.

Today, when Omicron needs symptomatic treatment, Xocova can shorten the duration of some cold-like symptoms by 1 day - Paxlovid can be used for infected people with high-risk factors, while Xocova can only shorten the duration of the 5 main symptoms caused by Omicron infection: nasal discharge, sore throat, cough, high fever, and fatigue, and the results of a phase III clinical trial of Xocova that included 1821 patients with mild/moderate symptoms of the new crown in Japan, South Korea and Vietnam showed that It took about 8 days for the placebo group to disappear symptoms, compared to about 7 days
for the group taking Xocova.

Xocova: This dispensable "1 day" didn't come easily
.
Paxlovid chose "time to all targeted COVID-19" among standard risk populations signs/symptoms", failed, but Shiono selected 5 main symptoms after the fact and was successfully approved
.
What is required in China is the time
from all symptoms (other than those related to the mechanism of action of the drug, such as adverse reactions such as diarrhea) to continue to disappear.

This "1 day" may meet a certain symbolic meaning, but it cannot solve the confusion of why Chinese pharmaceutical companies want to develop new crown specific drugs: infected people have different symptoms, and the main symptoms are relatively concentrated, so what is the clinical significance of my efforts to improve more than a dozen symptoms? Will doctors really prescribe specific drugs for people with mild and moderate infections to get better one day sooner? Will the patient take the medication in order to get better 1 day in advance? What kind of medicine do people with mild and moderate infections need?

Drug developers can only bite the bullet and try their luck
nervously.

"The idea of the development of new crown drugs is nothing more than to reduce the viral load in the patient's body and clean up the virus, it stands to reason that the clinical benefit to infected people should exist, but the reality is that it is extremely difficult to prove this", Chang Qing (pseudonym), another new crown drug developer, told Tongjiyi, although the improvement of clinical symptoms once became the consensus of domestic and international clinical endpoints of new crown drugs, but in fact, as a self-limiting infectious disease, its symptom measurement is very subjective.
The clinical background and onset symptoms of the subjects were difficult to align, and there was basically no comparison between different drugs and combinations of symptoms
.

Changqing told Tongjiyi that behind the uneven symptoms, their only quantifiable and standardized measurement indicator is still to reduce viral load and accelerate the conversion to negative
.

Reducing viral load and turning to yin for 1 day and Yin for 1 day in advance can theoretically meet the actual needs of personalized medication and sympathetic medication; It can also shorten the infection cycle
of the new crown as a highly contagious social disease.

But for doctors, viral load is a biomarker that points unclear
.

Although highly contagious is the characteristics of the new crown, but public health experts believe that the significance of drug intervention to control the epidemic of infectious diseases is "extremely limited", group intervention still relies on vaccines, although the effect of the new crown vaccine has robbed the task of drug treatment "severe disease and death", but therapeutic drugs cannot break through the boundaries to be used on a large scale to slow down the spread, clinicians' hope for "special drugs" is still to carry out early drug intervention for high-risk infections to reduce severe disease outcomes.
Post-exposure prophylaxis for high-risk groups also remains highly promising
.

Tongjiyi learned that the domestic clinical outsourcing program with a scale of 1,000 people is about 200 million yuan
.
In the face of huge investment and the changeable new crown situation, no one dares to easily assert whether the new crown anti-virus demand outside of non-severe disease and non-high-risk outcomes is the emperor's new clothes
.

Although a succession of clinical and real-world data proves that young and non-high-risk groups have little benefit from using new crown drugs, in the past year or so, time, money and limited clinical resources have been gathering towards mild and moderate diseases
.

Changqing believes that the current research and development of new crown drugs urgently needs consensus, and all parties need to discuss clearly, who is the specific drug developed for, what problems to be solved, and what
are the possible solution paths.

3 How do doctors use COVID drugs?

Doctors don't limit themselves
to instructions or guidelines.

Although there are various controversies about existing new crown drugs, the more urgent problem to be solved clinically than drug abuse is that there is no drug available
.
On December 23, a relevant official of a large eastern province told Tongjiyi that the province's Paxlovid reserve was about 1,000 boxes, and the local government spontaneously organized the purchase of 270 yuan a box of azvudine as a "flat replacement" of Pfizer P drug, and used azvudine in the hospital to prevent severe disease in high-risk groups
.

Clinical observation indicators such as "viral load" and "turning negative" are not so practical
in the eyes of doctors.
Zhang Yujiao, a tenured professor at MD Anderson Cancer Center in the United States, explained to Tongjian that the relationship between preventing severe disease and "reducing viral load and accelerating the conversion to negative" is "relevant but not necessarily"
.

Clinically, the viral load of infected people is high, and the symptoms are not necessarily obvious, such as positive asymptomatic infections, the symptoms of low viral load may also be serious; Some high-risk groups should be treated with antiviral therapy to prevent exacerbation of the underlying disease, even if they have a low viral load and mild disease after infection; The symptoms and severity of the patient, in addition to being affected by the viral load, are also related
to the body's immune response caused by the virus.
Therefore, there is not a strictly positive correlation
between viral load and clinical symptoms in an infected person.

If the viral load can still reflect the proliferation of the virus in the infected person, then turning negative is even more chicken
.

Clinicians do not focus unduly on whether the infected person is nucleic acid negative or positive, but rather on symptoms
.
Zhang Yujiao introduced to Tongjiao that although one of his tumor patients did not turn negative for three months after infection, he no longer had symptoms of infection in the later stage, so he did not continue to take drugs; Some infected people will also have certain recovery symptoms
after turning negative.

Even the relationship between nucleic acid positivity and infectivity is "related but not inevitable", and China set the Ct value greater than 35 as the baseline in the later stage, which is still an extremely sensitive detection standard, and positive infections are likely to be non-infectious in the later stage of infection
.

This series of related but not necessarily related relationships are strung together, although the clinical line waits for the urgent use of drugs, but the regulatory authorities have not rashly opened the approved mouth to reduce the viral load as an indicator
.

"If the mild and moderate specific drug is approved, it is equivalent to opening a popular drug similar to cold medicine to everyone," Li Ming told Tongjiyi, (pressure) blocked on the supervision, "approval, or non-approval, the pressure is great"
.

Changqing is a reminder, especially for ordinary infected people, it is necessary to pay special attention to the toxic side effects of drugs, to benefit patients, "drug damage can not be greater than the harm of the new crown itself, the safety standards of new crown small molecule drugs should be relatively high, after all, the test population is extremely large
.
"

Figure 1 Azvudine instructions

However, among the most critical high-risk groups, the consensus exists: it is difficult for the autoimmune system of high-risk and severely infected people to complete the virus cleanup in a timely and successful manner, and antiviral drugs need to be used for auxiliary intervention
.

Tongjiyi learned that Paxlovid and Azvudine are currently used in the clinical front line in China for two main purposes: one is to intervene in high-risk groups, but this part of the population is extremely limited, and can only be limited to a small number of high-risk infected people in the hospitalization scene, while the other part is used for antiviral treatment
for severe and critically ill patients.

For the former, in the current acute epidemic period of the new crown, the understanding of front-line doctors is that after high-risk groups are infected, it is necessary to use drugs and intervene early, and use antiviral drugs within 3 days, "whether imported or domestic", the sooner the better, and once infected for more than 7 days, the virus replicates in large quantities, and the patient becomes severely ill and critically ill, and taking antiviral drugs at this time can only be "gambling with fate"
.

In the past week, front-line doctors, including Lu Hongzhou, president of the Third People's Hospital of Shenzhen, and Li Manxiang, director of the Department of Respiratory and Critical Care Medicine of the First Affiliated Hospital of Xi'an Jiaotong University, have repeatedly called for timely antiviral treatment
after the elderly, pregnant women, patients with chronic diseases and other high-risk groups infected with Omicron.

Therefore, a doctor of pathology suggested that it is necessary to start from the practical dilemma and scientifically evaluate the clinical value of drugs to reduce viral load, and use useful theories
under the premise of safety and evidence-based.

After the drug is available, it is the control of the doctor's order and prescription, Zhang Yujiao reminds that even Paxlovid with excellent safety, there are strict symptomatic and contraindicated groups, in the United States, after evaluation, the doctor will prescribe medication for the elderly over 65 years old within 5 days of infection, unvaccinated people, obese people, patients with underlying diseases, and contraindications who are not suitable for taking Paxlovid can take Molnupiravir
.

4 Missed window after window

Will there still be new crown drugs on the market in China?

The indications of this compound B in Changqing's hands originally covered all mild, medium and severe diseases, but there were very few severe patients in the Omicron era, so the focus of research and development could only be shifted to the most crowded but potentially largest mild and moderate disease track
in China.

After the Omicron epidemic, "reducing the rate of severe disease" became the end point
that no drug could reach.
On December 2, the Guangzhou Municipal Government reported at a press conference that in this round of the epidemic, there were 162,700 cases of infection in Guangzhou, but only 4 cases of severe and critical infection
.
Such realistic data once again declares to all new crown specific drugs: reducing the rate of severe disease and mortality as the clinical endpoint, like finding a needle in a haystack, the gain is not worth the loss
.

And the reality is that in the past year, not only B, but also most of the new crown specific drugs with severe and death cases as the molecule are difficult to obtain obvious results
.

However, some clinicians have reported to Changqing that the reason why the early severe disease rate and mortality rate of China, where the immune barrier is relatively weak, is lower than the global level, is due to the all-encompassing management of early intervention and early treatment starting from nucleic acid testing, and once the control measures are withdrawn, the situation will inevitably change
.

On the eve of the first round of infection tide of "all staff carrying", Li Ming described A's fate as follows: If medical resources are sufficient or even redundant, and the severe disease and mortality rate of the new crown in China is extremely low, then A may also be shelved like countless SARS drugs; Otherwise, the enrollment and approval process of high-risk groups will be accelerated
.
But this is like Schrödinger's cat, only by opening the box does not know the ending
.

There is no way ahead, and there are pursuers
behind.
On the eve of the imminent outbreak of the first generation of infected people, there are eager people to enter the game
.
Throughout 2022, the pioneers are in the dilemma of no high-risk subjects and the clinical front is infinitely extended, and before that, during the Delta period, there were few infected people, severe cases, and deaths in China, and pharmaceutical companies had to spend huge amounts of money on overseas clinical trials
.
However, at a time when the tide of infections is surging and medical resources are under pressure, the pressure of drug clinical recruitment has suddenly been released, and it is PIs who are busy
.

The starters missed not only the wave of infections in China, but also the golden clinical window left by vaccines and strains
.
At present, except for Paxlovid, the chosen son, which has been repeatedly proven by real-world data, most other drugs are using Delta data to cure Omicron's disease, and the need for special antiviral treatment for non-high-risk groups infected with Omicron is inconclusive, and clinical trials of high-risk groups infected with Omicron are progressing slowly
.
Therefore, the special drugs that did not catch up with the timely data of the Delta period are particularly aggrieved
.

New crown drug developers are inadvertently forced to choose a disease that is forming and extremely unstable - the new crown strain is changing, the clinical symptoms are changing, the epidemic area is changing, and the drug population is also changing.
.
.
In addition to luck, it seems that only the traverser who opens God's perspective can play this game of time and make the most correct decision at every critical moment: it is best to be like Paxlovid and concentrate all resources on "severely ill people"
without hesitation while people have not yet been vaccinated and the virus has not significantly weakened.

However, the confidence of the first pharmaceutical company in the universe to mobilize the support of thousands of scientists, the accumulation during SARS and its resource integration and coordination capabilities, make small factories and biotechs unmatched
.

Drug cost and supply capacity are practical issues
that have to be considered.
Paxlovid is called "two thousand three" in the hospital, and a frequently mentioned hypothesis is that if it is supplied for 23 yuan a box or for free, will the actual medication situation be very different?

Specific drugs still need to produce convincing clinical data to prove themselves
to clinicians and infected people.
Xocova received emergency authorization in Japan in November this year, and on December 10, Shionogi announced the first drug use and side effect tracking
.

In the face of the new crown, the formation of all cognition has lagged behind the rapidly changing world
.
Scientists can come up with 10,000 possibilities and wait time to test one of them, but drug discovery requires hard results
.

In terms of consequentialism, China's special drugs always seem to be one step
behind.
Time in the clinical part of the drug to tie a dead knot, a duty of the drug clinical period, the vaccine popularized, the virus weakened, the clinical prevention of severe disease can not find the serious, the clinical treatment of mild disease has not yet made results, patients do not need antiviral drugs, in the end, when medical resources urgently need drug support, only to find that doctors have nothing in their hands
.

Missing out on China's first wave of infections is just a shame
for now.
In the past year, Chinese special drugs have also missed out on overseas coronavirus markets
that were once thought to be within reach.

2022 is also considered to be the peak year of the global new crown oral drug market, and the global infection tsunami caused by Omicron has brought an "unprecedented" first round of drug users
.
Paxlovid has surpassed $17 billion in actual sales in the first three quarters of this year, but GlobalData analyst Camila Dalitz predicts that its revenue will start from 2023 due to widespread vaccination of vaccine boosters, repeated group infections, and declining hospitalizations Began to decline
.
Distribution of Molnupiravir in the U.
S.
has begun to decline, and according to HHS tracking data, Molnupiravir's distribution in the past three months has been discounted
compared to the first quarter.
The global boom in new crown drug research and development has also gradually cooled
.

Clinical and approval remains a dead
end of time.
Li Ming determined that A and most of the small molecule drugs could not catch up with the climax of China's first wave of new crown drugs
.
Completing clinical trials and being approved for marketing in just a few months is simply a fantasy for a chemical drug
.

But his belief is that the new crown will not disappear in one round, and China must have its own and recognized new crown drug
.
It's just that patients can never be cured by drugs that cannot be touched during the infection period, whether they are far away in the clinic or lying in
the hospital pharmacy.