With the domestic COVID-19 oral medicine gradually from the research and development stage to the commercial stage, the demand for upstream intermediates and APIs is expected to show rapid growth, and a gold digging drama around the industrial chain is being staged.Although it has not yet been formally approved, with the disclosure of the progress of relevant research and development and commercial cooperation, COVID-19 oral drug concept stocks rise and fall by the limit, often only a paper announcement.

At present, there are more than ten kinds of oral drugs for COVID-19 in our country. Who can get the oral medicine head of COVID-19 made in China, and how big is the market space? After being approved, how to compete and win on this 10 billion track? Around the concerns of the above-mentioned market, a reporter from the Securities Times recently conducted a detailed interview with COVID-19 drug research and development enterprises, supply chain enterprises and their industry personnel.

According to the feedback of the interviewees of the Securities Times, the domestic clinical research progress of oral administration of domestic COVID-19 once lagged behind that of international clinics. one of the important reasons is that the number of domestic COVID-19 diagnosed is low, and the sample size of clinical research is insufficient. This problem has been solved with the recent sporadic outbreaks, but the sample size of critically ill patients may still be insufficient.

In the view of these respondents, the fastest progress in clinical research is Azvudine and VV116, which will compete for the crown of the first oral drug made in China, depending on the clinical efficacy, safety and speed of approval.As for the market space of COVID-19 's oral medicine, the market is controversial. Some people think that the market for cold medicine can be made with reference to hundreds of billions of yuan, while others think that if the domestic policy of dynamic zero prevention and control continues to be adhered to, then the market space for oral medicine is very small.However, it is certain that the price of domestic COVID-19 oral medicine will be lower than that of Pfizer Inc and Merck & Co Inc currently introduced, or even as low as 200 yuan.

The race of domestic new crown drugs is under development.

Since the outbreak of COVID-19, countries have continued to promote the research and development of related drugs, and domestic enterprises are not to be outdone. According to the reporter's incomplete statistics, so far, domestic small molecular drugs studied by COVID-19 include more than ten types of azivudine, VV116, procrumine, SIM0417, RAY003 and so on.The listed companies involved include Junshi Biology, Development Pharmaceutical Industry, Xiansheng Pharmaceutical Industry, Zhongsheng Pharmaceutical Industry and so on.

From the perspective of action mechanism, the main targets of COVID-19 's oral drug research are 3CL and RdRp. The former was used in the oral administration of Paxlovid, while the latter was used in VV116 and Azivudine rule. The principle of the latter is that drugs replace normal nucleotides at the active center of RdRp, competitively inhibit the activity of RdRp, hinder virus replication, or hinder virus proliferation through mutation.

In May, the domestic oral new crown under research spread the good news frequently. For example, Junshi announced on May 23rd that VV116 reached the main end point of a phase III registered clinical study comparing Nimatervir tablets / ritonavir tablets (Paxlovid) for early treatment of mild to moderate COVID-19. According to the announcement of Zhongsheng Pharmaceutical Industry on May 22nd, the Ⅰ phase clinical trial program of Zhongsheng Ruichuang, a subsidiary of Zhongsheng Ruichuang, was approved by the Ethics Committee of the first Hospital of Jilin University for oral anti-novel coronavirus RAY1216 protease inhibitor RAY1216, and completed the first patient to be enrolled in the group.

From the point of view of the above drug research and development, a total of 6 domestic new crown drugs under development are in clinical trials.Among them, the VV116 jointly developed by Junshi Biological and Wangshan Wangshui, the real biological Azvudine, and the pharmaceutical pioneering Puclosamide are nearing the end of the phase III clinical trial, from which the first domestic oral drug COVID-19 will be born. In addition, Gurley Pharmaceutical, Hexing Pharmaceutical, Guangshengtang, Xiansheng Pharmaceutical, Genting Xinyao and other pharmaceutical companies are also actively promoting their products into clinical trials.

From the clinical efficacy, VV116 treatment of non-severe Omicron infection novel coronavirus nucleic acid negative time effect, the effect is obvious.According to the data published by Huashan infection, the average time from the beginning of medication to the negative conversion of nucleic acid in patients infected with VV116 was 3.52. in the patients who used VV116 within 5 days of the first positive nucleic acid test, the average time from positive to negative in the control group was 8.56 days, less than 11.13 days in the control group.

With the recent disclosure of the progress of research and development of various drugs, how far is the domestic oral drug COVID-19 from being put on the market? In this regard, Tong Youzhi, chairman of the Development Pharmaceutical Industry, told the Securities Times that"whether the new drug can eventually be put on the market depends on the safety and effectiveness of the clinical data. At present, the fastest progress in China is the three phases of Pucruamide, VV116 and Azvudine, which have been or completed. At present, there is indeed a great need for one or more domestic COVID-19 oral drugs, and the new crown drugs cannot be controlled by others, including the listed Merck & Co Inc Molnupiravir and Pfizer Inc Paxlovid, which are also emergency use drugs approved by the US government in emergency situations, and do not approve their permanent market access status. Therefore, the speed of domestic new crown drugs on the market also depends to a certain extent on the decision of the government. "

It is understood that according to the general drug review and approval process, after the completion of the III phase of drug research and development, it will take about 2 months to uncover the blindness and 1 year to complete NDA approval. The time limit for approval to be included in the priority review process is 130 working days, equivalent to about 6 months. However, COVID-19 drugs are in great demand and may be authorized for emergency use or listed with additional conditions, and most of the industry insiders expect that emergency use will be approved by the end of May at the earliest.

"at present, the national drug regulatory authorities are also making every effort to speed up the examination and approval process, so that truly safe and effective drugs can enter the market as soon as possible, so as to protect patients infected with COVID-19. Only with the new crown medicine made in China, even if there is another regional epidemic, we can still have medicine available and do not panic in our hearts. " That's what Tong Youzhi said.

The difficulty lies in the rapid mutation of the virus and the shortage of critical samples.

VV116, Azvudine, Pucrumine, who will be approved the fastest in China, this is the most concerned issue for the market.

At present, from the latest experimental progress announced in China, the progress of VV116 is the fastest. According to the disclosure of Junshi Bio on the evening of May 23rd, the early treatment of mild to moderate COVID-19 with VV116 reached the main end point preset by the clinical program. The company will communicate with the drug regulatory authorities to submit applications for the listing of new drugs in the near future.

Earlier, news of azivudine has been reported that a total of more than 800 cases of domestic phase III clinical trials began to be blinded at the end of April. In the financial market, companies continue to say that they have signed strategic cooperation with real organisms, Azvudine production cooperation, but also detonated the relevant concept stocks. But so far, the clinical trial of Azvudine is still inconclusive.

However, Azvudine has already carried out three phases of clinical trials in Brazil, Russia and other places. Among them, phase III clinical trials for moderately and severe patients in Brazil have been completed, and mild clinical trials are expected to be completed in July.

Puclosamide's experiment was somewhat tortuous. The progress of global multicenter clinical trials for the treatment of non-hospitalized patients disclosed at the end of last year showed that the mid-term analysis of phase III clinical trials was not statistically significant. However, data disclosed in April showed that it could reduce hospitalization, mortality, novel coronavirus load and improve COVID-19 's symptoms. Since then, however, no new progress has been announced in the Puclosamide trial. From this point of view, the trial process of proclomide may lag slightly behind VV116 and Azvudine.

"Phase III clinical trials require the design of more sample sizes, longer clinical observation times, wider geographical areas, and even international multicenter clinical trials, usually with a sample size of more than 1000 cases." Deng Zhidong, general manager of Hainan Boao Medical Technology Co., Ltd., told the Securities Times.

It is understood that due to the adoption of the prevention and control policy of dynamic zero clearance, the actual number of confirmed diagnosis is small, and even fewer patients are willing to participate in new drug trials, so that the domestic clinical trials of related drugs were once pressed the pause button. However, the problem has been alleviated by the recent increase in the number of cases in many parts of the country, and the development of related drugs has accelerated. However, in spite of this, clinical trials for critically ill and hospitalized patients may still have the challenge of sample size.

It can be confirmed that, as an important research team in the VV116 clinical trial, the infection team of Shanghai Huashan Hospital recently announced the progress of the project, but also stated bluntly in the report, "the sample size included in this study is limited, and all the subjects have not developed into severe or critical illness. Therefore, this study failed to collect enough data to further analyze whether VV116 has a preventive effect on the severity of Omicron infection, only a preliminary evaluation of novel coronavirus nucleic acid negative time in non-severe infection. "

The disclosure of Junshi Bio on May 23 also shows that a number of clinical studies on mild to moderate and moderate to severe COVID-19 patients with VV116 are still in progress.

In addition, Tong Youzhi, chairman of the pioneering pharmaceutical industry, told reporters that in COVID-19 's clinical trial of oral medicine, the rapid mutation of the virus was a common challenge. Now, on the one hand, we hope that COVID-19 oral medicine will be put on the market as soon as possible, on the other hand, we are also exploring a correct and reasonable clinical trial plan to test the efficacy of anti-COVID-19 drugs with limited patient resources. At present, some enterprises choose to do COVID-19 preventive drug research, but in any case, this challenge will persist.

Domestic new crown drugs have attracted much attention.

"the reason why people pay so much attention to domestic new crown drugs is more of an emotional reflection of 'the world has been bitter and new for a long time'." Pharmaceutical companies providing intermediates for Pfizer Inc Paxlovid told reporters that at present, "dynamic zero clearance" is the general policy of the Chinese government on the COVID-19 epidemic, although strict control in various places has effectively brought the epidemic under control, but the national economy is under pressure. At present, the combination of new crown medicine and vaccine is the most effective means of treatment and epidemic prevention.

Up to now, only two COVID-19 small molecule drugs have been approved for sale in the world, namely Merck & Co Inc Molnupiravir and Pfizer Inc Paxlovid. According to quarterly data from the two companies, Molnupiravir, an oral drug developed by Merck & Co Inc, generated $3.2 billion in revenue in the first quarter of this year, more than half of its expected sales for the whole year. Pfizer Inc's Paxlovid earned $1.47 billion in the first quarter, accounting for 69 per cent of the US market. Pfizer Inc also predicts that annual sales of the drug will be $22 billion.

The above-mentioned pharmaceutical companies said that as a top international pharmaceutical company, it is impossible to casually forecast sales, which must be based on a comprehensive judgment based on market demand, product competitiveness, and potential competitors. From $1.4 billion in the first quarter to an estimated $20 billion in sales for the whole year. From this point, we can reflect the demand of the follow-up market of new crown drugs.

According to reports, in addition to the advantages of convenient use, low production cost, convenient storage and transportation, COVID-19 oral medicine has another more obvious advantage over neutralizing antibody injection, that is, it is less affected by the variation of the virus strain. Therefore, oral medicine is the most expected among all the current new crown drugs in the research pipeline, and its market space is also relatively large.

In fact, with the domestic new crown drugs gradually from the research and development stage to the commercial stage, the investment opportunities brought by the industrial chain have become the focus of the major securities firms. Recently, a number of brokerage research institutions give their own different analysis and judgment on the new crown drug.

Soochow Securities Research report pointed out that with reference to the national drug reserve during Influenza A H1N1 in 2009 and the recommended scheme in WHO's influenza pandemic plan, it is estimated that the domestic new crown medicine is expected to reserve 100 million to 300 million people per year. With reference to the pricing of VV116 in Uzbekistan, it is estimated that the domestic price per person may be between 600 and 1000 yuan. Under the prudent forecast, the domestic VV116 sales are about 6-100 billion yuan, and under the optimistic forecast, the sales are expected to reach 180 billion-300 billion yuan.

At present, Pfizer Inc's oral drug Paxlovid is priced at about US $530 for a course of treatment in the United States, equivalent to about 3500 yuan. VV116 has been approved for listing in Uzbekistan at a price of $185, or about 1243 yuan, at a 70 per cent discount to Pfizer.

An Guangyong, an expert from the Credit Management Committee of Quanlian mergers and acquisitions Association, told the Securities Times that the pricing of ordinary drugs on the market will be based on competitive product prices, production costs and other factors, but COVID-19 oral drugs are currently few competitive products and strong demand, more will be based on customer willingness pricing, that is, depending on how much customers are willing to pay.

An Guangyong believes that if the efficacy and side effects of domestic Xinguan oral medication are similar to Pfizer Inc's products, then considering that there are already corresponding competitive products on the market, coupled with domestic consumption level and future popularity, the price of domestic COVID-19 oral medicine is expected to be much lower than that of Pfizer Inc products and lower than that of Uzbek products.

Not long ago, an organization called the Clinton Health Initiative (CHAI) posted on its website that it had reached an agreement with several generic pharmaceutical manufacturers that Paxlovid generic drugs would cost no more than $25 per course of treatment to ensure access to residents in low-and middle-income countries and regions. This is equivalent to only 166 yuan for a course of treatment.

It can be predicted that with the acceleration of oral drug research and development, the pricing of drugs listed in succession is bound to be lower and lower. Deng Zhidong told reporters that China's Xinguan oral medicine market has great demand, can be mass produced, has a high degree of automatic production, and low raw materials and labor costs, coupled with government-guided prices and medical insurance collection. The unit price of domestic COVID-19 oral medicine can be controlled within 200 yuan per box.

However, some people believe that if the domestic policy of dynamic zero clearance continues, the market space for COVID-19 to take oral medicine will be very small, because the actual number of diagnoses is small. An Guangyong believes that under this background, most of the demand for COVID-19 oral medicine is standby; if the control is liberalized, then its market space can refer to cold medicine.

"the three prerequisites for the gradual liberalization of China's anti-epidemic policy in the future are efficient domestic vaccines, fully covered vaccine coverage rates, and domestic new crown drugs with high prices, so the market demand for domestic COVID-19 oral drugs must be enormous, but the market space of each drug depends on its efficacy."Zhou Yunnan, founder of Nanshan Investment in Beijing, thinks so.

"guaranteed supply Legion" continues to emerge.

While the market pays attention to the progress of the research and development of domestic COVID-19 oral medicine, it has also stirred the capital market frequently recently around the opportunities for cooperation between upstream and downstream.

Haizheng Pharmaceutical Co., Ltd. is the latest partner of VV116. On May 19th, Haizheng Pharmaceutical Co., Ltd. and Shanghai Wangshi Biopharmaceutical Technology Co., Ltd. signed the Strategic Cooperation Agreement and the entrusted production Framework Agreement. The two sides intend to establish strategic cooperation in the product processing, production, international registration, market development and other fields of small molecule innovative drug VV116.

Recently, Fuxiang Pharmaceutical said on the interactive platform that the company currently supplies RedSiVe intermediates to the participating company Lingfu. According to the announced production process of RedSivir and VV116 products, VV116 is based on the structural transformation of RedSivir, and some of RedSivir intermediates can be used to produce both RedSivir and VV116.

At the same time, Az legal A-share partners are constantly expanding. Recently, Xinhua Pharmaceutical, China Resources Shuanghe and Aoxiang Pharmaceutical have successively disclosed that they have reached cooperation agreements with real creatures on Azvudine and so on.

Compared with the above-mentioned newly hand-in-hand partners, Tuoxin Pharmaceutical Industry had an earlier legal fate with Az. As early as in January this year, Tuoxin Pharmaceutical Co., Ltd. said that Azvudine is an HIV reverse transcriptase inhibitor, and the company's subsidiary Xinxiang Pharmaceutical Co., Ltd. passed the evaluation of the association with Azvudine preparations.

With the cooperation of the industrial chain, Tuoxin Pharmaceutical Industry has been favored by the capital market. However, according to the reply to Tuoxin Pharmaceutical's disclosure inquiry letter in March this year, Azvudine API produced by Tuoxin Pharmaceutical subsidiary Xinxiang Pharmaceutical is Azvudine tablets downstream, which is suitable for the field of anti-HIV virus, and other indications are not clear.

Securities Times reporter noted that whether Azvudine or VV116, in the signing of the commissioned processing agreement, are not clear for the exclusive authorization, as well as the order plan.

"it is not surprising for a pharmaceutical company to choose multiple cooperative manufacturers, especially in terms of raw material supply, it is unlikely to bet the entire supply chain on one company, if the enterprise has problems because of an epidemic or other force majeure, it will cause problems throughout the supply chain. The new crown drug has a certain strategic reserve significance, for the role of strategic supply, but also needs a diversified supply chain to ensure. " To provide intermediates for Pfizer Inc Paxlovid, a pharmaceutical company told reporters.

Reporter observation: true and fake new crown medicine concept stocks investors need to practice the golden eye.

Just as the launch period of domestic COVID-19 oral medicine is approaching, the capital market has started a round of carnival. True and false concept stocks continue to emerge, but not all stocks rise with the concept. Investors need to practice the golden eye and judge from the source and specific content.

As the hot contestants of the first batch of drugs, Azvudine tablets of real life have continued to expand in the small partner team of A shares. Xinhua Pharmaceutical, China Resources Shuanghe and Aoxiang Pharmaceutical have all announced that they have signed production agreements with them to become suppliers or distributors of quasi-new crown drugs.

On May 23, Xinhua Pharmaceutical rose the limit again, gaining 15 limit boards in 21 trading days, with a cumulative increase of 215.68%. This is because, on the evening of April 26, the company announced that it had signed a "strategic cooperation agreement" with Real Biology. True Biology agrees that Xinhua Pharmaceutical is the manufacturer and distributor of its Azvudine and other products in China and other countries agreed by both parties.

China Resources Shuanghe and Aoxiang Pharmaceutical have also issued announcements confirming the signing of strategic cooperation with real organisms and the commissioned processing and production agreement of Azvudine tablets (signed by Aoxiang Pharmaceutical through its wholly-owned subsidiary Qizheng Pharmaceutical). However, the company's share price has performed poorly recently, has not danced with Xinhua Pharmaceuticals, and has basically returned to its pre-concept price.

Issued an announcement, signed cooperation, from these contents, the Azvudine film "one daughter, three marriages" news is basically true, and the large-scale production layout of Azvudine film has been initially completed. However, the share price performance of the three companies is different because Xinhua Pharmaceuticals won the "manufacturer + distributor" double license, while the latter two companies are only processing and production.

From this point of view, not all stocks with the Azvudine concept can rise, or fall back soon after a short-term rise.

The VV116 of Junshi Biology and Wangshan Wangshui is also the leading player in the first domestic COVID-19 oral medicine. On the evening of May 19th, Haizheng Pharmaceutical and Wangshi signed the Strategic Cooperation Agreement and the entrusting production Framework Agreement, intending to establish strategic cooperation in the fields of product processing, production, international registration and market development of small molecule innovative drug VV116.

Haizheng Pharmaceutical is the first A-share company to officially announce that it is entrusted with the production of VV116, and the market interprets it as a signal of the acceleration of VV116 research. After the news was released, Haizheng Pharmaceutical rose by the daily limit on May 20, but it soon fell back after it opened high on May 21, and individual investors basically had no opportunity to make money.

As the information becomes more transparent and market enthusiasm cools slightly, the probability of concept stocks replicating the continuous surge of Xinhua Pharmaceutical has been greatly reduced. Coupled with the current domestic COVID-19 oral medicine is still in the clinical stage, the relevant drugs before the real approval, there is still uncertainty, so investors need to be cautious.

In addition to the official announcement, there are also companies that reply to relevant information through investor interaction platforms, institutional research and other channels. It should be noted that before the official announcement, the truth and specific content of the news from these channels are still open to question.

According to the reporter's incomplete statistics, Boteng shares, Panlong Pharmaceutical, Shuanglu Pharmaceutical, Northeast Pharmaceutical, Ruizhi Pharmaceutical and other companies have made it clear on the investor interaction platform that they do not have related cooperation with Azvudine and VV116.

But there are also ambiguous answers, which need to be compared before and after.

Recently, Tuoxin Pharmaceutical Co., Ltd. has responded to questions about Azvudine many times on the interactive platform, saying that "the quality of the Azvudine API delivered to customers meets the relevant quality standards; at present, this production line and production capacity can meet the needs of the market and customers", and "the new production line has started operation and continuous production". In another reply, it said, "the subsidiary has delivered Azvudine API products in accordance with the contract, the delivery volume is small and has been delivered, and there are no orders on hand at present."

In terms of announcement, Tuoxin Pharmaceutical only said in the 2021 annual report that "in July 2021, Azvudine APIs were reviewed and approved by the State Drug Administration, registered on the CDE official website, and can be produced legally", "change the production address of Azvudine APIs", and did not disclose the relevant contents and income of the actual production of Azvudine APIs.

On May 11, in response to market rumors, Miki Group replied on the interactive platform that "the holding subsidiary Pacific Century Huijin invested in Real Biology as one of its main businesses", after which the share price soared. But in fact, Miki Group holds a 50.5% stake in PCG Huijin, which is only a fund investor in Hangzhou Taifu Yingrui Venture Capital Partnership (limited partnership), which invested only 10 million yuan in real biology. According to this logic, Miki Group's indirect participation in real life is not large.