Only by developing domestically produced drugs with excellent curative effect and safety, the tragic scene of “I’m Not the God of Medicine” will not be repeated.
How to get thousands of magical medicines, and protect the world‘s “Yang people” with joy?
On January 8, 2023, due to the high quotation, Pfizer’s Paxlovid failed to be included in the national medical insurance catalog through negotiation, and Paxlovid’s medical insurance will be temporarily paid until March 31, 2023.
This means that after April Fool’s Day this year, Paxlovid can only pay for itself.
In contrast, a box of Paxlovid is hard to find, and its underground transactions have exceeded 15,000 yuan a box.
Behind the huge price difference is the serious shortage of Paxlovid production capacity. Due to the complexity of drug design, Paxlovid manufacturing involves more than 20 different sites in more than 10 countries. Although Pfizer has expanded its production capacity, the short-term production of Paxlovid is still a drop in the bucket to meet the current demand.
At present, there are three new crown oral “specific drugs” (actually not specific drugs, but new crown virus inhibitors) approved for marketing in China. In addition to Pfizer’s Paxlovid, Merck’s Molnupiravir and Real Bio’s Azvudine tablets.
Paxlovid disagrees with the price reduction, and Molnupiravir has not yet applied for medical insurance, let alone a price reduction. There are only domestically produced azvudine tablets, which are relatively cheap, but their effectiveness and safety need to be further verified.
With the mutant strain XBB and the possibility of repeated infections in the future, it is a top priority for the domestic pharmaceutical industry to develop a domestically produced oral drug for the new crown with good efficacy and few side effects within 2023.
So, what is the progress of the domestic new crown specific medicine?
01 Azvudine tablets: further verification is required
There is a “double-ten rule” in pharmaceutical research and development, that is, it takes ten years and billions of dollars for a new drug to go from research and development to the market.
In February 2020, Azvudine tablets, used to treat HIV, were found to be effective against the new coronavirus. Therefore, in April of the same year, the State Food and Drug Administration approved the application of Azvudine Tablets for Phase III anti-new coronavirus clinical trials.
In July 2022, Azivudine Tablets was conditionally approved by the State Food and Drug Administration for the treatment of new coronary pneumonia. Currently 270 yuan / bottle, a bottle for a course of treatment.
Comparing with the “Double Ten Law”, everything is too fast.
Conditional approval for marketing refers to the existing clinical research data, which has not yet met all the requirements for conventional marketing registration, but clinical trials have shown curative effect. Due to urgent clinical needs (generally for life-threatening diseases for which there is no effective treatment), the drug can be approved for marketing by the Food and Drug Administration.
The attached condition is that it is often necessary to continue to carry out clinical trial research to verify the drug efficacy and side effects that drug review is concerned about.
It is worth noting that many medical professionals have raised doubts about the effectiveness and side effects of Azvudine.
On January 6, Nuohui Health (6606.HK) certified public account “Nuohui” issued an article stating that Azvudine has not published peer-reviewed phase III clinical trial data, and its effectiveness needs further confirmation.
In addition, disclosed documents show that Azvudine has risks of genotoxicity and reproductive toxicity, and additional carcinogenicity tests are needed.
Source: Nuohui
There are also views that the Azvudine Brazil trial was underrecruited and the primary endpoints were not met.
“Analysis of Azvudine’s Clinical Trial Data: A Pseudo-New Crown Special Drug That Kills No Complaints”, Source: A Science Park of Biological Dogs
As early as June 2022, the Center for Drug Evaluation of the State Food and Drug Administration announced the technical review report on the use of Azvudine tablets for HIV treatment. The paragraph before the conclusion is very meaningful.
Among the 8 experts present at the meeting, 3 experts clearly agreed to conditionally approve the marketing of this product based on the current data, 3 experts believed that the current clinical data showed that the product has good safety and effectiveness, and 2 experts believed that the results of phase II clinical research suggested that this product is safe and effective. The product is effective in HIV-naïve patients.
The expert group pointed out that the current data sample size is small, and the safety of large-scale application is uncertain. It is recommended to focus on safety in phase III studies.
In addition, the optimal oral time and treatment cycle of Azvudine tablets are also worthy of attention.
Both Azivudine tablets and Molnupiravir target RdRP, and the principle is to act on the new coronavirus polymerase (RdRP) to embed some “false” fragments in the RNA synthesis process of the new coronavirus, thereby inhibiting the replication of the new coronavirus.
The best time to use Molnupiravir and Paxlovid is within 5 days after the onset of symptoms, and it is required to take it for 5 consecutive days. However, in the instructions for use of Azvudine tablets, there is no restriction that “it must be taken within 5 days after the onset of symptoms”, and the course of treatment is as long as 14 days.
At present, there have been a large number of new crown patients in China. It is not difficult to organize clinical trials of thousands of people. I hope that the effectiveness of Azvudine tablets can be supported by more rigorous experiments and data.
In fact, long before Azivudine tablets were approved, the most highly anticipated product in China was Junshi Biotechnology (600180.SH)’s VV116.
02 VV116: The hope of the whole village?
On December 29, 2022, the internationally renowned medical journal “New England Journal of Medicine” (NEJM) published an article on a phase 3 randomized controlled clinical trial of a new crown drug made in China.
The drug, VV116, was jointly developed by Junshi Biotechnology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Wuhan Institute of Virology, Chinese Academy of Sciences and other institutions.
The results of the trial showed that for adult patients with mild to moderate COVID-19 with high risk factors, in terms of the time to continuous clinical recovery, the domestic COVID-19 drug VV116 was 4 days, which was not inferior to Paxlovid’s 5 days, and the hazard ratio of the two drugs was 1.17 , and VV116 had fewer adverse events.
VV116 has always been high hopes. Because the core of the compound skeleton of VV116 is Remdesivir, and Remdesivir has been proven effective.
Remdesivir was developed by Gilead in the United States. As early as May 2020 and October 2020, Japan and the United States successively approved Remdesivir for the treatment of new coronary pneumonia. It is the first new crown drug approved in Japan and the United States .
The original remdesivir compound cannot be used orally (the compound’s characteristics cannot be absorbed through the digestive system to achieve a therapeutic effect), so it can only be used intravenously, which greatly limits the application of remdesivir.
Based on this, Junshi Biosciences researched and developed remdesivir, through skeleton modification, transition, supplemented by an effective delivery system (which can be simply understood as reasonable packaging), so that it can be used orally.
In the field of pharmaceutical research and development, this kind of behavior is not stealing, it is normal. The secondary development of many compounds is much more effective than the original compounds, and due to the transition of the molecular skeleton, it also circumvents the patent restrictions of the original compounds.
In a theoretical sense, VV116 has a higher probability of being superior to remdesivir injection in terms of effectiveness and side effects.
So how effective is Remdesivir?
On April 25, 2022, the FDA urgently authorized the treatment of remdesivir to extend to infants who have reached 28 days and weigh up to 3.5 kg.
The drug was previously only available to people over the age of 12. As of now, even Paxlovid can only be used for people over 12 years old, which shows the effectiveness and safety of Remdesivir.
The price of Remdesivir in developed countries is as high as 2,340 US dollars (a course of treatment, a total of 6 bottles), about 16,000 yuan, and according to “Science” reports, the cost of the daily dose of Remdesivir is less than 1 US dollar. The entire course of treatment costs less than $5.
At present, Remdesivir injection has not been approved in China. Interestingly, after seeing peers developing oral dosage forms of Remdesivir one after another, Gilead also began to study the oral version.
Based on this, VV116 once became “the hope of the whole village”.
However, there is a reason why VV116 has not been approved. The problem lies in the phase 3 clinical trial published in the New England Journal of Medicine.
Many people in the industry questioned the phase 3 clinical trial of VV116. The core problem is that the experimental design is not rigorous, double-blind is not carried out, and the core indicators of reducing the rate of severe illness and mortality cannot be verified.
“Behind the new crown oral drug VV116 boarded NEJM”, source: Yaozhi.com
In response to doubts, VV116 started the journey again.
On January 2, Junshi Biotechnology announced that it is fully promoting the group.
On January 5, Shanghai Ruijin Hospital started clinical research on anti-new coronavirus drugs. Patients who have been infected within 5 days and have not yet progressed to severe disease can apply for participation after being evaluated by a doctor, and can receive the anti-new coronavirus drug VV116 or Paxlovid for free.
In addition, Professor Xu Huaqiang, the developer of VV116, after taking the VV116 developed by himself after being infected with new coronary pneumonia last month, the symptoms were significantly relieved.
03 RAY1216, CENOXIN: Breakthrough of 3CL target route
From the perspective of technical route, the new crown drugs in the world can be divided into two schools, namely RdRP target and 3CL target, which target two enzymes in the replication process of the new crown virus respectively.
For example, consider the fight between the human body and the new coronavirus as a war. RdRP-targeted drugs can be understood as poisoning the enemy’s water source, while 3CL-targeted drugs are like “grain copying”.
Azvudine and VV116 mentioned above are all RdRP targets, while RAY1216, Xenoxin mentioned in this chapter, and Paxlovid mentioned above are all 3CL targets.
Most ordinary people are relatively unfamiliar with RAY1216, but investors in the secondary market are familiar with Zhongsheng Pharmaceutical (002317. SZ), and RAY1216 is the new crown oral drug developed by Zhongsheng Pharmaceutical.
RAY1216 was approved for clinical trials on May 15, 2022, and all cases enrolled in the Phase III clinical study were completed on January 2 this year, with a total of 1,360 cases.
Share prices have also moved in tandem with this development. The lowest intraday price of Zhongsheng Pharmaceutical on November 8, 2021 was 7.88 yuan, and by November 22, 2022, the highest intraday price was 41.3 yuan, an increase of 424%.
In addition to RAY1216, a new drug worthy of attention in the 3CL target camp, there is another “fighter”-Xianoxin.
On January 6 this year, the Jiangsu Provincial Food and Drug Administration made a briefing. It is expected that Simcere Pharmaceuticals (2096. HK)’s new crown candidate oral drug, Simnuoxin (SIM0417), will be approved in February 2023 at the earliest.
Senuoxin was jointly developed by Simcere Pharmaceuticals, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Wuhan Institute of Virology, and it is also a 3CL target. On March 28, 2022, Senuoxin obtained the clinical approval, and completed the Phase III clinical study on December 18, 2022, with all 1,208 patients enrolled.
Both RAY1216 and Cenoxim have progressed very quickly after obtaining the clinical approval (IND). In fact, they both skipped the second phase clinical trial and directly entered the third phase clinical trial.
But so far, neither RAY1216 nor Cenoxin have released clinical trial data on effectiveness.
Inferred from the time, the enrollment is completed and followed up for two months, and the Phase III clinical trial of the two is expected to end in March this year. On the premise of achieving the primary endpoint of the clinical trial, RAY1216 and Cenoxin are expected to be approved from March to April this year.
It is worth mentioning that because it is a 3CL target, it is the same as Paxlovid, and it needs to be used in combination with ritonavir, which is a combination packaged drug. However, because RAY1216 has a higher drug concentration in the human body at the same dose, it can be developed as a single tablet, that is, it is not used in combination with ritonavir.
04 Proxalutamide: Real reversal or capital feast?
In the history of domestic new drug development, Proxalutamide of Kintor Pharmaceutical (09939.HK) has become an unavoidable topic due to its tortuous course.
Proxalutamide is an ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane protease serine 2) degrader, which belongs to the class of androgen receptor antagonist drugs.
Previously, proxalutamide was intended to be used in the treatment of prostate cancer. After the outbreak of the new crown, it was discovered for the treatment of patients with mild and severe new coronary pneumonia.
In 2021, the research trial of proxalutamide in Brazil showed that:
The hospital protection rates for preventing mild cases from turning into severe cases were 92% and 90%, respectively, and the ICU or death protection rates were 100%. After 7 days of treatment, the virus-positive negative conversion rate was 82% (31% in the placebo group). The death risk of severe COVID-19 patients was reduced by 78%, and the median time from enrollment to recovery and discharge was shortened by 5 days.
The data is excellent, but there are different voices in the industry. Well-known journals such as “New England Journal of Medicine” and “The Lancet” rejected the submission of clinical data of proxalutamide because its mechanism of action has not been clarified and no reasonable explanation has been given.
The numbers are too good to be true, and the stock prices are too good to be true. In 2021, Kintor Pharmaceutical’s Hong Kong stock market value will soar all the way.
On November 4, 2020, the lowest intraday price of Kintor Pharmaceuticals was 7.2 Hong Kong dollars. By September 1, 2021, Kintor Pharmaceuticals hit an intraday highest price of 89 Hong Kong dollars, and the stock price rose by 1136% within 10 months.
By December 2021, Kintor Pharmaceuticals announced the interim data of the Phase III clinical trial, and the results showed poor results and did not reach statistical significance. This was interpreted by the market as a failure, and Kintor’s stock price fell by more than 70% that day.
Four months later, Kintor Pharmaceuticals made a comeback. On April 6, 2022, Kintor Pharmaceuticals announced the phase III clinical trial data of proxalutamide in the treatment of non-hospitalized COVID-19 patients with mild to moderate disease, and announced that the clinical trial was successful.
On April 4, 2022, the stock price of Kintor Pharmaceuticals soared by 36.79%, and on April 6, it soared by a maximum of 229.04%, and the increase fell back to 106.37% at the close, and then fell all the way so far.
Even if the new clinical trial data is released again, many question marks around proxalutamide still exist, mainly focusing on the mechanism of action.
Since the epidemic, some researchers have found that the severe disease rate of adult women is significantly lower than that of men; the severe disease rate of cancer patients is higher, and the severe disease rate of patients receiving androgen deprivation therapy (ADT) has decreased.
However, this drug has not conducted in vitro anti-new coronavirus mechanism research. Proxalutamide is declared to be the only oral drug for mild, moderate and severe cases of the new crown in the world, but people in the industry have many doubts about it.
The early stage of new coronary pneumonia (mild to moderate) is the rapid replication period of the virus, and it is necessary to quickly inhibit the replication of the virus. In the middle and late stage (severe stage), the immune system “kills red eyes”, regardless of whether it is the enemy or ourselves, and causes damage. This situation requires drugs to regulate this.
In these two stages, proxalutamide can be used for multiple purposes and has a significant effect, which made “Science” call it “unbelievable”.
In addition, proxalutamide is an androgen receptor antagonist drug, which reduces androgen levels. Theoretically, there may be side effects such as impotence and loss of libido, which will make it difficult to obtain large-scale application of proxalutamide.
So far, we can only think that whether the reversal of proxalutamide is real is doubtful; but the “capital feast” of 11 times return is obvious.
05 Three Echelons
In summary, RdRP targets and 3CL targets are the two core routes of oral drugs for the new crown. It is not yet possible to confirm which target is better.
Domestically, RdRP targets are the first to go, among which Azvudine tablets have been approved, and VV116 is expected to be approved for marketing in the first half of this year. 3CL targets have rapidly broken through, RAY1216 and Cenoxin, after obtaining clinical approval last year, are expected to be approved for marketing in the first half of this year at the earliest.
From the perspective of curative effect and safety, VV116 is the most anticipated and belongs to the first echelon. RAY1216 and Cenoxin, whose efficacy and safety are unknown, are temporarily listed in the second echelon. Azivudine ranks in the third echelon, and proxeramide can only temporarily rank in the fourth echelon.
The cruel reality tells us that in the field of industrial products, as long as China breaks through a certain technology blockade, foreign giants will often cut prices significantly.
In the field of medicine, only domestically produced medicines with excellent curative effect and safety are developed, and the tragic scene of “I’m Not the God of Medicine” will not be repeated.
Original title: The life and death race of the domestic new crown “special medicine”