Under the new epidemic prevention and control measures, therapeutic drugs have gradually become the focus, entering the stage when Omicron is the mainstream virus. With reference to overseas experience, which domestic drugs have the potential to become specific drugs for the new crown?
/ 01 /
Stone from Other Hills
As of the third quarter, among the new crown drugs under research in the world, only oral drugs have reached 294, of which 7 have been launched. In addition, there are many new crown drugs administered by intravenous injection and intramuscular injection.
(1) Sluggish growth in sales revenue
Due to the early launch time, the sales of foreign small molecule oral new crown drugs have certain reference significance for domestic new crown drug companies:
Since Pfizer’s Paxlovid went public, it has achieved sales of US$1.5 billion, US$8.1 billion and US$7.5 billion in the first, second, and third quarters of this year, respectively. Although Pfizer still maintains an annual sales forecast of US$22 billion, weak growth has emerged ;
Merck’s Molnupiravir : sales of US$3.247 billion, US$1.177 billion and US$436 million were achieved in the first, second and third quarters of this year, respectively. Affected by the listing of Paxlovid, sales have declined sharply ;
(2) Changes in virus strains lead to decline in curative effect
Since Omicron has become the main type of COVID-19, the sales of neutralizing antibody drugs represented by Eli Lilly’s Bebtelovimab, AstraZeneca’s Evusheld, GlaxoSmithKline’s Xevudy, and Regeneron’s REGEN‑COV since this year The average income has fallen sharply, mainly because a number of studies have shown that antibody drugs have no therapeutic effect on Omicron virus.
For oral small molecule drugs, the therapeutic effect is also facing challenges : In August this year, the “New England Journal of Medicine” published an Israeli study:
For patients aged 40-60, the hospitalization rate was 15.2 per 100,000 versus 15.8 per 100,000 for those receiving Paxlovid versus those not receiving Paxlovid, with little difference between the two . The effect still exists in susceptible populations such as people and those with compromised immune systems.
(3) Can Xocova become a new generation of specific drugs
As far as Omicron is concerned, the drug Xocova of Shionogi Company, which has just been approved for marketing in Japan, has the potential to become an effective drug for the treatment of Omicron .
Xocova is the first drug to demonstrate simultaneous response to five typical Omicron-associated symptoms (primary endpoint) in patients with mild to moderate SARS-CoV-2 infection (regardless of risk factors or vaccination status) during the Omicron variant epidemic ) Antiviral drugs with clinical symptoms and antiviral efficacy (key secondary endpoints), and except for special groups such as pregnant women, can be used regardless of the risk of severe disease .
/02/
Lianhua Qingwen Capsule: Can the out-of-stock magic medicine become a special medicine?
Speaking of Lianhua Qingwen capsules (granules), I believe everyone is familiar with them.
This is a Chinese patent medicine composed of 13 herbs. Its main functions are to clear away plague and detoxify, ventilate the lungs and expel heat. It is often used in the treatment of colds and flu. At present, the capabilities of Lianhua Qingwen Capsules are not limited to this.
In April 2020, Lianhua Qingwen Capsule was approved by the Food and Drug Administration for the treatment of fever, cough, and fatigue caused by mild and common types of new crowns. The course of treatment is 7 to 10 days.
According to some small-sample, non-blinded controlled clinical studies, Lianhua Qingwen Capsules have shown curative effect in the treatment of mild and common patients, especially fever, cough, and fatigue disappear quickly, and can reduce the occurrence of mild and common patients turning severe. Promote nucleic acid turning negative.
Thanks to the miraculous efficacy, the public’s enthusiasm for buying Lianhua Qingwen Capsules continues to rise. Recently, Lianhua Qingwen Capsules have even been sold out due to price increases across the country.
On November 22, Qilu Hospital of Shandong University registered the Phase 4 clinical trial of Lianhua Qingwen for COVID-19 rehabilitation, and plans to enroll 4,000 adult COVID-19 infected patients.
So, how good is the treatment effect of Lianhua Qingwen Capsule? let us wait and see.
/ 03 /
Azvudine: The first domestically approved small molecule new crown oral drug
Similar to Lianhua Qingwen Capsules, Azvudine is also a new crown oral drug that has been used in clinical practice.
As a member of nucleoside (acid) reverse transcriptase inhibitors, azvudine may be embedded in the RNA synthesis process of the new coronavirus and inhibit the relevant polymerase, eventually leading to the termination of RNA replication, and ultimately has the potential to treat the new coronavirus potential for infection.
On July 25 this year, the Food and Drug Administration conditionally approved Azvudine, a real biological product, to increase the registration application for the treatment of new coronavirus pneumonia indications. The reason for the “increase” is that Azvudine has been approved for the treatment of HIV in 2021.
According to the instructions, Azvudine “the median time to improve the clinical symptoms of patients with new coronary pneumonia is about 10 days, and the virus clearance time is about 5 days”; Exactly how remains to be seen.
Unlike Lianhua Qingwen Capsules, Azvudine is currently limited to doctor’s prescriptions, and ordinary people cannot purchase it online or offline.
Real Bio was funded and established by Beijing Xingyu Zhongke Investment Co., Ltd. (hereinafter referred to as “Xingyu Zhongke”). Wang Chaoyang, the major shareholder of Xingyu Zhongke , had dabbled in coal, real estate and other fields for many years , and was once restricted due to debts and wages. consume .
/ 04 /
SHEN26: Sinovac launches oral drugs
For the technical route of oral version of remdesivir, Sinovac’s SHEN26 is also participating in the competition.
In terms of molecular structure design, SHEN26 is similar to VV116. According to preclinical research data, SHEN26 also has great potential.
The data of in vitro antiviral experiments show that the EC50 of SHEN26 capsules against the Omicron mutant strain is 13nM, and the inhibitory activity is 103 times that of remdesivir.
According to the results of drug metabolism, the oral bioavailability of SHEN26 rats is 98%, which is basically the same as that of intravenous administration. This also provides strong support for the design of oral drugs.
In mice, SHEN26 can reduce the viral load in mice and also significantly improve lung inflammation in mice, and has broad-spectrum potential.
On November 23, Sinovac Pharmaceuticals announced that the phase 2 clinical trial of SHEN26 in the treatment of patients with mild and common new coronaviruses has been approved.
At the investor exchange meeting a few days ago, Sinovac Pharmaceuticals stated that it has submitted a Pre-IND communication application for SHEN26 capsules to the FDA.
/05/
Proxalutamide: The star player who once pushed the stock price to double in a single day went into hiding
The development of new crown oral drugs is bound to be full of ups and downs. In this regard, Proxalutamide of Kintor Pharmaceutical is the best example.
Proxalutamide is an androgen receptor (AR) antagonist that blocks the binding of androgens to AR for the purpose of treating prostate cancer.
In the field of prostate cancer treatment, proxalutamide is difficult to hand over considerable data, so it has found another way to enter the field of new crown treatment. According to Kintor, anti-androgen therapy can indirectly target the transcription of TMPRSS2 and prevent the virus from entering normal cells.
However, proxalutamide has experienced continuous ups and downs in the field of COVID-19 treatment. On December 27, 2021, Kintor Pharmaceuticals announced that the Phase III clinical trial did not reach statistical significance. The next day, Kintor Pharmaceuticals’ stock price crashed by 85% within one minute of opening.
On April 6, 2022, things turned around. Kintor Pharmaceuticals stated that the protection rate of proxalutamide reached 100% among patients who took the medicine for more than seven days and middle-aged and elderly patients with high-risk factors, and the stock price also rose that day. Got 100%+ .
However, this data is only based on subgroup analysis, and there are uncertain factors such as small scale and long treatment time. So far, Kintor Pharmaceuticals has not announced the follow-up progress, and has gradually “disappeared” .
/ 06 /
RAY1216: Chinese version of Paxlovid?
Looking at the world, the most effective oral drug for the new crown is Pfizer’s Paxlovid. According to clinical data disclosed by Pfizer, Paxlovid reduced the risk of hospitalization and death of patients with new crowns by 89%.
Birth determines destiny. Paxlovid is a combination preparation consisting of the 3CL protease inhibitor PF-07321332 and a low dose of the HIV treatment drug ritonavir.
Among them, PF-07321332 is the main player against the new coronavirus. It inhibits the activity of 3CL protease, causing the viral protein precursors to fail to cleavage and form mature virions, terminating the self-replication process, thereby achieving the purpose of preventing the progression of the disease.
In China, many pharmaceutical companies have entered the research and development of 3CL protease inhibitors, and Zhongsheng Pharmaceutical’s RAY1216 is in the first camp.
On November 14, the company announced that the phase III clinical study of RAY1216 for the treatment of patients with mild and common new crown infection has completed the enrollment of the first subject.
According to the clinical design, the study intends to enroll 1,070 patients with mild and common neo-coronavirus infection. The placebo is used as the control. The clinical dosage regimen is a single drug RAY1216 tablet, which is taken orally for 5 consecutive days. The primary endpoint is the time until the clinical symptoms continue to recover. time.
/07/
VVV16: Oral version of Remdesivir
In addition to 3CL protease inhibitors, the direction of oral derivatives of remdesivir is also an area worthy of attention.
On December 26, 2021, phase III clinical data of Remdesivir published in the New England Journal of Medicine showed that in patients with symptomatic and high-risk of disease progression who were not hospitalized with new crown infection, Remdesivir was more effective than placebo in hospitalization. or an 87% reduction in the risk of death.
Good clinical data have verified that remdesivir has great potential in treating patients with new crown infection.
The VV116 of Wangshan Wangshui/Junshi Biotech has been optimized and designed according to the parent nucleoside structure obtained from the metabolism of remdesivir in the human body.
On the one hand, the company uses the isotope effect brought by deuterium to prolong the metabolism time in the body to enhance the curative effect; on the other hand, the company adds multiple hydroxyl groups to improve the water solubility of the drug and further enhance the oral bioavailability of VV116. Thanks to two major improvements, VV116 has the potential to achieve oral administration.
At present, VV116 has completed the head-to-head phase III clinical study with Pfizer Paxlovid in China and reached the primary endpoint. At the same time, VV116 is also in the phase III clinical research phase of multiple international multi-centers.
If the follow-up data is excellent, it may become a strong competitor of domestic oral drugs.
/ 08 /
FB2001: “Aerosol inhalation” version of Paxlovid?
Although the domestic 3CL protease inhibitor has not yet been approved for marketing, it has already begun to “volume” dosage forms.
Frontier Bio’s FB2001 is an aerosolized 3CL protease inhibitor. Since the main target organs of the new coronavirus are the respiratory tract and the lungs, there are theoretically two major advantages in the way of nebulization inhalation:
First, the drug can be delivered directly to the upper respiratory tract and lungs, directly acting on the target organ, and achieving high drug concentration locally, which is expected to speed up the relief of symptoms and the clearance of the virus.
Second, nebulized inhalation adopts a local drug delivery method, and less drugs enter the blood. It is expected that the systemic side effects caused by the drugs will be small, and the drug interactions will be less.
Of course, whether it has the above-mentioned “potential” advantages requires rigorous clinical verification.
On November 23, Frontier Bio announced that the II/III clinical trial of FB2001 aerosol dosage form for the treatment of patients with mild and common new coronavirus infection has been approved.
What is the result, frontier biology may soon be able to give the answer.
/09/
SIM0417: Indications for Challenging Paxlovid Losses
As mentioned above, many domestic pharmaceutical companies are participating in the competition for 3CL protease inhibitors. In addition to Zhongsheng Pharmaceutical, the first camp also includes SIM0417 of Simcere Pharmaceutical.
In September this year, SIM0417 started a phase III clinical trial in combination with ritonavir for the treatment of patients with mild to severe disease. According to public reports, hundreds of subjects have been enrolled in the Phase III clinical trials of SIM0417, and a mid-term analysis is expected around the end of the year.
Earlier in May, SIM0417 also started clinical trials for post-exposure prophylaxis. Compared with the treatment of patients with mild and severe diseases, the primary endpoint of this indication is relatively easy, which is “the incidence of post-exposure prophylactic infection”.
However, research and development is also more difficult. Pfizer’s Paxlovid’s previous research on post-exposure prevention ended in failure .
In the phase II/III study called EPIC-PEP conducted by Pfizer, compared with placebo in adults who received PAXLOVID for 5 days and 10 days, although the risk of preventing infection was reduced by 32% and 37%, respectively, the These results were not statistically significant.
In the case of Paxlovid’s defeat, can SIM0417 counterattack?
/ 10 /
who is the future star
At present, in addition to the above-mentioned several domestic pharmaceutical companies, there are also pharmaceutical companies such as Qilu Pharmaceutical, Essen Pharmaceutical, Ascletis Pharmaceutical, Genting Xinyao, Hansheng Pharmaceutical, and Yaoshi Technology entering the field of oral drug research and development, and the research progress is relatively early.
However, the early stage may not be a disadvantage, but there is an opportunity to advance the trial during the epidemic of Omicron. If the follow-up clinical data is excellent, these candidates will surely stand out.
Note: The second half of the article comes from Amino Watch , thanks to Amino for its support.
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