A number of domestic small molecule oral new crown drugs have been put into research and development, when to usher in the market

Since its emergence, the More insidious Aumicron variant, which has spread faster and more insidiously, has led to the emergence of a large number of infected people, and many people have been vaccinated against the new crown in the early stage, and most of the infected people are asymptomatic or mild, which is making it more difficult to prevent and control the epidemic.

In order to cope with the Omilon epidemic, in addition to the dynamic clearance of non-medical prevention and control methods and vaccines, the development of special drugs for new crown drugs is equally important, and there is also an urgent need for drugs that can block the spread of the virus at an early stage. Small molecule oral COVID-19 drugs that are convenient to administer, easy to produce and easy to store are high hopes.

At present, a number of domestic oral new crown drugs have been put into research and development, but when can they be listed?

Domestic drugs under intensive development

Since its first appearance in Tianjin in January this year, the Aumechon variant has spread to many provinces across the country. Since March, the number of reported COVID-19 infections on the mainland has exceeded 500,000.

In the process of racing against the new crown virus, more domestic small molecule oral drugs have been invested in research and development. Recently, there have been frequent progress in the research and development of domestic drugs.

In early April, Simcere Pharmaceutical (02096.HK) announced that sim0417, a small molecule of anti-new coronavirus in Research, has achieved the first case of drug use by subjects as the first approved clinical 3CL target new crown oral drug in China.

Also in early April, pioneering pharmaceuticals (09939. HK) announced key data from the phase III global multicenter clinical trial of the oral COVID-19 drug pkrutamine for non-hospitalized COVID-19 patients with mild and moderate illness, boosting the market. Ninety-nine percent of the participants in the clinical trial were from the United States, and enrollment did not exclude subjects from vaccination, nor did it require subjects to have risk factors. It has been shown to be effective in reducing hospitalisation/mortality in COVID-19 patients, especially in all patients who have been taking the drug for more than 7 days, with a corresponding protection rate of 100%, significantly reducing hospitalization/mortality in subjects with high-risk factors (especially in the middle and upper age groups), and significantly and sustainably reducing the load of COVID-19 and improving COVID-19-related symptoms.

Tong Youzhi, founder, chairman and CEO of Pioneering Pharmaceuticals, said: "These data rigorously prove the clinical efficacy of pkrutamine in the new crown population, mainly infected by Delta and Omicron variants, and are statistically significant. ”

Subsequently, on April 19, Junshi Bio (688180.SH, 01877.HK) registered a multicenter, single-blind, randomized, controlled clinical study evaluating the efficacy and safety of VV116 versus PAXLOVID in the early treatment of mild-to-moderate novel coronavirus pneumonia on the website of the China Clinical Registration And Trial Center.

VV116 is an oral nucleoside anti-COVID-19 drug jointly developed by Junshi Biology and Suzhou Wangshan Wangshui Biomedical Co., Ltd. PAXLOVID, a 3CL protease inhibitor developed by Pfizer for COVID-19, was approved for marketing in China in February this year. The head-to-head clinical trial launched by Junshi Bio this time can compare the efficacy of these two drugs, which has aroused strong concern from the outside world. The first financial reporter learned that the study has completed the first patient enrollment and administration in April 2022.

Also on April 19, Cerresi Pharma (01672. HK) announced the antiviral cell experiments of the oral small molecule new crown drug candidate 3CL protease inhibitor ASC11, which is superior to similar drugs from the preliminary data, and the company expects to submit a clinical trial application in the second half of 2022 and complete the Phase I clinical trial in healthy subjects by the end of 2022.

Wu Jinzi, founder, chairman of the board and CEO of Clydega Pharmaceuticals, told the first financial reporter that ASC11 plans to develop three new crown indications, which are used for the treatment of mild and severe new crown and the prevention of new crown.

In addition to the above-mentioned enterprises, there are also real organisms, Kexing Pharmaceutical (688136.SH), Genting Xinyao (01952.HK) and other enterprises are also working intensively to develop small molecule oral NEW crown drugs. It is worth mentioning that the number of individual enterprises developed as many as two or more.

Junshi Bio is also developing the 3CL protease inhibitor VV993 for fighting the new crown, which is in the pre-clinical development stage.

"VV116 and VV993 are drugs or drug candidates developed for different key and conservative targets of the virus life cycle, and in addition to being used alone to exert their respective clinical advantages or characteristics, they also have the development prospect of 'combination drug antiviral, complementary effect'." Junshi Biological related people told the first financial reporter.

When to go public

Most of the mechanisms of action of small molecule oral NEWCC drugs are to achieve the effect of eliminating the virus by interfering with the replication of the virus itself, because it mainly acts in the cell, the intracellular process is relatively conservative, and it is not easy to mutate, so the effect is not easily affected by the mutant strain. In addition, the convenience of taking, production, storage and transportation is also a major advantage of this type of drug.

Junshi Bio replied to the first financial reporter: "Production capacity will not become the bottleneck of VV116's subsequent industrialization. ”

Some markets believe that small molecule oral COVID-19 drugs are expected to become the government's strategic reserve drugs in the future.

Zhu Guoguang, an analyst at Soochow Securities, said in a research report released in March that the state would negotiate the price of domestic small molecule drugs in the process of participating in the strategic reserve. "The price of domestic reserve drugs can refer to the price of Tamiflu, assuming that the average reserve price negotiated by the government for domestic small molecule drugs is about 200 to 300 yuan / course of treatment, from 2022 onwards, the government will start the reserve of special drugs within three years, and the national small molecule drug annual reserve drug market is about 224 to 42 billion yuan."

At present, there is no domestic small molecule oral new crown drug on the market, and there is also a lack of small molecule oral drug use that can treat a large number of patients with mild and moderate disease and general risk. At present, there is only one small molecule drug approved for marketing, and it is imported, that is, Pfizer's PAXLOVID, but it is only used for the treatment of mild and ordinary patients with high risk factors for progression to severe disease within 5 days of onset. At the same time, the price of the drug is not cheap, up to 2300 yuan a box.

At present, domestic small molecule oral new crown drugs are stepping up the development of mild and medium-sized indications, and the main targets selected by related drugs are 3CL protease, RNA polymerase (RdRp), and androgen receptor (AR) antagonists.

Specifically, 3CL protease inhibitors can inhibit the action of 3CL proteases, thereby preventing a series of subsequent replication activities of the virus. RNA-dependent RNA polymerase (RdRp) is a polymerase in the process of viral RNA replication, and RdRp inhibitors inhibit the effect of RdRp and can also interfere with or inhibit viral replication. Androgen receptor (AR) antagonists can exert antiviral effects in two ways, one is to regulate the host cell key proteins ACE2 and TMPRSS2, inhibiting the new crown virus from invading the host cell, and the other is to activate the Nrf-2 pathway to inhibit the production of inflammatory factors and prevent the occurrence of factor storms, thereby reducing the severity of moderate to severe COVID-19 patients.

Most of the domestic small molecule oral drugs under research are still in the pre-clinical research stage, or have just entered the clinical research stage.

In the clinical trials carried out in China, the domestic small molecule new crown drugs with the fastest progress are alzvedine for real organisms, pkrutamine for pioneering pharmaceuticals and VV116 for Junshi Biologics, which are RdRp inhibitors, AR antagonists and RdRp inhibitors.

Among them, the real organism of Azvudine has completed a phase III clinical trial, and the data is waiting to be revealed. The global multicenter Phase III clinical trial of pkrutamine for the treatment of mild and moderate covid-19 patients in Pioneering Pharmaceuticals completed the enrollment and administration of china's first subject in Shenzhen Third People's Hospital on February 10, 2022. Junshi Bio's VV116 is an international multicentre, double-blind, randomized, placebo-controlled Phase II/III clinical study for the treatment of mild to moderate COVID-19 patients, and the first patient enrollment and administration has been completed at the Shanghai Public Health Clinical Center in March 2022.

However, when the relevant drugs can eventually be put on the market is still facing certain tests.

Recently, some people engaged in the research and development of small molecule oral new crown drugs told the first financial reporter that the assessment standards of the National Food and Drug Administration of the third phase of the new crown oral treatment drug take symptom improvement as the "clinical endpoint", especially "reducing the mortality rate of low-weight/ critically ill patients", which brings certain challenges to the current clinical trials of related drugs, the reason is that nowadays infected with Omicron, due to the early vaccination basis, the infected people are asymptomatic or mild, and the number of severe and hospitalized patients is small.

"At present, there are not many cases of death due to the new crown, and according to the current listing assessment standards, it is difficult for domestic small molecule oral drugs to accelerate the listing." We also call for 'reducing the viral load' as an assessment standard, after the viral load is down, the nucleic acid will soon turn negative, such an assessment standard is more in line with the current prevention and control reality. Some clinical research and development experts of new coronavirus drugs told the first financial reporter.