Home Business Experts talk about the first domestic oral drug for new crown: if only “improving clinical symptoms” is not a special drug – yqqlm

Experts talk about the first domestic oral drug for new crown: if only “improving clinical symptoms” is not a special drug – yqqlm

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Experts talk about the first domestic oral drug for new crown: if only “improving clinical symptoms” is not a special drug – yqqlm

Industry experts pointed out that the advantage of new use of old drugs is that it can reduce the risk of drug management, and the price of domestic drugs is relatively lower. However, because the primary endpoint of the Phase III clinical trial of Azvudine for the new crown is to “improve clinical symptoms” rather than reduce “all-cause mortality”, it is not a special drug.

On July 25, Henan Real Biotechnology Co., Ltd. (hereinafter referred to as “Real Bio”) Azvudine (FNC for short) added the registration application for the treatment of new coronavirus pneumonia with conditions and was approved for listing, becoming the first domestically. Approved domestic oral drug for COVID-19. On the same day, Fosun Pharma quickly issued an announcement saying that it signed a “Strategic Cooperation Agreement” with Real Biology to promote the joint development of the two parties.

Previously, on July 15, Real Biology announced on its official account that the results of the Phase III clinical trial of Azvudine Tablets for the treatment of new coronavirus pneumonia indications have reached expectations, and recently they have officially submitted a marketing application to the State Drug Administration.

According to the article, the results of clinical trials show that Azvudine tablets can significantly shorten the symptom improvement time of patients with moderate novel coronavirus infection pneumonia, increase the proportion of patients with improved clinical symptoms, and achieve clinically superior results. It has the effect of inhibiting the activity of the new coronavirus, and the virus clearance time is about 5 days; in terms of safety, the overall tolerance is good, and there is no statistical difference in the incidence of adverse events between the Azvudine group and the placebo group, and there is no increase in subjects. risk.

However, as of now, the final clinical results of the three registration studies of azvudine in the treatment of new coronavirus have not been announced. Industry experts pointed out that the advantage of new use of old drugs is that it can reduce the risk of drug management, and the price of domestic drugs is relatively lower. However, since the primary endpoint of the Phase III clinical trial of Azvudine for the new crown is to “improve clinical symptoms” rather than reduce “all-cause mortality”, it is not a special drug.

The first approved domestic oral drug for COVID-19

According to the website of the State Drug Administration, on July 25, the State Drug Administration conducted emergency review and approval in accordance with the relevant provisions of the “Drug Administration Law” and in accordance with the special approval procedures for drugs, and approved Henan True Biotechnology Co., Ltd. Aziz with conditions. The registration application of Fudine Tablets for the treatment of new coronavirus pneumonia has been added.

According to the article, this product is an oral small-molecule novel coronavirus pneumonia treatment drug independently developed by my country. On July 20, 2021, the State Food and Drug Administration has conditionally approved this product in combination with other reverse transcriptase inhibitors for the treatment of adult HIV-1 infected patients with high viral load. This is a conditional approval of an additional indication for the treatment of adult patients with common novel coronavirus pneumonia (COVID-19). Patients should strictly follow the instructions for medication under the guidance of a physician. The State Food and Drug Administration requires the marketing authorization holder to continue to carry out relevant research work, complete the conditional requirements within a time limit, and submit the follow-up research results in a timely manner.

According to the official account of Real Bio, the company was established in 2012 and is registered in Pingdingshan, Henan, focusing on the research and development of innovative drugs such as anti-virus, anti-tumor, cardiovascular and cerebrovascular. The company’s CEO and CSO Du Jinfa “has been designing and developing innovative drugs for more than 30 years, and has invented and led the development of the hepatitis C cure drug ‘sofosbuvir'”.

Azvudine (FNC) is the world‘s first dual-target inhibitor of HIV reverse transcriptase and accessory protein Vif, and the first oral anti-HIV drug with independent intellectual property rights in China. On January 19, 2022, Real Bio has obtained a drug production license; in April, the company’s product Azvudine tablets completed drug filing.

According to an article published by Guangming Daily on November 18, 2021, Azvudine has good anti-coronavirus activity at the cellular and animal levels in response to COVID-19. Phase III clinical trials are being carried out in China, Brazil and Russia.

Screenshot of the real creature public account.

On July 15, 2022, Real Biology announced on its official account that the results of the Phase III clinical trial of Azvudine Tablets for the treatment of new coronavirus pneumonia indications have reached expectations, and recently they have officially submitted a marketing application to the State Drug Administration.

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The paper introduces that the pivotal Phase III registration clinical trial adopts a multi-center, randomized, double-blind, placebo-controlled clinical trial design. The results of clinical trials show that Azvudine Tablets can significantly shorten the symptom improvement time of patients with moderate novel coronavirus infection pneumonia, increase the proportion of patients with improved clinical symptoms, and achieve clinically superior results; The effect of viral activity, the virus clearance time is about 5 days; in terms of safety, the overall tolerance is good, and the incidence of adverse events between the azvudine group and the placebo group is not statistically different, and the risk of subjects is not increased.

According to the article, Professor Chang Junbiao, the inventor of azvudine, the current deputy secretary and vice president of Zhengzhou University, said: “As a nucleoside analog that inhibits viral RNA-dependent RNA polymerase (RdRp), azvudine can be used to inhibit viral RNA-dependent RNA polymerase (RdRp). It specifically acts on the new coronavirus RdRp, thereby inhibiting virus replication, and its drug targeting is strong.” Academician Jiang Jiandong of the Institute of Materia Medica, Chinese Academy of Medical Sciences said: “Azvudine has obvious anti-new coronavirus effect, and it is suitable for clinical mild and severe patients. Effective, Azvudine treats the new crown through a molecular mechanism that treats both the symptoms and the root causes, which is its distinctive biological feature.”

Not long ago, Chang Junbiao said in an interview with Henan Radio and TV Station, “For different new coronary pneumonia virus variants (Alpha, Beta, Delta, Omicron, etc.), Azvudine has a very small dosage, good therapeutic effect, The virus is declining very fast.”

On the evening of July 25, after the State Food and Drug Administration issued the document, Fosun Pharma announced that the company and Real Bio have reached a strategic cooperation, and the two parties will jointly develop and exclusively commercialize Azvudine by the holding subsidiary Fosun Pharma Industry. Areas of cooperation include novel coronavirus, AIDS treatment and prevention.

Clinical trials for COVID-19 started as early as February 2020

In an interview with the media, Chang Junbiao said that the research and development of azvudine began in 2004, “From the current research progress, the stage of azvudine is not only in the field of AIDS, but also in the treatment of new crown virus and hand, foot and mouth virus. , which is also the direction of our future efforts.”

Chang Junbiao pointed out that Azvudine has three major characteristics: first, it does not produce cross-resistance with drugs on the market (such as 3TC), which can solve the problem of drug resistance; second, as a dual-targeted drug, it can block reverse transcription The enzyme can inhibit the Vif accessory protein of HIV; the third is that the drug has strong targeting and long-term effect.

“A randomized, open, controlled clinical trial of azvudine tablets in the treatment of novel coronavirus pneumonia (COVID-19).”Screenshot of the official website of China Clinical Trials Center

Surging News found on the official website of the China Clinical Trial Center that Guangshan County People’s Hospital in Henan, as the entrusting unit, carried out a randomized, open, controlled clinical trial of Azvudine Tablets in the treatment of novel coronavirus pneumonia (COVID-19). “, the registration time is February 15, 2020. The study was implemented for 2 months. A total of 20 people aged 18 and over were enrolled in the control group, of which 10 people in the experimental group were orally given azvudine tablets (once a day, 5 tablets each time).

The controlled trial was published in the comprehensive journal Advanced Science in August and October 2020. In the same month, Chang Junbiao, as one of the authors of the paper, published an article entitled “Azvudine (FNC): a promising clinical candidate for COVID-19 treatment (Azvudine (FNC): a Promising COVID-19 Clinical Treatment Candidates)” research paper, once again mentioning the results of the trial——

According to the article, preliminary clinical trial results show that azvudine can shorten the time of nucleic acid conversion to negative (NANC). Among the 10 patients in the experimental group, the nucleic acid negative rate within 4 days reached 100%, while the negative rate within 28 days in the conventional treatment group was 73%. The trial also showed that azvudine was well tolerated, with no drug-related adverse events.

The paper concludes that the triphosphate of azvudine can intercalate into the RNA synthesis process of the new coronavirus and inhibit the related polymerase, ultimately terminating the synthesis of RNA strands and viral replication. Overall, this is a safe and effective nucleoside drug candidate for the treatment of mild and common COVID-19, which also shows promise in the treatment of severe COVID-19. The data also suggest that repurposing existing broad-spectrum antiviral drugs is a viable and promising treatment strategy for Covid-19.

Surging News searched on PubMed, an authoritative search engine in the global life sciences and biomedicine fields, and found that there were 19 search results related to “Azvudine”, the earliest of which was a chemical synthesis-related paper published in 2009. Among them, including the aforementioned 3 papers, there are 5 research papers related to SARS-COV-2 (new coronavirus), and Chang Junbiao is one of the authors.

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Peng Mei News noticed that a study published online in December 2021 conducted a controlled trial on two groups of eight common rhesus monkeys infected with the new coronavirus and found that the viral load in the lungs of four monkeys in the experimental group was lower. One of the randomized single-arm trials also found that 31 positive patients had 100% negative viral RNA conversion within 3.29 ± 2.22 days (range: 1-9 days) after oral medication, and a 100% discharge rate was 9.00 ± 4.93 days (Range: 2-25 days), 5 of them experienced mild transient dizziness, nausea and other side effects.

The study believes that oral administration of azvudine to animals can largely concentrate the drug in the thymus in “active form”, effectively inhibit the replication of the new coronavirus in the body, maintain and promote the immune function of the thymus, and quickly cure the new crown patients (in the process of being apply for patent). The authors of the paper also include academician Jiang Jiandong, real creature Du Jinfa and others.

In February 2022, Chang Junbiao published a single signed paper in Accounts of Chemical Research, a journal of the American Chemical Society, which introduced the therapeutic prospects of 4′-modified nucleosides in antiviral therapy, and said that Aziz Fudine has conducted phase 3 clinical trials in COVID-19 patients in different countries (clinical trial numbers: NCT04668235 and NCT04425772), cured almost all patients of COVID-19 disease, and showed a better therapeutic effect than remdesivir.

Expert: If only “improving clinical symptoms” is not a special drug

The real biology phase III clinical trial includes more than 800 enrolled patients, covering mild, moderate and severe cases of new coronary pneumonia, with viral load and clinical benefit as evaluation indicators. However, as of now, the final clinical results of the three registration studies of azvudine in the treatment of new coronavirus have not been announced.

Virologist Chang Rongshan told The Paper that the widely used nucleoside antiviral drugs may have the potential to treat the new crown. Azvudine is an anti-AIDS drug developed in 2004. The advantage of new use of old drugs is that it can reduce the risk of drug management, and the price of domestic drugs is relatively lower.

However, he pointed out that in the aforementioned azvudine-related papers, there are too few test samples to ensure the quality and results of clinical trials, and there will be errors. At the same time, the primary endpoint of the drug’s new crown phase III clinical trial is “improving clinical symptoms” rather than reducing “all-cause mortality.” That is to say, this is not a special drug to treat the new crown and kill the virus, and it is not a broad-spectrum antiviral drug. Therefore, in terms of the current development trend of new coronavirus variants and the characteristics of the human immune system, there is a lack of clear clinical significance, “This is the biggest problem, because in any case, the main demand for drug treatment is always to reduce severe illness and reduce mortality. .”

In February this year, the “Technical Guidelines for Clinical Trials of New Antiviral Drugs for Novel Coronavirus Pneumonia (Trial)” (hereinafter referred to as the “Guiding Principles”) issued by the Center for Drug Evaluation (CDE) of the State Drug Administration pointed out that in light and ordinary In the new coronary pneumonia treatment study, the incidence of developing severe, critically ill or all-cause mortality at an appropriate time point (for example, at least 28 days) is first recommended as the primary efficacy endpoint, and it can also be evaluated at an appropriate time to continuous clinical trials. recovery time.

Immunology scholar Zhou Yebin told The Paper that HIV and the new coronavirus are very different. HIV drugs are optimized and screened for HIV, and have good binding ability to HIV targets. Broad-spectrum is not a strong point. Not so prominent, “Like Remdesivir’s current inhibition of the new coronavirus is still a little worse, after all, it is not a drug specially developed for coronavirus.”

At the same time, HIV drugs need to be taken long-term, while new crown drugs are short-term, and the data will vary. However, there is very little information about the new crown clinical trials released by Azvudine at present, especially the lack of some necessary data, so it is impossible to make a specific judgment, but from the past data, “it is not a drug with a long accumulation of safety data.” He Say.

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Zhou Yebin also mentioned that according to a technical review report of azvudine by a drug regulatory agency in July 2021 and the drug insert, the problem of genotoxicity and reproductive toxicity of the drug in animal experiments should also be considered. There are potentially serious security issues that require close attention. For example, when the new crown drug “Molnupiravir (Monupiravir)” was reviewed by the FDA, its genotoxicity became a key topic of discussion, and its use was strictly restricted in the follow-up, especially pregnant women and minors were directly excluded.

Screenshot of azvudine drug insert

At the China Pharmaceutical Development Conference held in February this year, Jiang Jiandong, a member of the Chinese Academy of Medical Sciences and academician of the Chinese Academy of Engineering, also mentioned the reproductive toxicity and teratogenicity of Molnupiravir.

However, Chang Rongshan believes that the current guided dosage of azvudine is very low, and it is still a safe dosage range for the vast majority of normal people, so there is no need to worry too much.

In response to the above-mentioned questions, The Paper has called the real biological side many times, but has not received a response as of press time.

New crown new drug development needs to face the problem of drug resistance mutation

As of the end of June this year, 2 small-molecule new crown oral drugs have been approved for marketing in the world, both of which are old drugs and new uses. One is Merck’s Molnupiravir, and the other is Pfizer’s Paxlovid, which consists of the active antiviral drug Nirmatrelvir and the compound Ritonavir, which slows the breakdown of Nirmatrelvir in the body, and was approved by China‘s State Food and Drug Administration with conditions in February.

On July 21, the Japanese virology team published an article in the New England Journal of Medicine entitled “Efficacy of Antibodies and Antiviral Drugs on Omicron Mutants BA.2.12.1, BA.4 and BA.5” ” research paper, claiming that small molecule antiviral drugs Remdesivir, Molnupirvir and Nirmatrelvir can effectively inhibit BA.2.12.1, BA.4 and BA. 5 activity.

The study also showed that although several monoclonal antibodies did not effectively neutralize the virus or had low efficacy, in the experiment, the combination of such drugs could inhibit the virus.

Academician Jiang Jiandong also pointed out at the aforementioned China Pharmaceutical Development Conference that there are currently about 100 antiviral drugs in the world, and there are two scientific issues we need to face: virus outbreaks and drug resistance.

However, an article published in the journal Science on June 22 this year pointed out that the recent emergence of various highly escaped new coronavirus variants and a series of new studies have shown that the increase in the use of oral drugs such as Paxlovid has imposed selection on the virus Sexual pressure – The new coronavirus has begun to mutate in the direction of developing resistance and finding multiple ways to evade the new crown drugs.

For example, citing the research results of the team of virologist Dirk Jochmans of the University of Leuven in Belgium, after 12 rounds of Nirmatrelvir treatment, the new coronavirus accumulated three mutations, and the sensitivity to Nirmatrelvir was reduced by 20 times (reduce 20-fold), suggest a potential drug resistance mutation.

Adam Godzik, a bioinformatics expert at the University of California, Riverside, found in his work that some mutations are already present in people infected with the coronavirus, with some flexibility that could help the virus bypass drugs.

And a paper published by medicinal chemist Jun Wang of Rutgers University and colleagues on the bioRxiv preprint platform confirmed that potential resistance mutations are increasing, and bluntly stated that “it is only a matter of time before resistance emerges.”

However, even so, the global new coronary pneumonia drug research and development is still in full swing. Chang Rongshan said that in the future, we will need a combined oral drug that inhibits important targets of the new coronavirus (such as 3CLpro, RdRp) and increases human immunity, “including at least 2 to 3 oral drugs, such as AIDS. The mortality rate is reduced to 0% like the cocktail therapy.”

The author of this article: Feng Yinlun, source: The Paper, original title: “Experts talk about the first domestic oral drug for new crown: If only “improving clinical symptoms” is not a special drug”

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