Recently, the domestic new crown oral antiviral drug Azvudine is gradually being rolled out in the clinic and is being chosen by more and more doctors and patients. At present, how is the research progress of azvudine? In clinical application, what problems should be paid attention to?
Anti-HIV oral drugs, is it effective against the new crown?
On July 25, 2022, the State Food and Drug Administration conditionally approved the registration application for the addition of azvudine tablets of Henan Real Biotechnology Co., Ltd. for the treatment of new coronavirus pneumonia, which can be used to treat adult patients with common new coronary pneumonia.
Screenshot of the official website of the State Food and Drug Administration
Prior to this, Azvudine was an oral dual-target nucleoside antiviral drug conditionally approved for use in adult HIV-1 infected patients, which has significant and broad-spectrum antiviral effects against HIV, HCV, EV71 and HBV in vitro, and has shown good efficacy and safety in phase II clinical trials for the treatment of HIV infection.
The novel coronavirus is a typical enveloped single-stranded positive RNA virus, and RNA synthesis requires nucleosides and nucleotides as raw materials. Nucleoside antiviral drugs can inhibit viral replication by imitating natural nucleosides entering host cells, then converting to nucleosides triphosphate through kinase catalysis, and embedding in viral RNA during viral RNA synthesis, resulting in termination of viral RNA chain synthesis.
Based on the above theory, since 2020, the R&D team has begun to explore the possibility of azvudine for the treatment of the new crown.
A randomized controlled trial of 20 mild and ordinary COVID patients showed that the mean time to first negative conversion to negative in the azvudine treatment group was 2.6 days, which was shorter than the control group of 5.6 days; There were no adverse events in the azvudine treatment group and 3 adverse events were reported in the control group.
Another randomized single-arm clinical trial of compassionate use showed that oral azvudine cured all 31 new crown patients, with a nucleic acid conversion time of 3.29 ± 2.22 days, and 5 patients experienced mild and transient dizziness and nausea.
It can be seen that in small sample studies, azvudine initially shows some potential. However, to scientifically evaluate the effectiveness of a drug, phase III clinical trials are indispensable.
Recently, the results of two phase III clinical trials of Azvudine in Brazil were published in preprint form, one for mild and one for moderate.
According to media reports, two studies confirmed that azvudine "can significantly shorten the nucleic acid conversion time in patients with mild and moderate SARS-CoV-2 infection, accelerate virus elimination, significantly reduce viral load, reduce symptoms and shorten the course of the disease, and has good safety and no significant impact on liver and kidney function in patients, safe and effective."
What do the two preprint papers say?
One study did not meet the primary endpoint, with the main difference being shortening the time to negative nucleic acids
Let's start with mild disease research. A total of 321 patients aged 18~65 years were included, and 281 successfully completed treatment.
Among them, 143 were in the azvudine group, taking 5mg of azvudine + basic treatment daily; 138 people were in the control group, taking placebo + basic treatment. Throughout the treatment period, patients undergo nucleic acid test analysis every 48 hours, and a CT value of ≤37 is considered positive.
The primary endpoint results of the study showed that in terms of clinical improvement, the proportion of azvudine groups with a score of 1 at clinical discharge was 2.0% and 98% scored 0 with a score of 0 at clinical discharge, compared with 2.2% in the placebo group with a score of 1 at discharge, and a score of 0 in 97.8%. There was no statistically significant difference between the two.
That is, the study did not meet the set primary endpoint.
WHO Clinical Progress Scale (Source: Reference 1)
Source: Media reports with pictures
Studies also looked at nucleic acid conversion time in different treatment groups, showing that the time to first negative was 8.27 days in the placebo group and 5.55 days in the azvudine group (p
Source: Reference 2
The study therefore concluded that although there was no significant difference in final symptom improvement scores between the two groups, the time required for discharge (i.e., two consecutive nucleic acid negatives) in the azvudine group was significantly shorter.
Let's look at the meso-symptomatic study. A total of 180 patients were included, 172 completed treatment, 7 were transferred to the ICU due to disease progression, and 1 withdrew before completion of treatment.
Of the 172 people, 89 were in the azvudine group and 83 in the control group. The observation is similar to that of mild studies, except that RT-PCR positivity is prescribed as a CT value of ≤30.5 in moderate studies, which is different from the CT value of ≤37 in mild studies.
The primary endpoint results of the study showed that there was a statistically significant difference between the two groups with an azvudine score of 0.02±0.15 at discharge and 0.11±0.31 in the control group (P=0.024).
In terms of nucleic acid negative time, compared with the placebo group, the first negative time (6.24 VS 7.94 days, P=0.002) and the second nucleic acid negative time (7.73 VS 8.89 days, p=0.028) were significantly shortened in the azvudine group.
Source: Reference 3
The paper has not been officially published, what should be paid attention to in clinical application?
After the above two articles were announced, they immediately attracted a lot of attention. Studies have shown some effectiveness of azvudine, but there are still voices pointing to possible shortcomings in the current two preprint papers.
First, as a phase III clinical study, the number of trials included in azvudine was relatively small, with only 281 people in the mild group and 172 people in the moderate group. In contrast, another domestic new crown drug, also an RdRp inhibitor, recently announced a head-to-head trial, in which 822 people were enrolled.
Second, the study of azvudine in patients with mild disease did not actually meet the primary endpoint. In the primary endpoint of the study in patients with moderate disease, the scores that produced significant differences were accurate to two decimal places (azvudine score 0.02±0.15 at discharge and 0.11±0.31 in the control group), while the WHO Clinical Progress Scale referenced by the study was scored in whole numbers, and the paper did not specify the criteria for detailed scoring; The WHO Clinical Scale has a minimum score of 0, but there is a negative number in the patient score based on the variance of the paper.
In addition, as preprint papers, both articles have some details that need to be improved. For example, the nucleic acid conversion time of infected people, the mild disease paper specifies the number of days as the average, but the medium disease paper does not elaborate on this; For example, the criteria for determining nucleic acid positivity in the two articles are also different, with a CT value of ≤30.5 for the middle case and a CT value of ≤37 for mild cases, but the paper does not explain this.
Source: Visual China
On January 8, 2023, the National Health Insurance Administration announced that azvudine successfully participated in the negotiation of the medical insurance drug list as a new crown treatment drug.
"In the past week, there have been many clinical applications of azvudine." Xia Yu, pharmacist in charge of the pharmacy department of Peking University People's Hospital, said. As a prescription drug that is conditionally approved for marketing, the indications on the label of Azvudine are aimed at "adult patients with common new coronary pneumonia".
"The concept of the ordinary type is based on the ninth version of the diagnosis and treatment plan." Xia Yu mentioned that in the latest tenth edition of the diagnosis and treatment plan, there is no expression of ordinary type, which is divided into light, medium, heavy and critical. "Patients who used to be ordinary now compare with what type are now looking forward to seeing that the instructions can be adjusted as soon as possible to provide guidance for clinical medication."
Source: Medication Assistant
In terms of specific applications, Xia Yu said, "Many hospitals are generally for high-risk groups such as the elderly, and if the risk of turning to severe disease is relatively high, some doctors will use azvudine when the disease is mild or asymptomatic, and some hospital ICUs will also use it."
Xia Yu introduced that in addition to the doctor's initiative to prescribe, there are also some patients who have purchased azvudine through various channels to consult. "Azvudine is now easier to prescribe in the outpatient clinic, and some online pharmacies also sell it, so there are patients who bring medicine to consult how to eat, which to a certain extent also forces doctors to take the initiative to learn."
Liu Zhihai, deputy director of the emergency department of the First Hospital of Zhejiang University, said that at present, his hospital has less application of azvudine. "From the direct clinical feedback, doctors may have more concerns when using it."
Previously, Cao Bin, chairman-elect of the Respiratory Disease Branch of the Chinese Medical Association and vice president of China-Japan Hospital, said when sharing the "progress of drug treatment of new crown infection", "the mechanism of action of azvudine is not particularly clear, and the results of clinical research have not yet been published", which requires attention to the clinical evidence chain.
On January 5, the Beijing Pharmaceutical Quality Control and Improvement Center issued a medication warning for new crown treatment drugs such as azvudine. The use of azvudine in pregnant and lactating patients is not recommended, with caution in patients with a history of severe renal insufficiency, moderate to severe hepatic insufficiency and pancreatitis, while noting that the drug has not been studied in elderly patients and children.
Interactions with drugs such as P-gp substrates (e.g., digoxin), P-gp inhibitors (e.g., cyclosporine, clarithromycin, grapefruit juice), and P-gp inducers (e.g., rifampicin) should also be noted.
Source: People's Daily Health Client
Previously, on December 19, 2022, the Henan Pharmaceutical Association issued the "Henan Pharmaceutical Expert Consensus on the Treatment of Novel Coronavirus Pneumonia by Azvudine", which is also not recommended for pregnant women, lactating women and children.
Source: People's Daily Health Client
Xia Yu also pointed out that azvudine needs to pay attention to reproductive toxicity. "The current research is still unclear whether recent pregnancy has an impact, and it is difficult for doctors to give specific clinical recommendations, such as whether it is possible to be pregnant after 3 months after taking it? What about 6 months?"
According to the technical review report of the drug evaluation center of the National Medical Products Administration on the marketing application of azvudine in June 2022, the drug has "positive results of Ames test, CHL chromosomal aberration test and in vivo mouse micronucleus test" in terms of genotoxicity, which means that azvudine has the ability to mutate the genetic material in cells, resulting in potential carcinogenicity and teratogenicity; In terms of reproductive toxicity, azvudine in rat and rabbit trials showed the effects of fertility decline and the potential risk of embryonic development.
In the recently published Azvudine study paper, the inclusion criteria also excluded pregnant women or women who were breastfeeding or may have had a family plan during the trial and up to 6 months after the trial ended.
"In terms of reproductive toxicity, we still don't know how well azvudine's tissue distribution is enriched in semen? How does it affect eggs and sperm? These issues require constant attention." Xia Yu said.
Currently, there are 5 coronavirus-related studies registered for azvudine, 2 of which are recruited.
"Azvudine is a class 1.1 new drug in China, and the data is currently only available in China. At present, drug interactions are mainly based on speculation, and it is difficult for clinicians to judge when to strengthen monitoring and when to stop using it, and many outpatient patients also have different perceptions of the instructions." Xia Yu said.
"I hope that more research data will be released soon, and drug databases and query tools will be established to provide clinicians with clearer medication guidance." (Curator: z_popeye| Executive Producer: Gyouza)
Acknowledgements: This article has been professionally reviewed by Zhou Yebin, a doctor of genetics and a pharmaceutical company R&D scientist
Source: Visual China
Resources:
[1]https://www.who.int/docs/default-source/documents/emergencies/minimalcoreoutcomemeasure.pdf
[2]https://www.researchsquare.com/article/rs-2273694/v1
[3]https://www.researchsquare.com/article/rs-2273657/v1
[4]https://file.wuxuwang.com/zhuce/ssypfiles/e5d36909ee1240d2e86b0c3a15e0ac29%E4%B8%8A%E5%B8%82%E5%AE%A1%E8%AF%84%E6%8A%A5%E5%91%8A.pdf