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🌏 | Pfizer, US, launches large-scale clinical trial of new oral corona preventive drug


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US Pfizer launches large-scale clinical trial of oral new corona prophylaxis

 
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At present, Gilead Sciences' IV drug "Remdesivir" is the only antiviral drug approved in the United States for the new corona.
 

[Reuters] – US Pharmaceutical Pfizer is developing on the XNUMXth to prevent infection with the new coronavirus ... → Continue reading

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US Pharmaceutical Gilead Sciences

Rem decivil

Rem decivil(British: redevive,: Red Sive,Development code:GS 5734, Product name: Veklury) is a new nucleotide analogProdrugso,Antiviral drug.Gilead SciencesDeveloped byEbolaas well as the Marburg virusInfection[1]Not only as a remedy for single-stranded RNA virus (RS virus,Junin virus,Lassa fever virus,Nipah virus,Hendra virus,MERSandSARSContains virusCoronavirus) Was found to show antiviral activity[2].

By follow-up2019 New Coronavirus Multiple coronaviruses including (SARS-CoV-2, 2019-nCoV)[3][4]And antiviral activity in Nipah virus and Hendra virus infections revealed[5][6].

GS 441524ThingsPhosphoramidateIt is a monophosphoramidate prodrug.

back ground 

August 2015, 10,United States Army Medical Research Institute for Infectious Diseases(USAMRIID) contains compound GS-5734Rhesus monkeyAnnounced preclinical results that it suppressed the Ebola virus.West African Ebola virus epidemicLasted from 2013 to 2016.

Travis Warren, who has been a senior researcher at USAMRIID since 2007, said, "This study is called USAMRIID.Gilead SciencesIt is the result of continued cooperation with. "[7].."Initial screening" using the "Gilead Sciences Compound Library" to find molecules with the desired antiviral activityCenter for Disease Control and PreventionMade by (CDC) scientists[7].

As a result of the research, GS-5734 was recommended that "development as a potential therapeutic drug should be continued", and from October 2015 to 10, 7.(English: San Diego Convention CenterHeld at(English: Infectious Diseases Society of AmericaAnnounced at the (IDSA) Annual ID Week Conference[7].

Ebola researchUnited States Department of DefenseWithin the organization ofBiosafety levelConducted at the USAMRIID Institute, the highest containment facility with a maximum of 4[7]..This studyDefense Threat Reduction AgencyAnd is funded by the Department of Defense Joint Project Management Office for Healthcare Systems[7].

Effect

At the laboratory level, remdesivir has been suggested to be effective against a wide range of viruses, including SARS-CoV and MERS-CoV.This drug is from 2013 to 2016West African Ebola virus epidemicPromoted to treat infections in.It turned out to be safe,Ebola virusIt was not very effective against.

Ebola virus

Remdesivir due to West African Ebola virus epidemic 2013-2016Clinical trialWas rapidly advanced and was administered to at least one human patient, despite its early development stage at the time.Preliminary results are promising and were used until August 1, along with hospital trials, during the Ebola epidemic emergency in North Kivu, Democratic Republic of the Congo, which began in 2018.According to Congolese health officialsMonoclonal antibodyIts effectiveness was significantly lower than that of treatments (such as mAb114 and REGN-EB3).However, this study administration established a safety profile.[8][9][10][11][12][13][14].

Other viruses

The active form of remdesivir, GS-441524, is promising for the treatment of feline coronavirus.[15].

Research case

Application to 2019 new coronavirus

May 2020, 5 in the United StatesUsing CompassionateIt is a new drug that has been approved, and in Japan, it will be officially officially approved on May 2020, 5 using the "special approval system".New coronavirus infection Approved for the first time in the world as a therapeutic drug for (COVID-19)[16][17][18].Intravenous injectionAdminister for up to 10 days[17][19].

2019 Caused by the new coronavirus (SARS-CoV-2)Epidemic of new coronavirus infectionCorresponding toGileadProvided remdesivir to "a small number of patients" to work with Chinese medical institutions to study its effects[20]..Gilead has also begun clinical testing of remdesivir for the new coronavirus infection.Gilead is RemdesivirSARSandMERS"Shown to be active" in animal studies.[21].

Unapproved drug in the first U.S. patient confirmed to be infected with the new coronavirus in late January 2020Using Compassionate[22]Was administered as.It was given after the patient had progressed to pneumonia, but the patient's condition improved dramatically the next day.[23], Finally discharged[24]..However, it cannot be clearly demonstrated whether this rapid recovery is due to the effects of the drug.

In late January, Chinese medical researchers conducted an exploratory study considering the selection of 1 drug candidates, three of which, remdesivir.Chloroquine,Lopinavir / RitonavirAnnounced to the press that "fairly good inhibitory effects" against the new coronavirus at the cellular level.[25].

March 2NatureIs a sister magazine ofCell ResearchTo the Chinese Academy of SciencesWuhan Institute of VaseAccording to a letter (flash paper) published by a research group such asvitro Standard cells of African green monkey origin under (in vitro) environment Vero E6 cellsThe antiviral effect of 7 substances including remdesivir against the new coronavirus is 50% effective concentration (EC50When a test was conducted to evaluate based on (value), the EC of remdesivir50The value was 0.77 μM (μmol / L), which was the most effective of the seven substances tested.[26].

Remdesivir clinical trials began in China on February 2[27].

Dated February 2Technology Daily(Published by: Ministry of Science and Technology of the People's Republic of China), based on the results of the above in vitro test, in addition to remdesivir,Fabipira BuildingAnnounced that it has started clinical trials of chloroquine[28][29].

On March 3, "The COVID-12 Investigation Team," a cross-sectional research team consisting of multiple researchers from the United States,medRxiVNot posted on the preprint serverPeer reviewAccording to the paper, from January 1th to February 20thCenter for Disease Control and Prevention They gathered information about the first 12 patients in the United States who were confirmed to be infected with the new coronavirus by (CDC), and found that 12 of the 7 patients received inpatient treatment, and this Remdesivir was administered to 3 of them.The researchers say that the therapeutic effect of remdesivir cannot be evaluated because it was not given in a controlled, random-controlled trial.Regarding the side effects of remdesivir, all 3 treated patients, including 7 patients who received it, show liver damage.Transaminase(Amino transfer,ASTandOTHER), But no conclusions have been reached regarding the causal relationship between this and remdesivir (only 3 in 1 people is likely to have a causal relationship from the graph).[30].. US investment information company dated March 3 The Motley Fool According to a report by investigator Cory Renauer, if the elevated blood levels of liver enzymes mentioned in this unpeer-reviewed paper are a side effect of remdesivir, they are serious enough to hold the breath of remdesivir. It is said that it is a problem.However, according to Renauer, it is premature to determine that it is a side effect of remdesivir because the remdesivir group and the other patient groups were not completely randomly assigned in this clinical trial. Is[31].

April 4, medical journalNew England Journal of Medicine "Compassionate Use of Remdesivir for Patients with Severe Covid-19", published in (NEJM), jointly written by researchers from various countries who conducted clinical research on remdesivir funded by Gilead.[32]According to Remdesivir for patients with severe corona pneumoniaCompassionate YouthAccording to data from clinical trials in Japan, 53 (36%) of the 64 patients showed improvement in respiratory function. Of the 53 critically ill patientsExtracorporeal membrane oxygenator (ECMO) orNegative pressure ventilatorThere were 34 users and 19 others.The standard dosage and administration was 200 mg on the first day and 1 mg daily thereafter for 100 days by intravenous drip infusion.The findings regarding improvement focused only on respiratory function, and did not mention improvement of chest X-ray imagery or PCR negative conversion.This clinical trial is for compassionate use onlyDouble blindRandomly administered group and control group (PlaceboAlthough it is not a rigorous control study to set up), it is mentioned that such control studies are currently underway in several countries and more rigorous evidence will be provided in the near future. Paper published on March 3 (mentioned above)[30]However, the increased blood levels of liver enzymes (ALT, AST), which indicate liver damage, were also mentioned in 53 of 12 patients (23%) in this study.Including this, 53 of 32 patients (60%) had some side effects.

April 4, US medical information reporting site STAT Reported that Gilead's draft report of a random sampling of remdesivir initial clinical trials in China was erroneously conducted.who It was posted on the (WHO) website and was quickly removed, but STAT staff noticed the posting and saved the image.According to this draft, of the 237 patients with corona pneumonia, 158 were in the remdesivir group and 79 were in the control group (PlaceboThe mortality rate was 13.9% in the remdesivir-administered group and 12.8% in the control group, and no significant difference was observed.[33].. Same day,Financial TimesReported that the initial clinical trial of remdesivir had failed due to the contents of the deleted draft, and the stock price of the manufacturer Gilead fell by about 6%.The Gilead side argued that the draft was based on a clinical trial with few subjects and the results were uncertain.[34].

On April 4, Gilead reported in a press release the usefulness of remdesivir. In the ACTT-30 trial, remdesivir reduced recovery time compared to placebo (1 vs 11 days)[35]Also tended to improve mortality on day 14 (7.1% vs 11.9%)[36]..In the SIMPLE study, 5-day and 10-day administration of remdesivir was compared, and there was no significant difference in efficacy.[37].

On May 5, the supply to medical sites in Japan started.(I.e.Minister of Health, Labour and WelfareWas announced by.

On June 6, Gilead announced that it would set a price for governments of developed countries with public insurance at $ 29 per patient.[38].. The drug price per bottle is $ 1, and the standard treatment is 390 bottles in 5 days.[38]..In the U.S. this pricing was rated relatively cheap[38].. In Veklury's patent application, in addition to 100 mg of remdesivir, sulfobutyl ether-β-cyclodextrin (trade name: Captisol or Dexolve) manufactured by Ligand Pharmaceuticals (San Diego, USA) or CycloLab Cyclodextrin R & D Laboratory Ltd. (Budapest, Hungary) ) Is used as a solubilizer in 3.0 g or 6.0 g.[39].

On October 10, WHO announced preliminary findings that remdesivir was ineffective against the new coronavirus as a result of a large clinical trial.[40]On November 11, it was recommended not to use it for patients with new coronavirus due to concerns about side effects and burden on medical practice.[41]..The Ministry of Health, Labor and Welfare is not considering revoking the special approval at this time, and according to the Ministry of Health, Labor and Welfare's "Medical Care Guide", it is supposed to be administered to critically ill patients in principle. Consider adding[42].

On December 12, former New York City Mayor Giuliani, who had the virus, announced that he had relieved in Remdesivir and returned to work.

Mechanism of action

Remdesivir is metabolized in the body to its active form, GS-441524 triphosphate. GS-441524 Triphosphate is a virusRNA polymeraseIt is an adenosine nucleotide analog (similar to the nucleic acid molecule adenosine) that confuses and interferes with viral exonuclease (ExoN) goog calibration (correcting to the correct base sequence), causing a decrease in viral RNA production. It is unclear whether it will terminate RNA strand synthesis or cause mutations.[43].

Mouse hepatitis virus that causes partial resistanceRNA replicaseMutation was confirmed in 2018.Researchers believe that these mutated viruses will weaken their vitality and fail to survive in a drug-free natural environment.[43].

footnote

  1. ^ “Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys”. Nature 531 (7594): 381–5. (March 2016). bibcode2016Natur.531..381W. two:10.1038 / nature17180. PMC 5551389. PMID 26934220. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551389/. 
  2. ^ “GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses”. Scientific Reports 7 (1): 43395. (March 2017). bibcode2017 NatSR ... 743395L. two:10.1038 / srep43395. PMC 5338263. PMID 28262699. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338263/. 
  3. ^ “Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses”. Science Translational Medicine 9 (396): eaal3653. (June 2017). two:10.1126 / scitranslmed.aal3653. PMC 5567817. PMID 28659436. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567817/. 
  4. ^ Baumann (January 2020, 1). “Coronavirus Vaccine Candidate Eyed for Human Trials by April". Blumberg Law. October 2020th, 1Browse.
  5. ^ "Experimental Ebola drug'remdesivir' may help protect against Nipah virus, say scientists". Times Now Digital (September 2019, 6). October 2020th, 2Browse.
  6. ^ "Scientists Claim Drug Designed to Beat Ebola Also Fights Off Nipah". The Wire (September 2019, 6). October 2020th, 2Browse.
  7. ^ a b c d e "Antiviral Compound Provides Full Protection from Ebola Virus in Nonhuman Primates". United States Army Medical Research Institute for Infectious Diseases (USAMRIID) (San Diego, California). (9 October 2015). http://www.usamriid.army.mil/press_releases/Travis%20ID%20Week%20FINAL.pdf October 2020th, 4Browse.. 
  8. ^ Preidt (June 2017, 6). “Experimental Drug Shows Promise Against Dangerous Viruses: Medicine worked in lab tests against germs that cause SARS and MERS infections”. As of May 2017, 7オ リ ジ ナ ルMore archives.October 2020th, 2Browse.
  9. ^ “Nucleotide Prodrug GS-5734 Is a Broad-Spectrum Filovirus Inhibitor That Provides Complete Therapeutic Protection Against the Development of Ebola Virus Disease (EVD) in Infected Non-human Primates”. Open Forum Infect Dis 2. (Fall 2015). two:10.1093 / ofid / ofv130.02. 
  10. ^ “Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys”. Nature 531 (7594): 381–5. (March 2016). bibcode2016Natur.531..381W. two:10.1038 / nature17180. PMC 5551389. PMID 26934220. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551389/. 
  11. ^ “Late Ebola virus relapse causing meningoencephalitis: a case report”. Lancet 388 (10043): 498–503. (July 2016). two:10.1016 / S0140-6736 (16) 30386-5. PMC 4967715. PMID 27209148. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967715/. 
  12. ^ "Ebola Treatment Trials Launched In Democratic Republic Of The Congo Amid Outbreak" (English). NPR.org. October 2019th, 5Browse.
  13. ^ (September 2019, 8). “A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo”. The New York Times. https://www.nytimes.com/2019/08/12/health/ebola-outbreak-cure.html October 2019th, 8Browse. 
  14. ^ Molteni, Megan (August 2019, 8). “Ebola is Now Curable. Here's How The New Treatments Work”. Wired. https://www.wired.com/story/ebola-is-now-curable-heres-how-the-new-treatments-work/ October 2019th, 8Browse. 
  15. ^ “Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis”. Journal of Feline Medicine and Surgery 21 (4): 271–281. (April 2019). two:10.1177 / 1098612X19825701. PMC 6435921. PMID 30755068. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435921/. 
  16. ^ "Corona treatment, certain effect on remdesivir ... Japan approved in early May: Medical / Health”(Japanese). Yomiuri Shimbun Online (September 2020, 4). October 2020th, 4Browse.
  17. ^ a b "Start of procedure for special approval of "Remdesivir" Expected to be effective for new corona”(Japanese). NHK web (September 2020, 5). October 2020th, 5Browse.
  18. ^ "Approved Remdesivir Japan's first new corona treatment (photo = Reuters)”(Japanese). Nikkei newspaper electronic version. October 2020th, 5Browse.
  19. ^ “Remdesivir approved as a COVID-19 treatment in Japan”Nikkei Newspaper. (May 2020, 5). https://medical.nikkeibp.co.jp/leaf/mem/pub/report/t344/202005/565472.html October 2020th, 5Browse. 
  20. ^ "Gilead mulls repositioning failed Ebola drug in China virus”. Fierce Biotech. October 2020th, 1Browse.
  21. ^ Joseph, Saumya Sibi; Samuel, Maju (January 2020, 1). “Gilead working with China to test Ebola drug as new coronavirus treatment”. Thomson Reuters. https://www.reuters.com/article/us-health-china-gilead-sciences/gilead-working-with-china-to-test-ebola-drug-as-new-coronavirus-treatment-idUSKBN1ZU2RX October 2020th, 1Browse. 
  22. ^ "Compassionate Youth --Glossary of Pharmacy Terminology --The Pharmaceutical Society of Japan". www.pharm.or.jp. October 2020th, 2Browse.
  23. ^ “First Case of 2019 Novel Coronavirus in the United States”. The New England Journal of Medicine 0. (January 2020). two:10.1056 / NEJMoa2001191. PMID 32004427. 
  24. ^ Harmon, Amy (February 2020, 2). “Inside the Race to Contain America's First Coronavirus Case” (English). The New York Times. ISSN 0362 4331. https://www.nytimes.com/2020/02/05/us/corona-virus-washington-state.html October 2020th, 2Browse. 
  25. ^ "Three drugs fairly effective on novel coronavirus at cellular level”(May 2020, 1). October 2020th, 2Browse.
  26. ^ "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro”. Nature (February 2020, 2). October 2020th, 2Browse.
  27. ^ Grady, Denise (February 2020, 2). “China Begins Testing an Antiviral Drug in Coronavirus Patients” (English). The New York Times. ISSN 0362 4331. https://www.nytimes.com/2020/02/06/health/coronavirus-treatments.html October 2020th, 2Browse. 
  28. ^ "Good news!Partial drug such as chloroquine, first step, good indication, chloroquine effect". Science and Technology Daily Reporter 丽 丽 刘 垠Ministry of Science and Technology, People's Republic of China (February 2020, 2). October 2020th, 2Browse.
  29. ^ Remdesivir, etc. Remdesivir, etc. (Chinese) Sina October 2020th, 2
  30. ^ a b “First 12 patients with coronavirus disease 2019 (COVID-19) in the United States”. medRxiV. (2020-03-12). two:10.1101/2020.03.09.20032896. https://www.medrxiv.org/content/10.1101/2020.03.09.20032896v1.full.pdf. 
  31. ^ “Early Results Dampen Outlook for Experimental COVID-19 Treatment”. The Motley Fool. (March 2020, 3). https://www.fool.com/investing/2020/03/14/early-results-dampen-outlook-for-experimental-covi.aspx October 2020th, 3Browse. 
  32. ^ “Compassionate Use of Remdesivir for Patients with Severe Covid-19”. The New England Journal of Medicine. (2020-04-10). two:10.1056 / NEJMoa2007016. https://www.nejm.org/doi/full/10.1056/NEJMoa2007016. 
  33. ^ “New data on Gilead's remdesivir, released by accident, show no benefit for coronavirus patients. Company still sees reason for hope”. STAT (USA). (April 2020, 4). https://www.statnews.com/2020/04/23/data-on-gileads-remdesivir-released-by-accident-show-no-benefit-for-coronavirus-patients/ October 2020th, 4Browse. 
  34. ^ "Gilead reports failure of new corona drug test WHO erroneously discloses information”. Reuters (June 2020, 4). October 2020th, 4Browse.
  35. ^ “Two potential therapies for covid-19 have some effect”. Economist (UK). (May 2020, 5). https://www.economist.com/science-and-technology/2020/05/09/two-potential-therapies-for-covid-19-have-some-effect October 2020th, 10Browse. 
  36. ^ Beigel, John H .; Tomashek, Kay M .; Dodd, Lori E .; Mehta, Aneesh K .; Zingman, Barry S .; Kalil, Andre C .; Hohmann, Elizabeth; Chu, Helen Y. et al. (2020) -05-22). “Remdesivir for the Treatment of Covid-19 — Preliminary Report”. New England Journal of Medicine 0 (0): null. two:10.1056 / NEJMoa2007764. ISSN 0028 4793. https://doi.org/10.1056/NEJMoa2007764. 
  37. ^ Goldman, Jason D .; Lye, David CB; Hui, David S .; Marks, Kristen M .; Bruno, Raffaele; Montejano, Rocio; Spinner, Christoph D .; Galli, Massimo et al. (2020-05-27) .. “Remdesivir for 5 or 10 Days in Patients with Severe Covid-19”. New England Journal of Medicine 0 (0): null. two:10.1056 / NEJMoa2015301. ISSN 0028 4793. https://doi.org/10.1056/NEJMoa2015301. 
  38. ^ a b c "Remdesivir 1 yen per person Corona drug, Gilead priced"Nikkei Newspaper. (May 2020, 6). https://www.nikkei.com/article/DGXMZO60952950Q0A630C2000000/ October 2020th, 7Browse. 
  39. ^ [1], Larson, Nate, "Compositions Comprising an Rna Polymerase Inhibitor and Cyclodextrin for Treating Viral Infections" 
  40. ^ "XNUMX drugs such as remdesivir have no effect-For corona inpatients-WHO". Current affairs dot com (September 2020, 10). October 2020th, 11Browse.
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  42. ^ "Remdesivir, WHO" does not recommend without therapeutic effect "... Ministry of Health, Labor and Welfare does not change administration policy"Yomiuri Shimbun. (August 2020, 11). https://www.yomiuri.co.jp/medical/20201120-OYT1T50122/ October 2020th, 11Browse. 
  43. ^ a b “Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease”. mBio 9 (2). (March 2018). two:10.1128 / mBio.00221-18. PMC 5844999. PMID 29511076. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844999/. 

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An antiviral drug classified as a nucleoside analog by adenosine analog

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