Continued from my blog post on 27th May.
8. Umifenovir
Umifenovir (Arbidol, Pharmstandard Group, Moscow, Russia) is a broad-spectrum antiviral drug similar to favipiravir, and has shown efficacy in Russia and China in the prophylactic (prevention) or treatment of infection by influenza viruses.1,2 It is a viral entry inhibitor, working by interacting with the virus hemagglutinin and thus preventing fusion of the viral envelope with the target human cell membranes. The molecule also affects other stages of the virus life cycle, either by direct targeting viral proteins or virus-associated host factors.3 The drug is licensed only in China and Russia; it is not approved for use in other countries. It is not in the US FDA's list of approved drugs for prevention of influenza.4
Since 2004, umifenovir has been patented for its medicinal use as an antiviral agent against atypical pneumonia induced by SARS-CoV.3 An in vitro study showed that umifenovir efficiently inhibited SARS-CoV-2 infection with 50% maximal effective concentration (EC50) of 4.11uM, which is within the range of safe clinical dose.5 However, the drug is less effective than favipiravir in a comparative study on COVID-19 patients. The seven-day recovery rate for the umifenovir group was significantly lower than that for the favipiravir group (55.86% vs 71.43%, p= 0.0199). Patients with hypertension or diabetes also showed better improvement in the favipiravir group than in the umifenovir group.6
Umifenovir has recently been added to the Guidelines for the Diagnosis and Treatment of COVID-19 (sixth and seventh editions) in China. Many phase 4 clinical trials, mainly performed in China, are currently running for umifenovir in the treatment of COVID-19.7,8,9
9. Remdesivir
Remdesivir (GS-5734) was developed by Gilead Sciences Inc. It is an adenosine analogue. It shuts down viral replication by inhibiting RNA-dependent RNA polymerase, and blocks the virus from making its genetic material. Research on the drug began in 2009 and antiviral profiling of the drug suggested it has the potential of a broad spectrum of antiviral activity. Before the outbreak of COVID-19, it was still an investigational product and had not been approved anywhere globally. Its safety and efficacy for any use had not been determined.10
The drug was first used to combat Ebola and related viruses but did not show effectiveness. In 2017, researchers at the University of North Carolina showed in in vitro and animal studies that the drug can inhibit the coronaviruses that cause SARS and MERS.11 Promising results suggested it may have some effect in patients infected with SARS-CoV-2.
Remdesivir was given to the first COVID-19 patient diagnosed in the United States when his condition worsened. The man improved the next day.12 A double-blind, randomized, placebo-controlled trial including 1,063 patients in hospitals around the world indicated that the drug shortened the length of illness from 15 days to 11 days.13
Gilead has initiated its own two phase 3 studies of the drug.10 Moreover, the drug is one of the candidates in WHO's megatrial SOLIDARITY and in the INSERM-sponsored DisCoVeRy trial in Europe.14,15
The Department of Health and Social Care has approved the drug as the first medicine to treat COVID-19 in the UK. It is likely that those patients with the most severe cases of the disease will have priority in receiving the drug treatment. However, there is a concern over the side effects related to the liver and kidneys. Moreover, whether the manufacturer can provide enough supply for the exponential demand of the drug is another concern.16 Outisde the UK, the US and Japan are also using this drug to treat COVID-19 patients.17,18
10. Sarilumab (Immune system inhibitors, anti-inflammatory drug)
Sarilumab (Kevzara®, Sanofi, New York, NY, USA and Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA) is approved for the treatment of rheumatoid arthritis in multiple countries. It is an antibody against the interleukin 6 (IL-6) receptor and can effectively block IL-6 signal transduction. IL-6 is one of the excessive cytokines produced as a result of COVID-19 infection and causes lung inflammation.19
A single group study of another IL-6 inhibitor similar to sarilumab, tocilizumab, with 21 severe, febrile hospitalized COVID-19 patients, showed fever returned to normal and improved oxygenation upon tocilizumab treatment.20
Based on the above findings, the two developers of sarilumab, Sanofi and Regeneron, are in partnership with Northwell Health's Feinstein Institutes for Medical Research, to evaluate the effects of sarilumab on fever and the need for supplemental oxygen in a phase 2/3 trial. Preliminary analysis showed that sarilumab, similar to tocilizumab, rapidly lowered C-reactive protein, a key marker of inflammation.20,21 However, sarilumab did not show notable clinical benefit versus placebo when combining the severe group (patients who required oxygen supplementation without mechanical or high-flow oxygenation) and the critical group (patients who required mechanical ventilation or high-flow oxygenation or required treatment in an intensive care unit). On the other hand, positive trends were reported for all outcomes in the critical group. They have now set a phase 3 trial with two amendments so that only the more advanced critical patients continue to be enrolled to receive treatment, and all new patients are to receive either higher-dose Kevzara or placebo.21
11. Colchicine
Colchicine is an anti-inflammatory drug used for rheumatic and non-rheumatic diseases such as gout, familial Mediterranean fever, and pericarditis (a condition in which the sac around the heart becomes inflamed).22 Colchicine prevents microtubule assembly and disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of cytokines, phagocytosis, and migration of neutrophils.23
Due to its ability to suppress the generation of cytokines, it has been suggested that colchicine may be effective in relieving cytokine storm seen during SARS-CoV-2 infection. The drug thus has been widely tested in clinical trials in the world for its efficiency in severe COVID-19 patients of different levels.24-26
However, there is a concern of causing of acute respiratory distress syndrome and multi-organ failure, the two common causes of death in COVID-19 patients, if an inappropriate dose of colchicine is used.27,28
2. M.Z. Wang, B.Q. Cai, L.Y. Li, J.T. Lin, et al. Efficacy and safety of arbidol in treatment of naturally acquired influenza. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2004;26:289-293. (Article in Chinese, abstract available in English)
3. J. Blaising, S.J. Polyak, & E.I. Pecheur. Arbidol as a broad-spectrum antiviral: an update. Antivir. Res. 107, 84-94 (2014). 4. "FDA approved drugs for influenza" https://www.fda.gov/drugs/information-drug-class/influenza-flu-antiviral-drugs-and-related-information#ApprovedDrugs
5. X. Wang, R. Cao, H. Zhang, et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discovery, 6, Article number: 28 (2020).
6. C. Chen, Y. Zhang, J. Huang J, et al. Favipiravir versus arbidol for COVID-19: A randomized clinical trial. MedRxiv preprint doi: https://doi.org/10.1101/2020.03.17.20037432 this version posted April 15, 2020.
7. "Clinical study of Arbidol hydrochloride tablets in the treatment of pneumonia caused by novel coronavirus." ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04260594
8. "A prospective, randomized controlled clinical study of antiviral therapy in the 2019-nCoV pneumonia." ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04255017
9. "The clinical study of carrimycin on treatment patients with Covid-19." ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04286503
10. "Development of Remdesivir" https://www.gilead.com/-/media/gilead-corporate/files/pdfs/covid-19/gilead_rdv-development-fact-sheet-2020.pdf
11. T.P. Sheahan, A.C. Sims, R.L. Graham, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine. Vol. 9, Issue396, eaal3653.
12. M.L. Holshue, C. DeBolt, S. Lindquist, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382:929-936.
13. J.H. Beigel, K.M. Tomashek, L.E. Dodd, et al. Remdesivir for the treatment of Covid-19 - preliminary report. NEJM. 2020 May 22;NEJMoa2007764. doi: 10.1056/NEJMoa2007764.
14. ""Solidarity" clinical trial for COVID-19 treatments" WHO. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
15."Launch of a European clinical trial against COVID-19" https://presse.inserm.fr/en/launch-of-a-european-clinical-trial-against-covid-19/38737/
16. "Gilead's virus drug seen in short supply for Americans" Bloomberg News. https://www.bloomberg.com/news/articles/2020-05-11/gilead-s-covid-19-drug-seen-in-short-supply-for-americans.
17. "Gilead's investigational antiviral Remdesivir receives U.S. Food and Drug Administration emergency use authorization for the treatment of COVID-19" https://www.gilead.com/news-and-press/press-room/press-releases/2020/5/gileads-investigational-antiviral-remdesivir-receives-us-food-and-drug-administration-emergency-use-authorization-for-the-treatment-of-covid19
18. "Gilead announces approval of Veklury® (remdesivir) in Japan for patients with severe COVID-19" https://www.gilead.com/news-and-press/press-room/press-releases/2020/5/gilead-announces-approval-of-veklury-remdesivir-in-japan-for-patients-with-severe-covid19
19. W. Ahsan, S. Javed, M.A. Bratty, et al. Treatment of SARS-CoV-2: How far have we reached? Review. Drug Discoveries & Therapeutics. 2020; 14(2):67-72.
20. X. Xu, M. Han, T. Li, et al. Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXiv. http://www.chinaxiv.org/abs/202003.00026
21. "Sanofi and Regeneron provide update on U.S. Phase 2/3 adaptive-designed trial in hospitalized COVID-19 patients" https://www.sanofi.com/en/media-room/press-releases/2020/2020-04-27-12-58-00
22. Y.Y. Leung, L.L.Y. Hui, and V.B. Kraus. Colchicine-update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum., 2015, 45:341-350.
23. N. Dalbeth, T.J. Lauterio, and H.R. Wolfe. Mechanism of action of colchicine in the treatment of gout. Clin Ther., 2014, 36:1465-1479.
24. "Could the ancient drug colchicine help fight COVID-19?" MedicineNet, 23rd April, 2020. https://www.medicinenet.com/script/main/art.asp?articlekey=230649
25. S.G. Deftereos, G. Siasos, G. Gianopouolos, et al. The Greek study in the effects of colchicine in COVID-19 complications prevention (GRECCO-19 Study): rationale and study design. Hellenic J Cardio. 2020 Apr 3;S1109-9666(20)30061-0. doi:10.1016/j.hjc.2020.03.002.
26. "The effects of standard protocol with or without colchicine in Covid-19 infection" (NCT04360980) https://clinicaltrials.gov/ct2/show/NCT04360980
27. M. Maurizi, N. Delorme, M.C. Laprévote-Heully, et al. Acute respiratory distress syndrome in adults in colchicine poisoning. Ann Fr Anesth Reanim., 1986, 5:530-532.
28. M.C.Cure, A. Kucuk, and E. Cure. Colchicine may not be effective in COVID-19 infection; it may even be harmful? Letter to the editor. Clinical Rheumatology, 2020. https://doi.org/10.1007/s10067-020-05144-x
8. Umifenovir
Umifenovir (Arbidol, Pharmstandard Group, Moscow, Russia) is a broad-spectrum antiviral drug similar to favipiravir, and has shown efficacy in Russia and China in the prophylactic (prevention) or treatment of infection by influenza viruses.1,2 It is a viral entry inhibitor, working by interacting with the virus hemagglutinin and thus preventing fusion of the viral envelope with the target human cell membranes. The molecule also affects other stages of the virus life cycle, either by direct targeting viral proteins or virus-associated host factors.3 The drug is licensed only in China and Russia; it is not approved for use in other countries. It is not in the US FDA's list of approved drugs for prevention of influenza.4
Since 2004, umifenovir has been patented for its medicinal use as an antiviral agent against atypical pneumonia induced by SARS-CoV.3 An in vitro study showed that umifenovir efficiently inhibited SARS-CoV-2 infection with 50% maximal effective concentration (EC50) of 4.11uM, which is within the range of safe clinical dose.5 However, the drug is less effective than favipiravir in a comparative study on COVID-19 patients. The seven-day recovery rate for the umifenovir group was significantly lower than that for the favipiravir group (55.86% vs 71.43%, p= 0.0199). Patients with hypertension or diabetes also showed better improvement in the favipiravir group than in the umifenovir group.6
Umifenovir has recently been added to the Guidelines for the Diagnosis and Treatment of COVID-19 (sixth and seventh editions) in China. Many phase 4 clinical trials, mainly performed in China, are currently running for umifenovir in the treatment of COVID-19.7,8,9
9. Remdesivir
Remdesivir (GS-5734) was developed by Gilead Sciences Inc. It is an adenosine analogue. It shuts down viral replication by inhibiting RNA-dependent RNA polymerase, and blocks the virus from making its genetic material. Research on the drug began in 2009 and antiviral profiling of the drug suggested it has the potential of a broad spectrum of antiviral activity. Before the outbreak of COVID-19, it was still an investigational product and had not been approved anywhere globally. Its safety and efficacy for any use had not been determined.10
The drug was first used to combat Ebola and related viruses but did not show effectiveness. In 2017, researchers at the University of North Carolina showed in in vitro and animal studies that the drug can inhibit the coronaviruses that cause SARS and MERS.11 Promising results suggested it may have some effect in patients infected with SARS-CoV-2.
Remdesivir was given to the first COVID-19 patient diagnosed in the United States when his condition worsened. The man improved the next day.12 A double-blind, randomized, placebo-controlled trial including 1,063 patients in hospitals around the world indicated that the drug shortened the length of illness from 15 days to 11 days.13
Gilead has initiated its own two phase 3 studies of the drug.10 Moreover, the drug is one of the candidates in WHO's megatrial SOLIDARITY and in the INSERM-sponsored DisCoVeRy trial in Europe.14,15
The Department of Health and Social Care has approved the drug as the first medicine to treat COVID-19 in the UK. It is likely that those patients with the most severe cases of the disease will have priority in receiving the drug treatment. However, there is a concern over the side effects related to the liver and kidneys. Moreover, whether the manufacturer can provide enough supply for the exponential demand of the drug is another concern.16 Outisde the UK, the US and Japan are also using this drug to treat COVID-19 patients.17,18
10. Sarilumab (Immune system inhibitors, anti-inflammatory drug)
Sarilumab (Kevzara®, Sanofi, New York, NY, USA and Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA) is approved for the treatment of rheumatoid arthritis in multiple countries. It is an antibody against the interleukin 6 (IL-6) receptor and can effectively block IL-6 signal transduction. IL-6 is one of the excessive cytokines produced as a result of COVID-19 infection and causes lung inflammation.19
A single group study of another IL-6 inhibitor similar to sarilumab, tocilizumab, with 21 severe, febrile hospitalized COVID-19 patients, showed fever returned to normal and improved oxygenation upon tocilizumab treatment.20
Based on the above findings, the two developers of sarilumab, Sanofi and Regeneron, are in partnership with Northwell Health's Feinstein Institutes for Medical Research, to evaluate the effects of sarilumab on fever and the need for supplemental oxygen in a phase 2/3 trial. Preliminary analysis showed that sarilumab, similar to tocilizumab, rapidly lowered C-reactive protein, a key marker of inflammation.20,21 However, sarilumab did not show notable clinical benefit versus placebo when combining the severe group (patients who required oxygen supplementation without mechanical or high-flow oxygenation) and the critical group (patients who required mechanical ventilation or high-flow oxygenation or required treatment in an intensive care unit). On the other hand, positive trends were reported for all outcomes in the critical group. They have now set a phase 3 trial with two amendments so that only the more advanced critical patients continue to be enrolled to receive treatment, and all new patients are to receive either higher-dose Kevzara or placebo.21
11. Colchicine
Colchicine is an anti-inflammatory drug used for rheumatic and non-rheumatic diseases such as gout, familial Mediterranean fever, and pericarditis (a condition in which the sac around the heart becomes inflamed).22 Colchicine prevents microtubule assembly and disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of cytokines, phagocytosis, and migration of neutrophils.23
Due to its ability to suppress the generation of cytokines, it has been suggested that colchicine may be effective in relieving cytokine storm seen during SARS-CoV-2 infection. The drug thus has been widely tested in clinical trials in the world for its efficiency in severe COVID-19 patients of different levels.24-26
However, there is a concern of causing of acute respiratory distress syndrome and multi-organ failure, the two common causes of death in COVID-19 patients, if an inappropriate dose of colchicine is used.27,28
References
1. V.M. Gagarinova, G.S. Ignat'eva, L.V. Sinitskaia, et al. The new chemical preparation arbidol: its prophylactic efficacy during influenza epidemics. Zh. Mikrobiol. Epidemiol. Immunobiol. 1993;5:40-43. (Article in Russian, abstract available in English)2. M.Z. Wang, B.Q. Cai, L.Y. Li, J.T. Lin, et al. Efficacy and safety of arbidol in treatment of naturally acquired influenza. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2004;26:289-293. (Article in Chinese, abstract available in English)
3. J. Blaising, S.J. Polyak, & E.I. Pecheur. Arbidol as a broad-spectrum antiviral: an update. Antivir. Res. 107, 84-94 (2014). 4. "FDA approved drugs for influenza" https://www.fda.gov/drugs/information-drug-class/influenza-flu-antiviral-drugs-and-related-information#ApprovedDrugs
5. X. Wang, R. Cao, H. Zhang, et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discovery, 6, Article number: 28 (2020).
6. C. Chen, Y. Zhang, J. Huang J, et al. Favipiravir versus arbidol for COVID-19: A randomized clinical trial. MedRxiv preprint doi: https://doi.org/10.1101/2020.03.17.20037432 this version posted April 15, 2020.
7. "Clinical study of Arbidol hydrochloride tablets in the treatment of pneumonia caused by novel coronavirus." ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04260594
8. "A prospective, randomized controlled clinical study of antiviral therapy in the 2019-nCoV pneumonia." ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04255017
9. "The clinical study of carrimycin on treatment patients with Covid-19." ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04286503
10. "Development of Remdesivir" https://www.gilead.com/-/media/gilead-corporate/files/pdfs/covid-19/gilead_rdv-development-fact-sheet-2020.pdf
11. T.P. Sheahan, A.C. Sims, R.L. Graham, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine. Vol. 9, Issue396, eaal3653.
12. M.L. Holshue, C. DeBolt, S. Lindquist, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382:929-936.
13. J.H. Beigel, K.M. Tomashek, L.E. Dodd, et al. Remdesivir for the treatment of Covid-19 - preliminary report. NEJM. 2020 May 22;NEJMoa2007764. doi: 10.1056/NEJMoa2007764.
14. ""Solidarity" clinical trial for COVID-19 treatments" WHO. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
15."Launch of a European clinical trial against COVID-19" https://presse.inserm.fr/en/launch-of-a-european-clinical-trial-against-covid-19/38737/
16. "Gilead's virus drug seen in short supply for Americans" Bloomberg News. https://www.bloomberg.com/news/articles/2020-05-11/gilead-s-covid-19-drug-seen-in-short-supply-for-americans.
17. "Gilead's investigational antiviral Remdesivir receives U.S. Food and Drug Administration emergency use authorization for the treatment of COVID-19" https://www.gilead.com/news-and-press/press-room/press-releases/2020/5/gileads-investigational-antiviral-remdesivir-receives-us-food-and-drug-administration-emergency-use-authorization-for-the-treatment-of-covid19
18. "Gilead announces approval of Veklury® (remdesivir) in Japan for patients with severe COVID-19" https://www.gilead.com/news-and-press/press-room/press-releases/2020/5/gilead-announces-approval-of-veklury-remdesivir-in-japan-for-patients-with-severe-covid19
19. W. Ahsan, S. Javed, M.A. Bratty, et al. Treatment of SARS-CoV-2: How far have we reached? Review. Drug Discoveries & Therapeutics. 2020; 14(2):67-72.
20. X. Xu, M. Han, T. Li, et al. Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXiv. http://www.chinaxiv.org/abs/202003.00026
21. "Sanofi and Regeneron provide update on U.S. Phase 2/3 adaptive-designed trial in hospitalized COVID-19 patients" https://www.sanofi.com/en/media-room/press-releases/2020/2020-04-27-12-58-00
22. Y.Y. Leung, L.L.Y. Hui, and V.B. Kraus. Colchicine-update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum., 2015, 45:341-350.
23. N. Dalbeth, T.J. Lauterio, and H.R. Wolfe. Mechanism of action of colchicine in the treatment of gout. Clin Ther., 2014, 36:1465-1479.
24. "Could the ancient drug colchicine help fight COVID-19?" MedicineNet, 23rd April, 2020. https://www.medicinenet.com/script/main/art.asp?articlekey=230649
25. S.G. Deftereos, G. Siasos, G. Gianopouolos, et al. The Greek study in the effects of colchicine in COVID-19 complications prevention (GRECCO-19 Study): rationale and study design. Hellenic J Cardio. 2020 Apr 3;S1109-9666(20)30061-0. doi:10.1016/j.hjc.2020.03.002.
26. "The effects of standard protocol with or without colchicine in Covid-19 infection" (NCT04360980) https://clinicaltrials.gov/ct2/show/NCT04360980
27. M. Maurizi, N. Delorme, M.C. Laprévote-Heully, et al. Acute respiratory distress syndrome in adults in colchicine poisoning. Ann Fr Anesth Reanim., 1986, 5:530-532.
28. M.C.Cure, A. Kucuk, and E. Cure. Colchicine may not be effective in COVID-19 infection; it may even be harmful? Letter to the editor. Clinical Rheumatology, 2020. https://doi.org/10.1007/s10067-020-05144-x
No comments:
Post a Comment