Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000075.xml
Semin Respir Crit Care Med 2023; 44(01): 118-129
DOI: 10.1055/s-0042-1758837
DOI: 10.1055/s-0042-1758837
Review Article
Use of Antiviral Agents and other Therapies for COVID-19
Abstract
The coronavirus disease 2019 (COVID-19) pandemic led to a remarkably rapid development of a range of effective prophylactic vaccines, including new technologies that had not previously been approved for human use. In contrast, the development of new small molecule antiviral therapeutics has taken years to produce the first approved drugs specifically targeting severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), with the intervening years filled with attempts to repurpose existing drugs and the development of biological therapeutics. This review will discuss the reasons behind this variation in timescale and provide a survey of the many new treatments that are progressing through the clinical pipeline.
Publication History
Article published online:
16 January 2023
© 2023. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 Guglielmi G. COVID was twice as deadly in poorer countries. Nature 2022; (e-pub ahead of print) DOI: 10.1038/d41586-022-01767-z.
- 2 Levin AT, Owusu-Boaitey N, Pugh S. et al. Assessing the burden of COVID-19 in developing countries: systematic review, meta-analysis and public policy implications. BMJ Glob Health 2022; 7 (05) e008477
- 3 Vardanyan R, Hruby V. Chapter 34–Antiviral Drugs. In: Vardanyan R, Hruby V. eds. Synthesis of Best-Seller Drugs. Boston, MA: Academic Press; 2016: 687-736
- 4 Brende B, Farrar J, Gashumba D. et al. CEPI-a new global R&D organisation for epidemic preparedness and response. Lancet 2017; 389 (10066): 233-235
- 5 Gouglas D, Christodoulou M, Plotkin SA, Hatchett R. CEPI: driving progress toward epidemic preparedness and response. Epidemiol Rev 2019; 41 (01) 28-33
- 6 World Health Organization. COVID-19 vaccine tracker and landscape. Accessed June 21 2022, at: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
- 7 Callaway E. Fast-evolving COVID variants complicate vaccine updates. Nature 2022; 607 (7917): 18-19
- 8 Õmura S, Crump A. The life and times of ivermectin – a success story. Nat Rev Microbiol 2004; 2 (12) 984-989
- 9 Martin RJ, Robertson AP, Choudhary S. Ivermectin: an anthelmintic, an insecticide, and much more. Trends Parasitol 2021; 37 (01) 48-64
- 10 Laing R, Gillan V, Devaney E. Ivermectin – old drug, new tricks?. Trends Parasitol 2017; 33 (06) 463-472
- 11 Barragry TB. A review of the pharmacology and clinical uses of ivermectin. Can Vet J 1987; 28 (08) 512-517
- 12 Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020; 178: 104787
- 13 Shirazi FM, Mirzaei R, Nakhaee S, Nejatian A, Ghafari S, Mehrpour O. Repurposing the drug, ivermectin, in COVID-19: toxicological points of view. Eur J Med Res 2022; 27 (01) 21
- 14 Bray M, Rayner C, Noël F, Jans D, Wagstaff K. Ivermectin and COVID-19: a report in antiviral research, widespread interest, an FDA warning, two letters to the editor and the authors' responses. Antiviral Res 2020; 178: 104805-104805
- 15 Kory P, Meduri GU, Varon J, Iglesias J, Marik PE. Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19. Am J Ther 2021; 28 (03) e299-e318
- 16 Lawrence JM, Meyerowitz-Katz G, Heathers JAJ, Brown NJL, Sheldrick KA. The lesson of ivermectin: meta-analyses based on summary data alone are inherently unreliable. Nat Med 2021; 27 (11) 1853-1854
- 17 Meyerowitz-Katz. Gideon. Is Ivermectin for COVID-19 Based on Fraudulent Research? July 16 2021. Accessed June 21, 2022, at: https://gidmk.medium.com/is-ivermectin-for-covid-19-based-on-fraudulent-research-5cc079278602
- 18 Barac A, Bartoletti M, Azap O. et al. Inappropriate use of ivermectin during the COVID-19 pandemic: primum non nocere!. Clin Microbiol Infect 2022; 28 (07) 908-910
- 19 Liu J, Cao R, Xu M. et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020; 6: 16
- 20 Wang M, Cao R, Zhang L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30 (03) 269-271
- 21 WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO solidarity randomised trial and updated meta-analyses. Lancet 2022; 399 (10339): 1941-1953
- 22 Jorge A. Hydroxychloroquine in the prevention of COVID-19 mortality. Lancet Rheumatol 2021; 3 (01) e2-e3
- 23 FDA. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems, June 15 2020. Accessed June 21, 2022, at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or
- 24 Pardo J, Shukla AM, Chamarthi G, Gupte A. The journey of remdesivir: from Ebola to COVID-19. Drugs Context 2020; 9: 9
- 25 Eastman RT, Roth JS, Brimacombe KR. et al. Remdesivir: a review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent Sci 2020; 6 (05) 672-683
- 26 Mulangu S, Dodd LE, Davey Jr RT. et al; PALM Writing Group, PALM Consortium Study Team. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med 2019; 381 (24) 2293-2303
- 27 Pardo J, Shukla AM, Chamarthi G, Gupte A. The journey of remdesivir: from Ebola to COVID-19. Drugs Context 2020; 9: 14
- 28 FDA. FDA Approves First Treatment for COVID-19, Oct 22 2020. Accessed June 21, 2022, at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19
- 29 Beigel JH, Tomashek KM, Dodd LE. et al; ACTT-1 Study Group Members. Remdesivir for the treatment of COVID-19–final report. N Engl J Med 2020; 383 (19) 1813-1826
- 30 Ader F, Bouscambert-Duchamp M, Hites M. et al; DisCoVeRy Study Group. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. Lancet Infect Dis 2022; 22 (02) 209-221
- 31 Gyselinck I, Janssens W. Remdesivir, on the road to DisCoVeRy. Lancet Infect Dis 2022; 22 (02) 153-155
- 32 Choy KT, Wong AY, Kaewpreedee P. et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res 2020; 178: 104786
- 33 Cao B, Wang Y, Wen D. et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med 2020; 382 (19) 1787-1799
- 34 Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad, Ser B, Phys Biol Sci 2017; 93 (07) 449-463
- 35 Hassanipour S, Arab-Zozani M, Amani B, Heidarzad F, Fathalipour M, Martinez-de-Hoyo R. Addendum: the efficacy and safety of favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials. Sci Rep 2022; 12 (01) 1996
- 36 Hassanipour S, Arab-Zozani M, Amani B, Heidarzad F, Fathalipour M, Martinez-de-Hoyo R. The efficacy and safety of favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials. Sci Rep 2021; 11 (01) 11022
- 37 Manabe T, Kambayashi D, Akatsu H, Kudo K. Favipiravir for the treatment of patients with COVID-19: a systematic review and meta-analysis. BMC Infect Dis 2021; 21 (01) 489
- 38 Therapeutic A. Appili Therapeutics Provides Update on Phase 3 PRESECO Clinical Trial Evaluating Avigan/Reeqonus, Nov 12 2021. Accessed June 21 2022, at: https://www.appilitherapeutics.com/newsfeed/Appili-Therapeutics-Provides-Update-on-Phase-3-PRESECO-Clinical-Trial-Evaluating-Avigan%C2%AE%2FReeqonus%E2%84%A2
- 39 Bosaeed M, Alharbi A, Mahmoud E. et al. Efficacy of favipiravir in adults with mild COVID-19: a randomized, double-blind, multicentre, placebo-controlled clinical trial. Clin Microbiol Infect 2022; 28 (04) 602-608
- 40 Berliba E, Bogus M, Vanhoutte F. et al. Safety, pharmacokinetics, and antiviral activity of AT-527, a novel purine nucleotide prodrug, in hepatitis C virus-infected subjects with or without cirrhosis. Antimicrob Agents Chemother 2019; 63: e01201-e01219
- 41 Fidler B, Gardner J. Biopharmadive. Atea, Roche change plans for oral COVID-19 drug after trial setback. Accessed June 21, 2022, at: https://www.biopharmadive.com/news/atea-roche-coronavirus-antiviral-drug-fails/608450/
- 42 Scavone C, Mascolo A, Rafaniello C. et al. Therapeutic strategies to fight COVID-19: which is the status artis?. Br J Pharmacol 2022; 179 (10) 2128-2148
- 43 Thomas K, Kolata G. New York Times. President Trump Received Experimental Antibody Treatment Oct 2 2020. Accessed June 21, 2022, at: https://www.nytimes.com/2020/10/02/health/trump-antibody-treatment.html
- 44 Weinreich DM, Sivapalasingam S, Norton T. et al; Trial Investigators. REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19. N Engl J Med 2021; 384 (03) 238-251
- 45 Weinreich DM, Sivapalasingam S, Norton T. et al; Trial Investigators. REGEN-COV antibody combination and outcomes in outpatients with COVID-19. N Engl J Med 2021; 385 (23) e81
- 46 Regeneron Pres Release. Regeneron Announces New U.S. Government Agreement to Purchase Additional Doses of REGEN-COV (casirivimab and imdevimab) Antibody Cocktail. Accessed June 23, 2022, https://investor.regeneron.com/news-releases/news-release-details/regeneron-announces-new-us-government-agreement-purchase
- 47 FDA. Coronavirus (COVID-19) update: FDA limits use of certain monoclonal antibodies to treat COVID-19 due to the omicron variant. Accessed June 24, 2022, at: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-limits-use-certain-monoclonal-antibodies-treat-covid-19-due-omicron
- 48 FDA. FDA updates Sotrovimab emergency use authorization. Accessed June 22, 2022, at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-sotrovimab-emergency-use-authorization
- 49 Gupta A, Gonzalez-Rojas Y, Juarez E. et al; COMET-ICE Investigators. Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate COVID-19: a randomized clinical trial. JAMA 2022; 327 (13) 1236-1246
- 50 Gottlieb RL, Nirula A, Chen P. et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA 2021; 325 (07) 632-644
- 51 Brii Biosciences press release. Brii Bio Presents Positive Phase 3 Data on BRII-196/BRII-198, the Company's SARS-CoV-2 Monoclonal Neutralizing Antibody Combination Therapy, in an Oral Late-Breaker Presentation at IDWeek 2021. Accessed June 24, 2022, at: https://www.briibio.com/news-detail.php?id=354
- 52 Zost SJ, Gilchuk P, Case JB. et al. Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 2020; 584 (7821): 443-449
- 53 Astrazeneca press release. AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing COVID-19. Accessed July 24, 2022, at: https://www.astrazeneca.com/media-centre/press-releases/2021/azd7442-prophylaxis-trial-met-primary-endpoint.html
- 54 Mullard A. COVID antibody drugs have saved lives - so why aren't they more popular?. Nature 2022; 606 (7916): 854-856
- 55 Painter GR, Natchus MG, Cohen O, Holman W, Painter WP. Developing a direct acting, orally available antiviral agent in a pandemic: the evolution of molnupiravir as a potential treatment for COVID-19. Curr Opin Virol 2021; 50: 17-22
- 56 Cully M. A tale of two antiviral targets – and the COVID-19 drugs that bind them. Nat Rev Drug Discov 2022; 21 (01) 3-5
- 57 Fischer II WA, Eron Jr JJ, Holman W. et al. A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med 2022; 14 (628) eabl7430
- 58 Whitley R. Molnupiravir – a step toward orally bioavailable therapies for COVID-19. N Engl J Med 2022; 386 (06) 592-593
- 59 Jayk Bernal A, Gomes da Silva MM, Musungaie DB. et al; MOVe-OUT Study Group. Molnupiravir for oral treatment of COVID-19 in non-hospitalized patients. N Engl J Med 2022; 386 (06) 509-520
- 60 Masyeni S, Iqhrammullah M, Frediansyah A. et al. Molnupiravir: a lethal mutagenic drug against rapidly mutating severe acute respiratory syndrome coronavirus 2: a narrative review. J Med Virol 2022; 94 (07) 3006-3016
- 61 Vandyck K, Deval J. Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection. Curr Opin Virol 2021; 49: 36-40
- 62 Halford B. Chemical & Engineering News. How Pfizer scientists transformed an old drug lead into a COVID-19 antiviral. Accessed June 24, 2022, at: https://cen.acs.org/pharmaceuticals/drug-discovery/How-Pfizer-scientists-transformed-an-old-drug-lead-into-a-COVID-19-antiviral/100/i3
- 63 Owen DR, Allerton CMN, Anderson AS. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 2021; 374 (6575): 1586-1593
- 64 Halford B. Chemical & Engineering News. Pfizer unveils its oral SARS-CoV-2 inhibitor. Accessed June 24, 2022, at: https://cen.acs.org/acs-news/acs-meeting-news/Pfizer-unveils-oral-SARS-CoV/99/i13
- 65 Hammond J, Leister-Tebbe H, Gardner A. et al; EPIC-HR Investigators. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19. N Engl J Med 2022; 386 (15) 1397-1408
- 66 Boras B, Jones RM, Anson BJ. et al. Discovery of a novel inhibitor of coronavirus 3CL protease for the potential treatment of COVID-19. bioRxiv 2021; DOI: 10.1101/2020.09.12.293498.
- 67 Tyndall JDA. S-217622, a 3CL protease inhibitor and clinical candidate for SARS-CoV-2. J Med Chem 2022; 65 (09) 6496-6498
- 68 Unoh Y, Uehara S, Nakahara K. et al. Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19. J Med Chem 2022; 65 (09) 6499-6512
- 69 Tian D, Liu Y, Liang C. et al. An update review of emerging small-molecule therapeutic options for COVID-19. Biomed Pharmacother 2021; 137: 111313
- 70 Ho WS, Zhang R, Tan YL, Chai CLL. COVID-19 and the promise of small molecule therapeutics: are there lessons to be learnt?. Pharmacol Res 2022; 179: 106201
- 71 Hu S, Jiang S, Qi X, Bai R, Ye X-Y, Xie T. Races of small molecule clinical trials for the treatment of COVID-19: an up-to-date comprehensive review. Drug Dev Res 2022; 83 (01) 16-54
- 72 Biotechnology Innovation Organization. BIO COVID-19 Therapeutic Development Tracker. Accessed June 24, 2022, at: https://www.bio.org/policy/human-health/vaccines-biodefense/coronavirus/pipeline-tracker
- 73 De Savi C, Hughes DL, Kvaerno L. Quest for a COVID-19 cure by repurposing small-molecule drugs: mechanism of action, clinical development, synthesis at scale, and outlook for supply. Org Process Res Dev 2020; 24: 940-976
- 74 Wang Q, Zhang Y, Wu L. et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 2020; 181 (04) 894-904.e9
- 75 Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 2022; 23 (01) 3-20
- 76 Bestle D, Heindl MR, Limburg H. et al. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Sci Alliance 2020; 3 (09) e202000786
- 77 Hoffmann M, Kleine-Weber H, Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181 (02) 271-280.e8
- 78 Lo MK, Shrivastava-Ranjan P, Chatterjee P. et al. Broad-spectrum in vitro antiviral activity of ODBG-P-RVn: an orally-available, lipid-modified monophosphate prodrug of remdesivir parent nucleoside (GS-441524). Microbiol Spectr 2021; 9 (03) e0153721
- 79 Bharadwaj S. The Times of India., Jubilant Pharma develops oral version of Covid-19 drug Remdesivir. Accessed June 29, 2022, at: https://timesofindia.indiatimes.com/business/india-business/jubilant-pharma-develops-oral-version-of-covid-19-drug-remdesivir/articleshow/82150314.cms
- 80 Schäfer A, Martinez DR, Won JJ. et al. Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice. Sci Transl Med 2022; 14 (643) eabm3410
- 81 Cox RM, Wolf JD, Lieber CM. et al. Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets. Nat Commun 2021; 12 (01) 6415
- 82 Mengist HM, Mekonnen D, Mohammed A, Shi R, Jin T. Potency, safety, and pharmacokinetic profiles of potential inhibitors targeting SARS-CoV-2 main protease. Front Pharmacol 2021; 11: 630500
- 83 Discoovery and Development of PBI-0451. 35th International Conference on Antiviral Research. Accessed June 24, 2022, at: https://www.sec.gov/Archives/edgar/data/1822711/000095017022004540/prds-ex99_1.htm
- 84 Zhang L, Lin D, Sun X. et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 2020; 368 (6489): 409-412
- 85 Whitlock J. The next generation of COVID-19 antivirals. Chem Eng News 2022; 100: 17-18
- 86 Balakrishnan A, Reyes A, Shen R. et al. Molecular basis for antiviral action of EDP-235: a potent and selective SARS-CoV-2 3CLpro inhibitor for the treatment of COVID 19. FASEB J 2022; 36: 10
- 87 Enanta Pharmaceuticals Pipeline - SARS-CoV-2. Accessed June 26, 2022, at: https://www.enanta.com/pipeline/sars-cov-2/
- 88 CoCrystal Press Release. ”Cocrystal Pharma Receives FDA Guidance to Advance Clinical Development of its COVID-19 Antiviral CDI-45205” Jan 6 2022. Accessed June 24, 2022, at: https://www.globenewswire.com/en/news-release/2022/01/06/2362348/0/en/Cocrystal-Pharma-Receives-FDA-Guidance-to-Advance-Clinical-Development-of-its-COVID-19-Antiviral-CDI-45205.html
- 89 Sharun K, Tiwari R, Dhama K. Protease inhibitor GC376 for COVID-19: Lessons learned from feline infectious peritonitis. Ann Med Surg (Lond) 2020; 61: 122-125
- 90 Lu J, Chen SA, Khan MB. et al. Crystallization of feline coronavirus Mpro with GC376 reveals mechanism of inhibition. Front Chem 2022; 10: 852210
- 91 Gao Y-M, Xu G, Wang B, Liu B-C. Cytokine storm syndrome in coronavirus disease 2019: a narrative review. J Intern Med 2021; 289 (02) 147-161
- 92 Choudhary S, Sharma K, Silakari O. The interplay between inflammatory pathways and COVID-19: a critical review on pathogenesis and therapeutic options. Microb Pathog 2021; 150: 104673
- 93 Cron RQ, Caricchio R, Chatham WW. Calming the cytokine storm in COVID-19. Nat Med 2021; 27 (10) 1674-1675
- 94 Miesbach W, Makris M. COVID-19: coagulopathy, risk of thrombosis, and the rationale for anticoagulation. Clin Appl Thromb Hemost 2020; 26: 1076029620938149
- 95 Montiel V, Lobysheva I, Gérard L. et al. Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients. EBioMedicine 2022; 77: 103893
- 96 Taccone FS, Hites M, Dauby N. From hydroxychloroquine to ivermectin: how unproven “cures” can go viral. Clin Microbiol Infect 2022; 28 (04) 472-474
- 97 Sagonowsky E. Fierce Pharma. WHO plots multibillion-dollar campaign to buy COVID-19 antivirals for $10 per course: Reuters. Accessed June 23, 2022, at: https://www.fiercepharma.com/pharma/who-plots-multibillion-dollar-campaign-to-buy-covid-19-antivirals-for-10-per-course-reuters