Therapeutics for COVID-19: established and in development
Kasha P Singh A B , Joe Sasadeusz A B C , Sharon R Lewin A B C D and Jennifer Audsley A
+ Author Affiliations
- Author Affiliations
A The Peter Doherty Institute for infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Vic., Australia
B Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, Vic., Australia
C Department of Infectious Diseases, Alfred Health and Monash University, Melbourne, Vic., Australia
D Tel.: +61 3 8344 3159, Email: sharon.lewin@unimelb.edu.au
Microbiology Australia 41(4) 217-223 https://doi.org/10.1071/MA20058
Published: 10 November 2020
Abstract
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first recognised in late 2019, with over 30 000 000 cases and over 1 000 000 deaths reported by the end of September 2020. SARS-CoV-2 infection is usually associated with fever, cough, coryza, dyspnoea, anosmia, headache and fatigue and may cause pneumonia and hypoxemia. An excessive/dysregulated inflammatory response may lead to lung damage including acute respiratory distress syndrome (ARDS), coagulopathy and other complications. Mortality amongst hospitalised patients is higher in those needing intensive care. In Australia over 27 000 cases with 882 deaths had been reported by 30 September, most in Victoria. Two therapies have proven beneficial in treatment of hospitalised patients in expedited randomised placebo-controlled trials and are now in widespread use. Dexamethasone improved survival of those requiring respiratory support and the antiviral agent remdesivir decreased time to recovery in mild-moderate disease. Remdesivir was authorised by the Australian Therapeutic Goods Administration in July 2020. Over 200 other therapeutics are being tested for COVID-19 in more than 2000 clinical trials, and many more agents are in preclinical development. We review the evidence for some of the candidates for therapy in COVID-19.
References
[1] Oberfeld, B. et al. (2020) SnapShot: COVID-19. Cell 181, 954–954e.1[2] National COVID-19 Clinical Evidence Taskforce (2020) Caring for people with COVID-19. Living Guidelines. https://covid19evidence.net.au/#living-guidelines (accessed 11 August 2020).
[3] BioCentury (2020) COVID-19 Clinical Trial Dashboard. https://www. biocentury.com/reports/covid-19-clinical-trial-dashboard (accessed 16 August 2020).
[4] Thorlund, K. et al. (2020) A real-time dashboard of clinical trials for COVID-19. The Lancet Digital Health 2, e286–e287.
| 32363333PubMed |
[5] Beigel, J.H. et al. (2020) Remdesivir for the treatment of Covid-19 – preliminary report. N. Engl. J. Med. , .
| Remdesivir for the treatment of Covid-19 – preliminary report.Crossref | GoogleScholarGoogle Scholar | 32991794PubMed |
[6] Goldman, J.D. et al. (2020) Remdesivir for 5 or 10 days in patients with severe Covid-19. N. Engl. J. Med. , .
| Remdesivir for 5 or 10 days in patients with severe Covid-19.Crossref | GoogleScholarGoogle Scholar | 32459919PubMed |
[7] Furuta, Y. et al. (2017) Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 93, 449–463.
| Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase.Crossref | GoogleScholarGoogle Scholar |
[8] Cai, Q. et al. (2020) Experimental treatment with Favipiravir for COVID-19: an open-label control study. Engineering (Beijing) , .
| Experimental treatment with Favipiravir for COVID-19: an open-label control study.Crossref | GoogleScholarGoogle Scholar | 33145303PubMed |
[9] ClinicalTrials.gov. An adaptive clinical trial of antivirals for COVID-19 infection (VIRCO). Identifier NCT04445467, 2020 Jun 24, Bethesda, MD: National Library of Medicine (US). http://clinicaltrials.gov/ct/show/NCT04445467 (accessed 26 August 2020).
[10] Irie, K. et al. (2020) Pharmacokinetics of favipiravir in critically ill patients with COVID-19. Clin. Transl. Sci. , .
| Pharmacokinetics of favipiravir in critically ill patients with COVID-19.Crossref | GoogleScholarGoogle Scholar | 32475019PubMed |
[11] Wang, X. et al. (2020) The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discov. 6, 28.
| The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro.Crossref | GoogleScholarGoogle Scholar | 32373347PubMed |
[12] Lian, N. et al. (2020) Umifenovir treatment is not associated with improved outcomes in patients with coronavirus disease 2019: a retrospective study. Clin. Microbiol. Infect. 26, 917–921.
| Umifenovir treatment is not associated with improved outcomes in patients with coronavirus disease 2019: a retrospective study.Crossref | GoogleScholarGoogle Scholar | 32344167PubMed |
[13] Li, Y. et al. (2020) Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med (NY). , .
| Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial.Crossref | GoogleScholarGoogle Scholar | 33136711PubMed |
[14] Hung, I.F. et al. (2020) Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet 395, 1695–1704.
| Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial.Crossref | GoogleScholarGoogle Scholar | 32401715PubMed |
[15] Shalhoub, S. (2020) Interferon beta-1b for COVID-19. Lancet 395, 1670–1671.
| Interferon beta-1b for COVID-19.Crossref | GoogleScholarGoogle Scholar | 32401712PubMed |
[16] Lee, J.S. and Shin, E.C. (2020) The type I interferon response in COVID-19: implications for treatment. Nat. Rev. Immunol. , .
| The type I interferon response in COVID-19: implications for treatment.Crossref | GoogleScholarGoogle Scholar | 32788708PubMed |
[17] Wang, N. et al. (2020) Retrospective multicenter cohort study shows early interferon therapy is associated with favorable clinical responses in COVID-19 patients. Cell Host Microbe , .
| Retrospective multicenter cohort study shows early interferon therapy is associated with favorable clinical responses in COVID-19 patients.Crossref | GoogleScholarGoogle Scholar | 32707096PubMed |
[18] Caly, L. et al. (2020) The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 178, 104787.
| The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro.Crossref | GoogleScholarGoogle Scholar | 32251768PubMed |
[19] Hong, S.K. et al. (2012) Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice. Int. Immunopharmacol. 13, 23–27.
| Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice.Crossref | GoogleScholarGoogle Scholar | 22430099PubMed |
[20] Chu, C.M. et al. (2004) Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 59, 252–256.
| Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings.Crossref | GoogleScholarGoogle Scholar | 14985565PubMed |
[21] Choy, K.T. et al. (2020) Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 178, 104786.
| Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro.Crossref | GoogleScholarGoogle Scholar | 32251767PubMed |
[22] Cao, B. et al. (2020) A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N. Engl. J. Med. 382, 1787–1799.
| A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19.Crossref | GoogleScholarGoogle Scholar | 32187464PubMed |
[23] (2020) Recovery, Statement from the Chief Investigators: no clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY (Randomised Evaluation of COVID-19 Therapy), Lopinavir-Ritonavir results.
[24] WHO (2020) WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19.
[25] Yao, X. et al. (2020) In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin. Infect. Dis. 71, 732–739.
| In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Crossref | GoogleScholarGoogle Scholar | 32150618PubMed |
[26] Hernandez, A.V. et al. (2020) Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review. Ann. Intern. Med. , .
| Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review.Crossref | GoogleScholarGoogle Scholar | 33085507PubMed |
[27] Skipper, C.P. et al. (2020) Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann. Intern. Med. , .
| Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial.Crossref | GoogleScholarGoogle Scholar | 32673060PubMed |
[28] Boulware, D.R. et al. (2020) A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N. Engl. J. Med. 383, 517–525.
| A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19.Crossref | GoogleScholarGoogle Scholar | 32492293PubMed |
[29] Horby, P. et al. (2020) Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. medRxiv. , .
| Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial.Crossref | GoogleScholarGoogle Scholar |
[30] (2020) COVID-SHIELD clinical trial. https://www.covidshieldtrial.com.au/#!/ (accessed 17 August 2020).
[31] Hoffmann, M. et al. (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8.
| SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Crossref | GoogleScholarGoogle Scholar | 32142651PubMed |
[32] Hoffmann, M. et al. (2020) Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19. Antimicrob. Agents Chemother. 64, e00754-20.
| Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19.Crossref | GoogleScholarGoogle Scholar | 32312781PubMed |
[33] Doi, K. et al. (2020) Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: a case series. Crit. Care 24, 392.
| Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: a case series.Crossref | GoogleScholarGoogle Scholar | 32620147PubMed |
[34] Salazar, G. et al. (2017) Antibody therapies for the prevention and treatment of viral infections. NPJ Vaccines 2, 19.
| Antibody therapies for the prevention and treatment of viral infections.Crossref | GoogleScholarGoogle Scholar | 29263875PubMed |
[35] Baum, A. et al. (2020) Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014–1018.
| Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies.Crossref | GoogleScholarGoogle Scholar | 32540904PubMed |
[36] ClinicalTrials.gov. Study assessing the efficacy and safety of anti-spike SARS-CoV2 Monoclonal Antibodies for Prevention of SARS CoV-2 Infection in Healthy Adults Who are Household Contacts to an Individual With a Positive SARS-CoV-2 RT-PCR Assay. Identifier NCT04452318, 2020 Jun 30, Bethesda, MD: National Library of Medicine (US). http://clinicaltrials.gov/ct/show/NCT04452318 (accessed 30 September 2020).
[37] NIH (2020) Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). https://www.nih.gov/research-training/medical-research-initiatives/activ/covid-19-therapeutics-prioritized-testing-clinical-trials (accessed 27 August 2020).
[38] Cheng, Y. et al. (2005) Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur. J. Clin. Microbiol. Infect. Dis. 24, 44–46.
| Use of convalescent plasma therapy in SARS patients in Hong Kong.Crossref | GoogleScholarGoogle Scholar | 15616839PubMed |
[39] Li, L. et al. (2020) Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA , .
| Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.Crossref | GoogleScholarGoogle Scholar | 32492084PubMed |
[40] Horby, P. et al. (2020) Dexamethasone in hospitalized patients with Covid-19 – preliminary report. N. Engl. J. Med. , .
| Dexamethasone in hospitalized patients with Covid-19 – preliminary report.Crossref | GoogleScholarGoogle Scholar | 33031652PubMed |
[41] Sterne, J.A.C. et al. (2020) Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA , e2017023..
[42] Cortegiani, A. et al. (2020) Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review. Pulmonology. , .
| Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review.Crossref | GoogleScholarGoogle Scholar | 32828727PubMed |
[43] Somers, E.C. et al. (2020) Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin. Infect. Dis. , ciaa954.
| Tocilizumab for treatment of mechanically ventilated patients with COVID-19.Crossref | GoogleScholarGoogle Scholar | 32651997PubMed |
[44] Richardson, P. et al. (2020) Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 395, e30–e31.
| Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.Crossref | GoogleScholarGoogle Scholar | 32032529PubMed |
[45] Titanji, B.K. et al. (2020) Use of baricitinib in patients with moderate to severe COVID-19. Clin. Infect. Dis. , ciaa879..
| Use of baricitinib in patients with moderate to severe COVID-19.Crossref | GoogleScholarGoogle Scholar | 32926165PubMed |
[46] Lucas, C. et al. (2020) Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 584, 463–469.
| Longitudinal analyses reveal immunological misfiring in severe COVID-19.Crossref | GoogleScholarGoogle Scholar | 32717743PubMed |
[47] de Abajo, F.J. et al. (2020) Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet 395, 1705–1714.
| Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study.Crossref | GoogleScholarGoogle Scholar | 32416785PubMed |
[48] Gurwitz, D. (2020) Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev. Res. 81, 537–540.
| Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.Crossref | GoogleScholarGoogle Scholar | 32129518PubMed |
[49] Zhou, F. et al. (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062.
| Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Crossref | GoogleScholarGoogle Scholar | 32171076PubMed |
[50] Garcia-Vidal, C. et al. (2020) Personalized therapy approach for hospitalized patients with COVID-19. Clin. Infect. Dis. , ciaa964.
| Personalized therapy approach for hospitalized patients with COVID-19.Crossref | GoogleScholarGoogle Scholar | 32649747PubMed |
[51] Kuri-Cervantes, L. et al. (2020) Comprehensive mapping of immune perturbations associated with severe COVID-19. Sci. Immunol. 5, eabd7114.
| Comprehensive mapping of immune perturbations associated with severe COVID-19.Crossref | GoogleScholarGoogle Scholar | 32669287PubMed |
[52] Giamarellos-Bourboulis, E.J. et al. (2020) Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 27, 992–1000.e3.
| Complex immune dysregulation in COVID-19 patients with severe respiratory failure.Crossref | GoogleScholarGoogle Scholar | 32320677PubMed |
