Therapies under Investigation for Treatment of Covid-19: A Review
A REVIEW
Abstract
The novel coronavirus (SARS-CoV-2) infection, more commonly referred to as COVID-19, has rapidly developed into a worldwide pandemic with a significant health burden. At the time of this research there are no approved pharmacological treatments or preventative therapeutic strategies in place to combat the infection. However, globally, hundreds of clinical studies that aim to discover effective COVID-19 treatments are ongoing. This article summarises the rationale behind several of these interventional trials, including evidence from in vitro studies, and early results to provide an insight into the global response. As patients are being enrolled in clinical trials across the UK, some of the safety and practical considerations for the investigational medicines that pharmacists are most likely to encounter in practice are discussed as part of this review.
Keywords: coronavirus; SARS-CoV-2; COVID-19; 2019-nCoV; clinical trial; remdesivir; favipiravir; hydroxychloroquine; lopinavir; ritonavir; corticosteroids; interferons.
Keywords:
coronavirus, SARS-CoV-2, COVID-19, 2019-nCoV, clinical trial, remdesivir, favipiravir, hydroxychloroquine, lopinavir; ritonavir; corticosteroids, interferonsDOI
https://doi.org/10.22270/jddt.v10i4-s.4272References
World Health Organization. Updated WHO advice for international traffic in relation to the outbreak of the novel coronavirus 2019-nCoV. 2020. Available at: https://www.who.int/ith/2020-24-01-outbreak-of-pneumonia-caused-by-new-coronavirus/en/ (accessed June 2020)
Zumla A, Chan JF, Azhar EI et al. Coronaviruses — drug discovery and therapeutic options. Nat Rev Drug Discov. 2016; 15(5):327–347. doi: 10.1038/nrd.2015.37
Wang M, Cao R, Zhang L, Yang X et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30(3):269–271. doi: 10.1038/s41422-020-0282-0
World Health Organization. “Solidarity” clinical trial for COVID-19 treatments. 2020. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments (accessed June 2020)
University of Oxford. Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial. 2020. Available at: https://www.recoverytrial.net (accessed June 2020)
Robinson J. RECOVERY trial to stop enrolling patients to ‘ineffective’ hydroxychloroquine arm. Pharm J. 2020. Available at: https://www.pharmaceutical-journal.com/news-and-analysis/news/recovery-trial-to-stop-enrolling-patients-to-ineffective-hydroxychloroquine-arm/20208044.article?firstPass=false (accessed June 2020)
University of Oxford. Recovery. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. 2020. Available at: https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19 (accessed June 2020)
Connelly D. Targeting COVID-19: the drugs being fast-tracked through clinical trials and how they work. Pharm J 304;(7937):312-313. doi: 10.1211/PJ.2020.20207949
University of Liverpool. Interactions with experimental COVID-19 therapies. 2020. Available at: https://www.covid19-druginteractions.org/ (accessed June 2020)
Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020; 395(10236):1569–1578. doi: 10.1016/S0140-6736(20)31022-9
Gilead. Gilead Announces Approval of Veklury (remdesivir) in Japan for Patients With Severe COVID-19. 2020. Available at: 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 (accessed June 2020)
MHRA. Early access to medicines scheme (EAMS) scientific opinion: Remdesivir in the treatment of patients hospitalised with suspected or laboratory-confirmed SARS-CoV-2 infection who meet the clinical criteria. 2020. Available at: https://www.gov.uk/government/publications/early-access-to-medicines-scheme-eams-scientific-opinion-remdesivir-in-the-treatment-of-patients-hospitalised-with-suspected-or-laboratory-confirme (accessed June 2020)
US Food and Drug Administration. Remdesivir EUA Letter of Authorization. 2020. Available at: https://www.fda.gov/media/137564/download (accessed June 2020)
Gilead. Working to supply remdesivir for COVID-19. 2020. Available at: https://www.gilead.com/purpose/advancing-global-health/covid-19/working-to-supply-remdesivir-for-covid-19 (accessed June 2020)
Amirian SE & Levy JK. Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health 2020; 9:100128. doi: 10.1016/j.onehlt.2020.100128
Warren TK, Jordan R & Bavari S. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016; 531(7594):381–385. doi: 10.1038/nature17180
Pritchetta JC, Naesens L & Montoya J. Treating HHV-6 infections: the laboratory efficacy and clinical use of anti-HHV-6 agents. In: Flamand L, Lautenschlager I, Krueger G, Ablashi D (eds.) Human Herpesviruses HHV-6A, HHV-6B & HHV-7 (Third Edition). Diagnosis and Clinical Management. Oxford: Elsevier; 2014. pp.311–331.
Holshue ML, DeBolt C, Lindquist S et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 2020; 382:929-936. doi: 10.1056/NEJMoa2001191
World Health Organization. WHO R&D Blueprint – Ad-hoc expert consultation on clinical trials for Ebola therapeutics. Deliberations on design options for randomized controlled clinical trials to assess the safety and efficacy of investigational therapeutics for the treatment of patients with Ebola virus disease. Appendix 4: Summaries of evidence from selected experimental therapeutics, as of October 2018. 2018. Available at: https://www.who.int/ebola/drc-2018/summaries-of-evidence-experimental-therapeutics.pdf
US National Library of Medicine. A trial of remdesivir in adults with mild and moderate COVID-19. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04252664 (accessed June 2020)
US National Library of Medicine. A trial of remdesivir in adults with severe COVID-19. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04257656 (accessed June 2020)
US National Library of Medicine. Adaptive COVID-19 Treatment Trial. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04280705 (accessed June 2020)
University College London. Preliminary results of COVID-19 drug treatment trial found to improve recovery. 2020. Available at: https://www.ucl.ac.uk/news/2020/apr/preliminary-results-covid-19-drug-treatment-trial-found-improve-recovery (accessed June 2020)
US Food and Drug Administration. Coronavirus (COVID-19) update: FDA issues emergency use authorization for potential COVID-19 treatment. 2020. Available at: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment (accessed June 2020)
US National Library of Medicine. Trial of treatments for COVID-19 in hospitalized adults (DisCoVeRy). 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04315948 (accessed June 2020)
Prabhala A & Hoen E. We’ll find a treatment for coronavirus – but drug companies will decide who gets it. 15 April 2020. Available at: https://www.theguardian.com/commentisfree/2020/apr/15/coronavirus-treatment-drug-companies (accessed June 2020)
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(7):449–463. doi:10.2183/pjab.93.027
Delang L, Abdelnabi R & Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res 2018; 153:85–94. doi: 10.1016/j.antiviral.2018.03.003
Cai Q, Yang M, Liu D et al. Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering. 2020. Available at: https://doi.org/10.1016/j.eng.2020.03.007
US National Library of Medicine. Clinical trial of favipiravir tablets combine with chloroquine phosphate in the treatment of novel coronavirus pneumonia. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04319900?term=favipiravir&cond=Coronavirus&draw=2&rank=1 (accessed June 2020)
US National Library of Medicine. Favipiravir combined with tocilizumab in the treatment of corona virus disease 2019. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04310228?term=favipiravir&cond=Coronavirus&draw=2&rank=3 (accessed June 2020)
US National Library of Medicine. Corona virus disease 2019 patients whose nucleic acids changed from negative to positive. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04333589?term=favipiravir&cond=Coronavirus&draw=2&rank=5 (accessed June 2020)
Rosenke K, Feldmann H, Westover JB, et al. Use of favipiravir to treat Lassa virus infection in macaques. Emerg Infect Dis 2018;24(9):1696–1699. doi: 10.3201/eid2409.180233
Chinello P, Petrosillo N, Pittalis S et al. QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient. PLoS Negl Trop Dis. 2017; 11(12):e0006034. doi: 10.1371/journal.pntd.0006034
Zhao Y, Harmatz J, Epstein, C et al. Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen. Br J Clin Pharmacol 2015; 80(5):1076–1085. doi: 10.1111/bcp.12644
World Health Organization. WHO R&D Blueprint. COVID-19 Informal consultation on the potential inclusion of Favipiravir in a clinical trial. 2020. Available at: http://origin.who.int/blueprint/priority-diseases/key-action/RDBlueprintbtxexpertgrouponFavipiravircallApril10th2020.pdf (accessed June 2020)
Yao X, Ye F, Zhang M et al. 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. 2020. Available at: https://doi.org/10.1093/cid/ciaa237
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. doi: 10.1038/s41421-020-0156-0
National Institute for Health Research. Crown Coronation. (Hydroxy)Chloroquine RepurpOsing to healthWorkers for Novel CORONAvirus mitigaTION: An international, multi-site, Bayesian platform adaptive, randomised, double-blind, placebo-controlled trial assessing the effectiveness of varied doses of oral Chloroquin. 2020. Available at: https://www.nihr.ac.uk/covid-studies/study-detail.htm?entryId=282280 (accessed June 2020)
US National Library of Medicine. CROWN CORONATION: Chloroquine RepurpOsing to healthWorkers for Novel CORONAvirus mitigaTION (CROWN CORONA). 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04333732 (accessed June 2020)
Vincent MJ, Bergeron E, Benjannet S et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005;2:69. doi: 10.1186/1743-422X-2-69
Keyaerts E, Vijgen L, Maes P et al. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 2004; 323:264–268. doi: 10.1016/j.bbrc.2004.08.085
De Wilde AH, Jochmans D, Posthuma CC et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014; 58(8):4875–4884. doi: 10.1128/AAC.03011-14
Owens B. Excitement around hydroxychloroquine for treating COVID-19 causes challenges for rheumatology. Lancet Rheumatol 2020; 2(5):e257. doi: 10.1016/S2665-9913(20)30089-8
Electronic medicines compendium. Plaquenil-Hydroxychloroquine sulfate 200mg film-coated tablets - Summary of Product Characteristics. 2020. Available at: https://www.medicines.org.uk/emc/product/1764/smpc (accessed June 2020)
Dyall J, Coleman CM, Hart BJ et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 2014; 58(8):4885–4893. doi:10.1128/AAC.03036-14
Gautret P, Lagier J, Parol Pet al. Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents online. 2020. doi:10.1016/j.ijantimicag.2020.105949
Chen J, Liu D, Liu L et al. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. J Zhejiang Univ (Med Sci) 2020; 49(2):215–219. doi: 10.3785/j.issn.1008-9292.2020.03.03
Zhu N, Zhang D, Wang W et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8):727–733. doi: 10.1056/NEJMoa2001017
Mohidol Oxford Tropical Medicine Research Unit. COPCOV key messages. 2020. Available from https://www.tropmedres.ac/covid-19/copcov/copcov-key-messages (accessed June 2020)
US National Library of Medicine. Chloroquine/hydroxychloroquine prevention of coronavirus disease (COVID-19) in the healthcare setting (COPCOV). 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04303507?term=copcov&draw=2 (accessed June 2020)
NHS Health Research Authority. An adaptive phase 2/3, randomized, open-label study assessing efficacy and safety of hydroxychloroquine for hospitalized patients with moderate to severe COVID-19. 2020. Available at: https://www.hra.nhs.uk/covid-19-research/approved-covid-19-research/282362/ (accessed June 2020)
EU Clinical Trials Register. Clinical Trials. 2020. Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001270-29/GB (accessed June 2020)
Cambridge University Hospitals NHS Foundation Trust. ChemoPROphyLaxIs For covId-19 infeCtious disease (the PROLIFIC trial). 2020. Available at: https://cambridgebrc.nihr.ac.uk/wp-content/uploads/2020/05/PROLIFIC_Protocol_V1.0-07April2020.pdf (accessed June 2020)
US Food and Drug Administration. 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. 2020. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or (accessed June 2020)
Mehra M, Desai S, Ruschitzka G, Patel A. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet online. 2020. Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext (accessed June 2020)
Medicines and Healthcare products Regulatory Agency. Chloroquine and hydroxychloroquine not licensed for coronavirus (COVID-19) treatment. 2020. Available at: https://www.gov.uk/government/news/chloroquine-and-hydroxychloroquine-not-licensed-for-coronavirus-covid-19-treatment (accessed June 2020)
British National Formulary. Hydroxychloroquine sulfate. 2020. Available at: https://bnf.nice.org.uk/drug/hydroxychloroquine-sulfate.html (accessed June 2020)
Electronics Medicines Compendium. Kaletra 200mg/50mg film-coated tablets — summary of product characteristics. 2020. Available at: https://www.medicines.org.uk/emc/product/221/smpc (accessed June 2020)
Chu C, Cheng V, Hung I et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004;59:252-256. doi: 10.1136/thorax.2003.012658
Cao B, Wang Y, Wen Det al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. New Engl J Med 2020;382(19):1787–1799.doi: 10.1056/NEJMoa2001282
Young BE, Ong SWX, Kalimuddin S et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020; 323(15):1488–1494. doi:10.1001/jama.2020.3204
British National Formulary. Lopinavir with ritonavir. 2017. Available at: https://bnf.nice.org.uk/drug/lopinavir-with-ritonavir.html#nationalFunding (accessed June 2020)
British National Formulary. Corticosteroids, general use. 2017. Available at: https://bnf.nice.org.uk/treatment-summary/corticosteroids-general-use.html (accessed June 2020)
Cruz-Topete D & Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 2015; 22(1–2):20–32. doi: 10.1159/000362724
Russell C, Millar J & Baillie J. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020;395:473-475. doi: 10.1016/S0140-6736(20)30317-2
Arabi YM, Mandourah Y, Al-Hameed F et al. Corticosteroid therapy for critically ill patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med 2018; 197:757–767. doi: 10.1164/rccm.201706-1172OC
Lee N, Allen Chan KC, Hui DS et al. Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients. J Clin Virol. 2004; 31(4):304–309. doi: 10.1016/j.jcv.2004.07.006
Lee DTS, Wing YK, Leung HCM et al. Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study. Clin Infect Dis 2004; 39(8):1247–1249. doi: 10.1086/424016
Li YM, Wang SX, Gao HS et al. Factors of avascular necrosis of femoral head and osteoporosis in SARS patients’ convalescence. Zhonghua Yi Xue Za Zhi 2004; 84(16):1348–1353. PMID: 15387943
Xiao JZ, Ma L, Gao J et al. Glucocorticoid-induced diabetes in severe acute respiratory syndrome: the impact of high dosage and duration of methylprednisolone therapy. Zhonghua Nei Ke Za Zhi 2004;43(3):179–182. Chinese. PMID: 15059370.
Chen RC, Tang XP, Tan SY et al. Treatment of severe acute respiratory syndrome with glucosteroids: the Guangzhou experience. Chest 2006; 129:1441–1452. doi: 10.1378/chest.129.6.1441
Yang Z, Liu J, Zhou Y et al. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect 2020; e13–e20. doi: 10.1016/j.jinf.2020.03.06
US National Library of Medicine. Glucocorticoid therapy for COVID-19 critically ill patients with severe acute respiratory failure. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04244591?draw=3 (accessed June 2020)
University of Oxford. Recruitment of adult patients to the Dexamethasone arm of the RECOVERY Trial is now closed. 2020. Available from https://www.recoverytrial.net/for-site-staff (accessed June 2020)
British National Formulary. Dexamethasone. 2020. Available at: https://bnf.nice.org.uk/drug/dexamethasone.html (accessed June 2020)
Medicines complete. Drugs in Pregnancy and Lactation. 2017. Available at: https://www.medicinescomplete.com/#/browse/dpl (accessed June 2020)
Pestka S. The interferons: 50 years after their discovery, there is much more to learn. J Biol Chem 2007; 282(28):20047–20051. doi: 10.1074/jbc.R700004200
Gralinski LE & Baric RS. Molecular pathology of emerging coronavirus infections. J Pathol 2015; 235(2):185–195. doi: 10.1002/path.4454
Arabi Y, Shalhoub S, Mandourah Y. Al-Hameed et al. Ribavirin and interferon therapy for critically ill patients with Middle East Respiratory Syndrome: a multicenter observational study. Clin Infect Dis 2020;70(9):1837–1844. doi: 10.1093/cid/ciz544
Al Ghamdi M, Alghamdi KM, Ghandoora Y et al. Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia. BMC Infect Dis 2016;16:174. doi: 10.1186/s12879-016-1492-4
Chan JF, Yao Y, Yeung M et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common Marmoset. J Infect Dis 2015; 212(12):1904–1913. doi: 10.1093/infdis/jiv392
Scagnolari C, Vicenzi E, Bellomi F et al. Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons. Antivir Ther 2004; 9(6):1003-1011. PMID: 15651759
EU Clinical Trials Register. 2020. Available at: https://www.clinicaltrialsregister.eu/ (accessed June 2020)
US National Library of Medicine. 2020. Available at: https://clinicaltrials.gov/ (accessed June 2020)
EU Clinical Trials Register. A randomised double-blind placebo-controlled trial to determine the safety and efficacy of inhaled SNG001. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04385095#contacts (accessed June 2020)
University Medical Center Utrecht. Randomized, Embedded, Multifactorial, Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP). 2019. Available at: https://www.remapcap.org/ (accessed June 2020)
Keating GM. Peginterferon-α-2a (40 kD): a review of its use in chronic hepatitis B. Drugs 2009; 69:2633–2660. doi: 10.2165/11203660-000000000-00000
Antonelli G, Scagnolari C, Vicenzi E et al. Treatment of SARS with human interferons. Lancet 2003; 362 (9390):1158. doi: 10.1016/S0140-6736(03)14482-0
National Institute for Health and Care Excellence. Beta interferons and glatiramer acetate for treating multiple sclerosis. Technology appraisal guidance [TA527]. 2018. Available at: https://www.nice.org.uk/guidance/ta527 (accessed June 2020)
World Health Organization. Coronavirus disease (COVID-19) pandemic. 2020. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019?gclid=EAIaIQobChMIwOeUtr_U6QIV1IBQBh2nhADpEAAYASAAEgJcbfD_BwE (accessed June 2020)
Stewart K. Community management of pneumonia and suspected COVID-19. 2020. Pharm J 2020; 304(7937):336–339. doi: 10.1211/PJ.2020.20207964
Medicines and Healthcare products Regulatory Agency. MHRA issues a scientific opinion for the first medicine to treat COVID-19 in the UK. 2020. Available at: https://www.gov.uk/government/news/mhra-supports-the-use-of-remdesivir-as-the-first-medicine-to-treat-covid-19-in-the-uk (accessed June 2020)
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