Continuing from my last blog post, this one will introduce the popular drugs currently being clinically tested for effectiveness in COVID-19 treatment. The drugs are listed in order of highest popularity first according to the figure in the Cytel's Global coronavirus COVID-19 trial tracker.1 However, it should be noted that there may be some drugs which are not listed here but are still effective at treating the disease.
1. Chloroquine/Hydroxychloroquine
These drugs have been used for decades in the treatment of malaria, and are FDA approved. They are also frequently used in treating autoimmune diseases such as rheumatoid arthritis and lupus.2 Hydroxychloroquine has a hydroxyl group which makes it less toxic than chloroquine while maintaining similar activity.
Chloroquine blocks virus infection by increasing endosomal pH required for virus-cell fusion, as well as by interfering with the glycosylation of receptors of SARS-CoV.3 This suggests that chloroquine treatment might be more effective in the early stages of infection. Preclinical studies showed that chloroquine functioned at both entry and post-entry stages of the SARS-CoV-2 infection in Vero E6 cells.4 Besides its antiviral activity, chloroquine might also mitigate the cytokine storm associated with severe pneumonia caused by coronaviruses by inhibiting the lipopolysaccharide-induced release of inflammatory cytokines.5
Early clinical trials conducted in COVID-19 Chinese patients showed that chloroquine had a significant effect, both in terms of clinical outcome and viral clearance, when compared to control groups.6 As chloroquine was identified to disrupt the early stages of coronavirus replication, a Correspondence article in The Lancet even suggested the use of chloroquine or hydroxychloroquine for prophylaxis.7 US President Donald Trump tweeted earlier this month that he was taking hydroxychloroquine as a preventative measure against COVID-19.
However, a multinational registry analysis of 96,032 patients found that people taking chloroquine or hydroxychloroquine with or without a azithromycin (macrolide) were at higher risk of death and de-novo ventricular arrhythmia.8 In view of this, the WHO announced the pausing of the testing of hydroxychloroquine and its combination from the global megatrial SOLIDARITY, and reviewed all evidence available globally to evaluate the potential benefits and risks of hydroxychloroquine.9*
2. Lopinavir/ritonavir
This two-drug combination is FDA approved for HIV treatment. It was developed by Abbot Laboratory and is sold under the brand name Kaletra.10 It is being tested in the WHO global megatrial SOLIDARITY. Lopinavir is specifically designed to inhibit the protease of HIV, an important enzyme that cleaves a long protein chain into peptides during the assembly of new viruses, thus blocking the HIV replication. Ritonavir, another protease inhibitor, is used in combination with lopinavir to slow down the decomposition of lopinavir in the human body by our own proteases.11
Kaletra has shown efficacy in MERS infected marmosets.12 A retrospective matched cohort study including 1,052 SARS patients (75 treated patients and 977 control patients) showed that the addition of the drug as an initial treatment was associated with a reduced death rate and intubation rate compared with that in a matched cohort who received standard treatment (2.3% vs 11.0% and 0% vs 15.6%, respectively, P < .05).13
However, the first trial with COVD-19 was not encouraging. The study in Wuhan showed no significant difference between the groups receiving the lopinavir/ritonavir and the group receiving standard care alone.14 The authors explained that the treatment may have been given too late to help, as the patients were very ill.
The drug combination is generally safe, but it may interact with drugs that usually given to severely ill patients, and it could cause significant liver damage.15
3. Azithromycin
Azithromycin (AZ) is an antibiotic with the brand name Zithromaz®(Pfizer Inc., New York, NY, USA). The drug is a broad-spectrum macrolide antibiotic with a long half-life. It has not yet been approved for antiviral therapy, although preclinical and clinical data suggest that it has antiviral properties.16,17,18,19,20
Similar to chloroquine/hydroxychloroquine, the drug confers its antiviral activity by changing the acidic environment of the endosomes and lysosomes, thus potentially blocking endocytosis and/or viral genetic shedding from lysosomes, thereby limiting viral replication. The alkaline environment also prevents the uncoating of enveloped viruses in host cells, thus further inhibiting the virus's replication.21,22 AZ has the ability to induce pattern-recognition receptors, IFNs, and IFN-stimulated genes, leading to a reduction of viral replication.23 In addition, AZ directly acts on bronchial epithelial cells to maintain their function and reduce mucus secretion to facilitate lung function.20,24
The drug is usually used in combination with chloroquine or hydroxychloroquine in clinical trials for COVID-19. An open-label study in France found a significant reduction of viral load in COVID-19 patients using a combination of hydroxychloroquine and AZ.25
4. Tocilizumab
Tocilizumab (Actemra/RoActemra®, F. Hochmann-La Roche AG, Basel, Switzerland) is an FDA approved drug for rheumatoid arthritis. It is a recombinant humanized monoclonal anti-interleukin6 receptor (anti-IL-6R) antibody. It binds to both soluble and membrane-bound IL-6R to inhibit IL-6-mediated signalling. IL-6 is one of the excessive cytokines produced by activated macrophages as a result of COVID-19 infection.26
Evidence from independent studies of tocilizumab appear promising. In preliminary data from a non-peer reviewed study, patients showed rapid fever reduction and a reduced need for supplemental oxygen withina few days of receiving tocilizumab, in a single-arm Chinese trial involving 21 patients with severe or critical COVID-19 infection.27
Roche has launched a global, randomised, double-blind, placebo-controlled phase 3 trial (NCT04320615) with tocilizumab, in collaboration with the US Health and Human Services Biomedical Advanced Research and Development Authority (BARDA), for the treatment of people hospitalised with COVID-19 pneumonia. The study will evaluate the safety and efficacy of tocilizumab (in combination with a high standard of care) compared with placebo.28
The National Health Commission of China have included tocilizumab in their 7th updated diagnosis and treatment plan issued for COVID-19 patients with extensive lung lesions and severe cases who also show an increased level of IL-6 in laboratory testing.29
The other popular drugs currently being clinically tested for effectiveness in COVID-19 treatment will be introduced in my next blog post.
*According to the WHO, "chloroquine and hydroxychloroquine had both been selected as potential drugs to be tested within the Solidarity Trial as per the initial trial protocol. However the trial was only ever pursued with hydroxychloroquine, so chloroquine was removed from this page as a listed treatment option under study." They did not explain clearly the reason for removing of chloroquine in the SOLIDARITY study. However, it is understandable, as hydroxychloroquine is safer than chloroquine for usage while having similar antiviral effects.
2. Rynes R. Antimalarial drugs in the treatment of rheumatological diseases. Rheumatology. 1997;36(7):799-805.
3. M.J. Vincent, E. Bergeron, S. Benjannet, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology Journal, 2005 Aug 22;2:69. doi: 10.1186/1743-422X-2-69.
4. M. Wang, R. Cao, L. Zhang, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 2020 Mar;30(3):269-271.
5. S. Grassin-Delyle, H.Salvator, M. Brollo, et al. Chloroquine inhibits the release of inflammatory cytokines by human lung explants. Clinical Infectious Diseases, 2020 May 8;ciaa546. doi: 10.1093/cid/ciaa546.
6. J. Gao, Z. Tian, and X. Yang. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends, 2020 Mar 16;14(1):72-73.
7. N. Principi, and S. Esposito. Chloroquine or hydroxychloroquine for prophylaxis of COVID-19. Lancet Infect Dis. 2020 Apr 17:S1473-3099(20)30296-6. doi: 10.1016/S1473-3099(20)30296-6.
8. M.R. Mehra, S.S. Desai, F. Ruschitzka, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 May 22:S0140-6736(20)31180-6.
9. ""SOLIDARITY" clinical trial for COVID-19" https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
10. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021251s058slp. KALETRA (lopinavir and ritonavir) tablet. 12/2019.
11. European Medicines Agency. European public assessment report (EPAR) for Kaletra. https://www.ema.europa.eu/en/documents/overview/kaletra-epar-summary-public_en.pdf
12. J.F. Chan, Y. Yao, M.L. Yeung, et al. Treatment with lopinavir/ritonavir or interferon-?1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis, 2015 Dec 15;212(12):1904-13.
13. K.S. Chan, S.T. Lai, C.M. Chu, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9(6):399-406.
14. B. Cao, Y. Wang, D. Wen, et al. A Trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; 382:1787-1799.
15. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]: Lopinavir. https://www.ncbi.nlm.nih.gov/books/NBK547961/
16. B. Damle, M. Vourvahis, E. Wang, et al. Clinical pharmacology perspectives on the antiviral activity of Azithromycin and use in COVID-19. Review. Clin Pharmacol Ther, 2020 Apr 17. doi: 10.1002/cpt.1857.
17. H. Retallack, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc. Natl. Acad. Sci. 113, 14408-14413 (2016).
18. D.H. Tran, R. Sugamata, T. Hirose, et al. Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering with virus internalization process. J. Antibiot. 72, 759-768 (2019).
19. J. Kouznetsova, W. Sun, C. Martinez-Romero, et al. Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg. Microbes Infect. 3, 1-7 (2014).
20. V. Gielen, S.L. Johnston, and M.R. Edwards. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur. Respir. J. 36, 646-654 (2010).
21. D. Tytec, P.V. Smissen, M. Marcel, et al. Azithromycin, a lysosomotropic antibiotic, has distinct effects on fluid-phase and receptor-mediated endocytosis, but does not impair phagocytosis in J774 macrophages. Exp. Cell Res. 281, 86-100 (2002).
22. U.F. Greber, I. Singh, & A. Helenius. Mechanisms of virus uncoating. Trends Microbiol. 2, 52-56 (1994).
23. Li, C, S. Zhu, Y. Deng, et al. Azithromycin protects against Zika virus infection by upregulating virus-induced type I and III interferon responses. Antimicrob Agents Chemother 63, e00394-e00419 (2019).
24. C.L. Cramer, A. Patterson, A. Alchakaki, et al. Immunomodulatory indications of azithromycin in respiratory disease: a concise review for the clinician. Postgrad. Med. 129, 493-499 (2017).
25. P. Gautret, J. Lagier, P. Parola, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents, 2020 Mar 20;105949.
26. "Actemra/RoActemra (tocilizumab)" https://www.roche.com/products/product-details.htm?productId=42bf9d08-8573-491a-944a-fdbc030ec44b
27. E.A. Coomes, and H. Haghbayan. Interleukin-6 in COVID-19: a systematic review and meta-analysis. https://www.medrxiv.org/content/10.1101/2020.03.30.20048058v1.full.pdf
28. "Roche initiates Phase III clinical trial of Actemra/RoActemra in hospitalised patients with severe COVID-19 pneumonia" https://www.roche.com/media/releases/med-cor-2020-03-19.htm
29. "Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7)." https://www.chinadaily.com.cn/pdf/2020/1.Clinical.Protocols.for.the.Diagnosis.and.Treatment.of.COVID-19.V7.pdf
1. Chloroquine/Hydroxychloroquine
These drugs have been used for decades in the treatment of malaria, and are FDA approved. They are also frequently used in treating autoimmune diseases such as rheumatoid arthritis and lupus.2 Hydroxychloroquine has a hydroxyl group which makes it less toxic than chloroquine while maintaining similar activity.
Chloroquine blocks virus infection by increasing endosomal pH required for virus-cell fusion, as well as by interfering with the glycosylation of receptors of SARS-CoV.3 This suggests that chloroquine treatment might be more effective in the early stages of infection. Preclinical studies showed that chloroquine functioned at both entry and post-entry stages of the SARS-CoV-2 infection in Vero E6 cells.4 Besides its antiviral activity, chloroquine might also mitigate the cytokine storm associated with severe pneumonia caused by coronaviruses by inhibiting the lipopolysaccharide-induced release of inflammatory cytokines.5
Early clinical trials conducted in COVID-19 Chinese patients showed that chloroquine had a significant effect, both in terms of clinical outcome and viral clearance, when compared to control groups.6 As chloroquine was identified to disrupt the early stages of coronavirus replication, a Correspondence article in The Lancet even suggested the use of chloroquine or hydroxychloroquine for prophylaxis.7 US President Donald Trump tweeted earlier this month that he was taking hydroxychloroquine as a preventative measure against COVID-19.
However, a multinational registry analysis of 96,032 patients found that people taking chloroquine or hydroxychloroquine with or without a azithromycin (macrolide) were at higher risk of death and de-novo ventricular arrhythmia.8 In view of this, the WHO announced the pausing of the testing of hydroxychloroquine and its combination from the global megatrial SOLIDARITY, and reviewed all evidence available globally to evaluate the potential benefits and risks of hydroxychloroquine.9*
2. Lopinavir/ritonavir
This two-drug combination is FDA approved for HIV treatment. It was developed by Abbot Laboratory and is sold under the brand name Kaletra.10 It is being tested in the WHO global megatrial SOLIDARITY. Lopinavir is specifically designed to inhibit the protease of HIV, an important enzyme that cleaves a long protein chain into peptides during the assembly of new viruses, thus blocking the HIV replication. Ritonavir, another protease inhibitor, is used in combination with lopinavir to slow down the decomposition of lopinavir in the human body by our own proteases.11
Kaletra has shown efficacy in MERS infected marmosets.12 A retrospective matched cohort study including 1,052 SARS patients (75 treated patients and 977 control patients) showed that the addition of the drug as an initial treatment was associated with a reduced death rate and intubation rate compared with that in a matched cohort who received standard treatment (2.3% vs 11.0% and 0% vs 15.6%, respectively, P < .05).13
However, the first trial with COVD-19 was not encouraging. The study in Wuhan showed no significant difference between the groups receiving the lopinavir/ritonavir and the group receiving standard care alone.14 The authors explained that the treatment may have been given too late to help, as the patients were very ill.
The drug combination is generally safe, but it may interact with drugs that usually given to severely ill patients, and it could cause significant liver damage.15
3. Azithromycin
Azithromycin (AZ) is an antibiotic with the brand name Zithromaz®(Pfizer Inc., New York, NY, USA). The drug is a broad-spectrum macrolide antibiotic with a long half-life. It has not yet been approved for antiviral therapy, although preclinical and clinical data suggest that it has antiviral properties.16,17,18,19,20
Similar to chloroquine/hydroxychloroquine, the drug confers its antiviral activity by changing the acidic environment of the endosomes and lysosomes, thus potentially blocking endocytosis and/or viral genetic shedding from lysosomes, thereby limiting viral replication. The alkaline environment also prevents the uncoating of enveloped viruses in host cells, thus further inhibiting the virus's replication.21,22 AZ has the ability to induce pattern-recognition receptors, IFNs, and IFN-stimulated genes, leading to a reduction of viral replication.23 In addition, AZ directly acts on bronchial epithelial cells to maintain their function and reduce mucus secretion to facilitate lung function.20,24
The drug is usually used in combination with chloroquine or hydroxychloroquine in clinical trials for COVID-19. An open-label study in France found a significant reduction of viral load in COVID-19 patients using a combination of hydroxychloroquine and AZ.25
4. Tocilizumab
Tocilizumab (Actemra/RoActemra®, F. Hochmann-La Roche AG, Basel, Switzerland) is an FDA approved drug for rheumatoid arthritis. It is a recombinant humanized monoclonal anti-interleukin6 receptor (anti-IL-6R) antibody. It binds to both soluble and membrane-bound IL-6R to inhibit IL-6-mediated signalling. IL-6 is one of the excessive cytokines produced by activated macrophages as a result of COVID-19 infection.26
Evidence from independent studies of tocilizumab appear promising. In preliminary data from a non-peer reviewed study, patients showed rapid fever reduction and a reduced need for supplemental oxygen withina few days of receiving tocilizumab, in a single-arm Chinese trial involving 21 patients with severe or critical COVID-19 infection.27
Roche has launched a global, randomised, double-blind, placebo-controlled phase 3 trial (NCT04320615) with tocilizumab, in collaboration with the US Health and Human Services Biomedical Advanced Research and Development Authority (BARDA), for the treatment of people hospitalised with COVID-19 pneumonia. The study will evaluate the safety and efficacy of tocilizumab (in combination with a high standard of care) compared with placebo.28
The National Health Commission of China have included tocilizumab in their 7th updated diagnosis and treatment plan issued for COVID-19 patients with extensive lung lesions and severe cases who also show an increased level of IL-6 in laboratory testing.29
The other popular drugs currently being clinically tested for effectiveness in COVID-19 treatment will be introduced in my next blog post.
*According to the WHO, "chloroquine and hydroxychloroquine had both been selected as potential drugs to be tested within the Solidarity Trial as per the initial trial protocol. However the trial was only ever pursued with hydroxychloroquine, so chloroquine was removed from this page as a listed treatment option under study." They did not explain clearly the reason for removing of chloroquine in the SOLIDARITY study. However, it is understandable, as hydroxychloroquine is safer than chloroquine for usage while having similar antiviral effects.
References
1. Global coronavirus COVID-19 trial tracker. https://www.covid19-trials.com/2. Rynes R. Antimalarial drugs in the treatment of rheumatological diseases. Rheumatology. 1997;36(7):799-805.
3. M.J. Vincent, E. Bergeron, S. Benjannet, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology Journal, 2005 Aug 22;2:69. doi: 10.1186/1743-422X-2-69.
4. M. Wang, R. Cao, L. Zhang, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 2020 Mar;30(3):269-271.
5. S. Grassin-Delyle, H.Salvator, M. Brollo, et al. Chloroquine inhibits the release of inflammatory cytokines by human lung explants. Clinical Infectious Diseases, 2020 May 8;ciaa546. doi: 10.1093/cid/ciaa546.
6. J. Gao, Z. Tian, and X. Yang. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends, 2020 Mar 16;14(1):72-73.
7. N. Principi, and S. Esposito. Chloroquine or hydroxychloroquine for prophylaxis of COVID-19. Lancet Infect Dis. 2020 Apr 17:S1473-3099(20)30296-6. doi: 10.1016/S1473-3099(20)30296-6.
8. M.R. Mehra, S.S. Desai, F. Ruschitzka, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 May 22:S0140-6736(20)31180-6.
9. ""SOLIDARITY" clinical trial for COVID-19" https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
10. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021251s058slp. KALETRA (lopinavir and ritonavir) tablet. 12/2019.
11. European Medicines Agency. European public assessment report (EPAR) for Kaletra. https://www.ema.europa.eu/en/documents/overview/kaletra-epar-summary-public_en.pdf
12. J.F. Chan, Y. Yao, M.L. Yeung, et al. Treatment with lopinavir/ritonavir or interferon-?1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis, 2015 Dec 15;212(12):1904-13.
13. K.S. Chan, S.T. Lai, C.M. Chu, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9(6):399-406.
14. B. Cao, Y. Wang, D. Wen, et al. A Trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; 382:1787-1799.
15. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]: Lopinavir. https://www.ncbi.nlm.nih.gov/books/NBK547961/
16. B. Damle, M. Vourvahis, E. Wang, et al. Clinical pharmacology perspectives on the antiviral activity of Azithromycin and use in COVID-19. Review. Clin Pharmacol Ther, 2020 Apr 17. doi: 10.1002/cpt.1857.
17. H. Retallack, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc. Natl. Acad. Sci. 113, 14408-14413 (2016).
18. D.H. Tran, R. Sugamata, T. Hirose, et al. Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering with virus internalization process. J. Antibiot. 72, 759-768 (2019).
19. J. Kouznetsova, W. Sun, C. Martinez-Romero, et al. Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg. Microbes Infect. 3, 1-7 (2014).
20. V. Gielen, S.L. Johnston, and M.R. Edwards. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur. Respir. J. 36, 646-654 (2010).
21. D. Tytec, P.V. Smissen, M. Marcel, et al. Azithromycin, a lysosomotropic antibiotic, has distinct effects on fluid-phase and receptor-mediated endocytosis, but does not impair phagocytosis in J774 macrophages. Exp. Cell Res. 281, 86-100 (2002).
22. U.F. Greber, I. Singh, & A. Helenius. Mechanisms of virus uncoating. Trends Microbiol. 2, 52-56 (1994).
23. Li, C, S. Zhu, Y. Deng, et al. Azithromycin protects against Zika virus infection by upregulating virus-induced type I and III interferon responses. Antimicrob Agents Chemother 63, e00394-e00419 (2019).
24. C.L. Cramer, A. Patterson, A. Alchakaki, et al. Immunomodulatory indications of azithromycin in respiratory disease: a concise review for the clinician. Postgrad. Med. 129, 493-499 (2017).
25. P. Gautret, J. Lagier, P. Parola, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents, 2020 Mar 20;105949.
26. "Actemra/RoActemra (tocilizumab)" https://www.roche.com/products/product-details.htm?productId=42bf9d08-8573-491a-944a-fdbc030ec44b
27. E.A. Coomes, and H. Haghbayan. Interleukin-6 in COVID-19: a systematic review and meta-analysis. https://www.medrxiv.org/content/10.1101/2020.03.30.20048058v1.full.pdf
28. "Roche initiates Phase III clinical trial of Actemra/RoActemra in hospitalised patients with severe COVID-19 pneumonia" https://www.roche.com/media/releases/med-cor-2020-03-19.htm
29. "Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7)." https://www.chinadaily.com.cn/pdf/2020/1.Clinical.Protocols.for.the.Diagnosis.and.Treatment.of.COVID-19.V7.pdf
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