Continued from a series of my blog posts started from 27th May.
12. Ruxolitinib
Ruxolitinib (Jakafi®, Incyte Corporation, Wilmington, DE, USA) is a Janus Kinase 1 (JAK1)/JAK2 inhibitor approved by the US FDA and European Medicines Agnecy for bone-marrow diseases such as polycythaemia vera (PV) and myelofibrosis (MF), which are characterized by aberrant activation of the JAK-STAT pathway.1
Severe COVID-19 patients develop cytokine storm due to overreaction of the immune system. Many cytokines, including IL-2, IL-6, IL-7, IL-10, G-CSF, GM-CSF, and IFN gamma, are implicated in COVID-19-associated cytokine storm via the JAK-STAT pathway.2,3,4 Therefore, compared with molecules that target to only a single cytokine or cytokine receptor, JAK inhibitors, including ruxolutinib, have the potential advantage of inhibiting the activity of multiple cytokines simultaneously.
On the basis of the above hypothesis, a randomised, multi-centre, placebo-controlled, single-blind phase 2 trial in 43 hospitalized patients with severe COVID-19 were first conducted in China to evaluate the efficacy and safety of ruxolitinib for COVID-19.5 Although no statistical difference from the placebo group was observed, ruxolitinib recipients had numerically faster clinical improvement including significant chest CT improvement, faster recovery from lymphopenia, and favourable side-effect profile.
A phase 3 clinical trial of ruxolitinib, RUXCOVID (NCT04331665), launched by Incyte and Novartis will be started soon. The study is to evaluate the safety and efficacy of ruxolitinib in people diagnosed with COVID-19 pneumonia by determining the number of people whose conditions worsen (requiring machines to help with breathing or needing supplemental oxygen) while receiving the drug.6
As mentioned above, JAK inhibitors can inhibit a variety of inflammatory cytokines. This can also inhibit some cytokines which play an important role in curbing virus activity, such as interferon alpha.7 Therefore, detailed analysis of ruxolitinib for its efficacy and safety is very important.
13. Enoxaparin
Enoxaparin (Lovenox) is a low molecular weight heparin (LMWH), an anticoagulant (blood thinner) which is used to prevent blood clots. High D-dimer level, which indicates significant formation and breakdown of fibrin clots in the body, and cytokine storm, are highly correlated with the severity of COVID-19.8-10 In fact, thrombosis (a process of blood clot formation) and inflammation processes mutually reinforce each other.11-13 Therefore, heparins such as enoxaparin, which has anti-inflammatory activity besides the anti-coagulant effects, are tested for their effectiveness in the treatment of severe cases of COVID-19.14 Moreover, LMWH inhibits heparanase activity, which in turn decreases the transcription of IL-6.15,16 Enoxaparin may has similar effect.17
In addition, it was found that heparin interacts with the SARS-CoV-2 spike S1 protein receptor binding domain, thereby attenuating viral attachment and infection.18 This theoretically suggests that enoxaparin is also useful in COVID-19 prevention.
A retrospective study examining 42 hospitalized COVID-19 patients in China revealed a significant decrease in IL-6 levels in an LMWH treatment group compared with a non-LMWH treatment group (p=0.006).17
COVID-19 hospitalized patients have a higher possibility of developing venous thromboembolism (VTE), a condition in which a blood clots form, most often in the deep veins of the leg, groin or arm, and travel in the circulation, lodging in the lungs, causing pulmonary embolism.19 A randomized clinical trial aiming to include 2,712 COVID-19 patients hospitalised on non-intensive care unit, has been approved by the Italian Medicines Agency (AIFA) to compare efficacy (prevention of VTE) and safety (incidence of major/clinically relevant bleeding) of the standard prophylactic dose of enoxaparin with those of a higher dose.20
Enoxaparin is an anticoagulant. Overdose may cause excessive bleeding. Patients should be monitored closely if the drug is applied, as the safety range of the drug is different for different people.
The application of these drugs range from preventive to treatment for patients with different severity levels of the disease. Some of the drugs are tested by themselves, while some antiviral drugs, which have no specific activity, are tested in combinations. The clinical trials of these drugs hopefully can find a drug or combination of drugs that can be repurposed for prevention or treatment of COVID-19, with the correct dose and length of the course, before a vaccine becomes available.
It is becoming clear that many patients who are dying with COVID-19 have underlying comorbidities, such as heart or lung problems. Therefore, it is also important to manage the patient’s pre-existing conditions while trying the drugs repurposed for the COVID-19.21
Currently, the UK is centrally controlling the supply of drugs that may be relevant for the management of COVID-19. The above drugs are not to be prescribed outside of a trial. This is not only because the efficacy of such drugs is unproven and they all have potential side effects, it is also because some people rely on these medicines to control other illnesses.
2. M. Gadina, M.T. Le, D.M. Schwartz DM, et al. Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatology (Oxford). 2019; 58 (suppl 1): i4-i16. doi:10.1093/rheumatology/key432
3. S. Kang, T. Tanaka, M. Narazaki, et al. Targeting interleukin-6 signaling in clinic. Immunity. 2019;50(4):1007-1023. doi:10.1016/j.immuni.2019.03.026
4. W. Damsky, and B. King. Calming the cytokine storm: the potential role of JAK inhibitors in treating COVID-19. The Dermatologist. 2000, Vol. 8, issue 5.
5. Y. Cao, J. Wei, L. Zou, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial. J Allergy Clin Immun. 2020 May 26;S0091-6749(20)30738-7. doi: 10.1016/j.jaci.2020.05.019
6. “Incyte Announces Initiation of Evaluating Ruxolitinib (Jakafi®) as a Treatment for Patients with COVID-19 Associated Cytokine Storm” https://investor.incyte.com/news-releases/news-release-details/incyte-announces-initiation-phase-3-ruxcovid-study-evaluating
7. W. Zhang, Y. Zhao, F. Zhang, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol. 2020 May; 214: 108393. doi: 10.1016/j.clim.2020.108393
8. N. Tang, D. Li, X. Wang, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost., 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768
9. C. Huang, Y. Wang, X. Li, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506.
10. P. Sarzi-Puttini, V. Giorgi, S. Sirotti, et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol 202; 38: 337-342.
11. S.P. Jackson, R. Darbousset, S.M. Schoenwaelder, et al. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood 2019; 133: 906-918.
12. T.A.M. Claushuis, S.F. de Stoppelaar, I. Stroo, et al. Thrombin contributes to protective immunity in pneumonia-derived sepsis via fibrin polymerization and platelet-neutrophil interactions. J Thromb Haemost 2017; 15: 744-757.
13. J. Bester, C. Matshailwe, and E. Pretorius. Simultaneous presence of hypercoagulation and increased clot lysis time due to IL-1β, IL-6 and IL-8. Cytokine. 2018;110:237-242.
14. M. Marietta, W. Ageno, A. Artoni, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus 2020; 18: 167-169. Doi: 10.2450/2020.0083-20
15. I. Vlodavsky, N. Ilan, A. Naggi, et al. Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des. 2007;13(20):2057–2073.
16. A.M. Agelidis, S.R. Hadigal, D. Jaishankar, et al. Viral activation of heparanase drives pathogenesis of Herpes Simplex Virus-1. Cell Rep. 2017;20(2):439–450.
17. C. Shi, C. Wang, H. Wang, et al. The potential of low molecular weight heparin to mitigate cytokine storm in1severe COVID-19 patients: a retrospective clinical study. MedRxiv, 15th April, 2020. doi: https://doi.org/10.1101/2020.03.28.20046144
18. C. Mycroft-West, D. Su, S. Elli, et al. The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding. BioRxiv preprint. doi: https://doi.org/10.1101/2020.02.29.971093
19. S. Tal, G. Spectre, R. Kornowski, et al. Venous thromboembolism complicated with COVID-19: what do we know so far? Review. Acta Haematologica, 2020 May 12;1-8. doi: 10.1159/000508233
20. Marco Cattaneo, Nuccia Morici. Is thromboprophylaxis with high-dose enoxaparin really necessary for COVID-19 patients? A new “prudent” randomised clinical trial. Blood Transfusion. 2020; 18: 237-238. doi: 10.2450/2020.0109-20
21. "The hunt for an effective treatment for COVID-19." The Pharmaceutical Journal, 9 April, 2020. https://www.pharmaceutical-journal.com/news-and-analysis/features/the-hunt-for-an-effective-treatment-for-covid-19/20207883.article?firstPass=false
12. Ruxolitinib
Ruxolitinib (Jakafi®, Incyte Corporation, Wilmington, DE, USA) is a Janus Kinase 1 (JAK1)/JAK2 inhibitor approved by the US FDA and European Medicines Agnecy for bone-marrow diseases such as polycythaemia vera (PV) and myelofibrosis (MF), which are characterized by aberrant activation of the JAK-STAT pathway.1
Severe COVID-19 patients develop cytokine storm due to overreaction of the immune system. Many cytokines, including IL-2, IL-6, IL-7, IL-10, G-CSF, GM-CSF, and IFN gamma, are implicated in COVID-19-associated cytokine storm via the JAK-STAT pathway.2,3,4 Therefore, compared with molecules that target to only a single cytokine or cytokine receptor, JAK inhibitors, including ruxolutinib, have the potential advantage of inhibiting the activity of multiple cytokines simultaneously.
On the basis of the above hypothesis, a randomised, multi-centre, placebo-controlled, single-blind phase 2 trial in 43 hospitalized patients with severe COVID-19 were first conducted in China to evaluate the efficacy and safety of ruxolitinib for COVID-19.5 Although no statistical difference from the placebo group was observed, ruxolitinib recipients had numerically faster clinical improvement including significant chest CT improvement, faster recovery from lymphopenia, and favourable side-effect profile.
A phase 3 clinical trial of ruxolitinib, RUXCOVID (NCT04331665), launched by Incyte and Novartis will be started soon. The study is to evaluate the safety and efficacy of ruxolitinib in people diagnosed with COVID-19 pneumonia by determining the number of people whose conditions worsen (requiring machines to help with breathing or needing supplemental oxygen) while receiving the drug.6
As mentioned above, JAK inhibitors can inhibit a variety of inflammatory cytokines. This can also inhibit some cytokines which play an important role in curbing virus activity, such as interferon alpha.7 Therefore, detailed analysis of ruxolitinib for its efficacy and safety is very important.
13. Enoxaparin
Enoxaparin (Lovenox) is a low molecular weight heparin (LMWH), an anticoagulant (blood thinner) which is used to prevent blood clots. High D-dimer level, which indicates significant formation and breakdown of fibrin clots in the body, and cytokine storm, are highly correlated with the severity of COVID-19.8-10 In fact, thrombosis (a process of blood clot formation) and inflammation processes mutually reinforce each other.11-13 Therefore, heparins such as enoxaparin, which has anti-inflammatory activity besides the anti-coagulant effects, are tested for their effectiveness in the treatment of severe cases of COVID-19.14 Moreover, LMWH inhibits heparanase activity, which in turn decreases the transcription of IL-6.15,16 Enoxaparin may has similar effect.17
In addition, it was found that heparin interacts with the SARS-CoV-2 spike S1 protein receptor binding domain, thereby attenuating viral attachment and infection.18 This theoretically suggests that enoxaparin is also useful in COVID-19 prevention.
A retrospective study examining 42 hospitalized COVID-19 patients in China revealed a significant decrease in IL-6 levels in an LMWH treatment group compared with a non-LMWH treatment group (p=0.006).17
COVID-19 hospitalized patients have a higher possibility of developing venous thromboembolism (VTE), a condition in which a blood clots form, most often in the deep veins of the leg, groin or arm, and travel in the circulation, lodging in the lungs, causing pulmonary embolism.19 A randomized clinical trial aiming to include 2,712 COVID-19 patients hospitalised on non-intensive care unit, has been approved by the Italian Medicines Agency (AIFA) to compare efficacy (prevention of VTE) and safety (incidence of major/clinically relevant bleeding) of the standard prophylactic dose of enoxaparin with those of a higher dose.20
Enoxaparin is an anticoagulant. Overdose may cause excessive bleeding. Patients should be monitored closely if the drug is applied, as the safety range of the drug is different for different people.
Summary
As we can see from the above list, the drugs being tested range from monoclonal antibodies (e.g. tocilizumab, sarilumab), to steroids (e.g. corticosteroids), nucleic acid analogues (e.g. favipiravir, Remdesivir), and viral protease/polymerase inhibitors (e.g. lopinavir/ritonavir). Their actions range from inhibiting SARS-CoV-2 viral entry (e.g. umifenovir), to inhibiting the viral replication (e.g. chloroquine, hydroxychloroquine, lopinavir/ritonavir, azithromycin, favipiravir, Remdesivir), relieving cytokine storm that occurred in severe COVID-19 cases (e.g. tocilizumab, corticosteroids, INF beta, sarilumab, ruxolitinib), and inhibiting coagulation that may cause blood clotting (e.g. enoxaparin).The application of these drugs range from preventive to treatment for patients with different severity levels of the disease. Some of the drugs are tested by themselves, while some antiviral drugs, which have no specific activity, are tested in combinations. The clinical trials of these drugs hopefully can find a drug or combination of drugs that can be repurposed for prevention or treatment of COVID-19, with the correct dose and length of the course, before a vaccine becomes available.
It is becoming clear that many patients who are dying with COVID-19 have underlying comorbidities, such as heart or lung problems. Therefore, it is also important to manage the patient’s pre-existing conditions while trying the drugs repurposed for the COVID-19.21
Currently, the UK is centrally controlling the supply of drugs that may be relevant for the management of COVID-19. The above drugs are not to be prescribed outside of a trial. This is not only because the efficacy of such drugs is unproven and they all have potential side effects, it is also because some people rely on these medicines to control other illnesses.
References
1. S. Ajayi, H. Becker, H. Reinhardt, et al. Ruxolitinib. Recent Results Cancer Res., 2018; 212:119-32.2. M. Gadina, M.T. Le, D.M. Schwartz DM, et al. Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatology (Oxford). 2019; 58 (suppl 1): i4-i16. doi:10.1093/rheumatology/key432
3. S. Kang, T. Tanaka, M. Narazaki, et al. Targeting interleukin-6 signaling in clinic. Immunity. 2019;50(4):1007-1023. doi:10.1016/j.immuni.2019.03.026
4. W. Damsky, and B. King. Calming the cytokine storm: the potential role of JAK inhibitors in treating COVID-19. The Dermatologist. 2000, Vol. 8, issue 5.
5. Y. Cao, J. Wei, L. Zou, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial. J Allergy Clin Immun. 2020 May 26;S0091-6749(20)30738-7. doi: 10.1016/j.jaci.2020.05.019
6. “Incyte Announces Initiation of Evaluating Ruxolitinib (Jakafi®) as a Treatment for Patients with COVID-19 Associated Cytokine Storm” https://investor.incyte.com/news-releases/news-release-details/incyte-announces-initiation-phase-3-ruxcovid-study-evaluating
7. W. Zhang, Y. Zhao, F. Zhang, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol. 2020 May; 214: 108393. doi: 10.1016/j.clim.2020.108393
8. N. Tang, D. Li, X. Wang, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost., 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768
9. C. Huang, Y. Wang, X. Li, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506.
10. P. Sarzi-Puttini, V. Giorgi, S. Sirotti, et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol 202; 38: 337-342.
11. S.P. Jackson, R. Darbousset, S.M. Schoenwaelder, et al. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood 2019; 133: 906-918.
12. T.A.M. Claushuis, S.F. de Stoppelaar, I. Stroo, et al. Thrombin contributes to protective immunity in pneumonia-derived sepsis via fibrin polymerization and platelet-neutrophil interactions. J Thromb Haemost 2017; 15: 744-757.
13. J. Bester, C. Matshailwe, and E. Pretorius. Simultaneous presence of hypercoagulation and increased clot lysis time due to IL-1β, IL-6 and IL-8. Cytokine. 2018;110:237-242.
14. M. Marietta, W. Ageno, A. Artoni, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus 2020; 18: 167-169. Doi: 10.2450/2020.0083-20
15. I. Vlodavsky, N. Ilan, A. Naggi, et al. Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des. 2007;13(20):2057–2073.
16. A.M. Agelidis, S.R. Hadigal, D. Jaishankar, et al. Viral activation of heparanase drives pathogenesis of Herpes Simplex Virus-1. Cell Rep. 2017;20(2):439–450.
17. C. Shi, C. Wang, H. Wang, et al. The potential of low molecular weight heparin to mitigate cytokine storm in1severe COVID-19 patients: a retrospective clinical study. MedRxiv, 15th April, 2020. doi: https://doi.org/10.1101/2020.03.28.20046144
18. C. Mycroft-West, D. Su, S. Elli, et al. The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding. BioRxiv preprint. doi: https://doi.org/10.1101/2020.02.29.971093
19. S. Tal, G. Spectre, R. Kornowski, et al. Venous thromboembolism complicated with COVID-19: what do we know so far? Review. Acta Haematologica, 2020 May 12;1-8. doi: 10.1159/000508233
20. Marco Cattaneo, Nuccia Morici. Is thromboprophylaxis with high-dose enoxaparin really necessary for COVID-19 patients? A new “prudent” randomised clinical trial. Blood Transfusion. 2020; 18: 237-238. doi: 10.2450/2020.0109-20
21. "The hunt for an effective treatment for COVID-19." The Pharmaceutical Journal, 9 April, 2020. https://www.pharmaceutical-journal.com/news-and-analysis/features/the-hunt-for-an-effective-treatment-for-covid-19/20207883.article?firstPass=false
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