Coronavirus (16) Non-specific effects of BCG vaccine to prevent COVID-19?

After reading my blog posts introducing the existing drugs being tested for COVID-19 treatment, you may wonder if there are any existing vaccines being tested for prevention of COVID-19. The answer is yes. This is a vaccine for tuberculosis (TB) called Bacille Calmette Guérin (BCG) which is now being tested in several clinical trials globally.

BCG was developed in France by Albert Calmette and Camille Guérin in order to prevent TB in the last century. The two scientists made use of a strain of bacteria that caused bovine tuberculosis (Mycobacterium bovis), diminished its virulent activity, and applied it to humans.¹ The application of the weakened cattle bacteria induces the generation of antibodies which can also recognize and neutralize the bacteria that causes TB in humans, Mycobacterium tuberculosis. This makes BCG very effective in preventing TB.

However, the cattle bacteria that causes TB is very different from the human virus SARS-CoV-2. The perceived benefit of the BCG vaccine for COVID-19 prevention is not based on the cross neutralizing effect of the antibody generated against the vaccine. Rather, it is the vaccine's ability to initiate an overall boost to the immune system.

BCG is a live attenuated vaccine (live but with substantially weakened virulence activity). For a long time, scientists have observed a phenomena that live attenuated vaccines have "non-specific effects", which means that the protective effect of vaccine can extend to some infectious or inflammatory diseases other than its initial specific target.²

Since the introduction of the vaccine in the 1920s, several studies reported a reduction of neonatal mortality in countries where BCG vaccines are administered to newborns. The reduction rate could not be explained only by the reduction of tuberculosis.³ Later in the 2000s in Guinea-Bissau, a random controlled trial showed that BCG vaccine administered at birth to low-birth-weight infants showed an up-to-50% reduction of mortality in young children. This reduction was suggested to be due to the protection against unrelated infectious agents that cause respiratory tract infections, septicemia (a blood poisoning which occurs when a bacterial infection elsewhere in the body, such as the lungs or skin, enters the bloodstream),⁴ and fever.⁵

Moreover, it seems that the protection from the "non-specific effects" conferred by the administration of BCG is not only limited to newborn children. A study taken from 1971 to 2010 in Denmark showed that BCG given at school entry was associated with a significant reduction in the risk of dying from natural causes before the age of 45 years.⁶ Additionally, a clinical trial giving the BCG vaccine to tuberculin-negative elderly in Japan showed a protection against pneumonia. This demonstrates that the BCG vaccine can also confer non-specific protection when administered late in life.⁷

In fact, an experimental infection provides evidence that the vaccine can reduce the severity of infections by other viruses in vivo. It is demonstrated by the finding that a BCG vaccine given 4 weeks prior to a yellow fever vaccine reduced the viraemia (the presence of a virus in bloodstream) by 71% in volunteers in the Netherlands.⁸ Because of its non-specific effects, the BCG vaccine is also used as adjuvant immunotherapy for patients with non-muscle-invasive bladder cancer, to induce immune-stimulating effects that slow down tumour progression.^9,10

Above are some of the examples of the non-specific effects the BCG vaccine conferred. But how did the BCG vaccine correlate with COVID-19? Since the outbreak of the disease, there is a high heterogeneity of infection and mortality rates across countries, and scientists tried to find out the reasons behind this. One of the hypotheses is the vaccination coverage. When analysing the BCG and another 8 vaccines' coverages in the years of 2018, 2008, 1998 and 1988, in 125 countries around the world, a study found a significant moderate negative correlation between BCG coverage and the number of COVID-19 cases. This means the higher the BCG coverage, the less the number of COVID-19 cases per unit population.¹¹ Some observation speculative reports also found that ratio of COVID-19 cases per population and the ratio of deaths per COVID-19 cases are significantly lower in BCG-vaccinated countries.^12-14

The combination of reduced morbidity and mortality has led to the suggestion that vaccination with BCG might have a role in protecting health-care workers and other vulnerable individuals against COVID-19.

According to the data from the ClinicalTrials.org (a database of privately and publicly funded clinical studies conducted around the world), there are 18 trials registered to test the BCG vaccines on their effectiveness at protection against COVID-19.¹⁵ Among these, eight are currently in progress: randomised controlled trials in the Netherlands, South Africa, Australia, and the USA are to test whether BCG vaccination of health-care workers could protect them from COVID-19; a randomised controlled trial in Greece is to test the effect of BCG vaccination on the prevention of severe COVID-19 infection among older people; two random placebo-controlled trials in Germany are testing a genetically modified BCG vaccine, VPM1002, on health-care workers and older patients, respectively; and a clinical trial in Egypt is to check if COVID-19 cases admitted to hospitals or intensive care units had been vaccinated with BCG before.

These clinical trials are useful for us to understand whether and how the vaccine confers resistance to the causal virus of COVID-19.



References
1. S. Luca, and T. Mihaescu. History of BCG vaccine. Maedica, 2013, 8:53-58.
2. P. Aaby, and C. S. Benn. Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies. Review. Clin. Microbiol. Infect, 2019, 25(12):1459-1467.
3. Shann, F. The non-specific effects of vaccines. Arch. Dis. Child, 2010, 95, 662-667.
4. https://www.healthline.com/health/septicemia
5. P. Aaby, A. Roth, H. Ravn, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J. Infect. Dis., 2011, 204, 245-252.
6. A. Rieckmann, M. Villumsen, S. Sorup, et al. Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971-2010. Int J Epidemiol., 2017, 46: 695-705.
7. T. Ohrui, K. Nakayama, T. Fukushima, et al. Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations [Japanese]. Nihon Ronen Igakkai Zasshi, 2005, 42, 34-36.
8. R.J.W. Arts, S.J.C.F.M. Moorlag, B. Novakovic, et al. BCG Vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe, 2018, 23: 89-100.
9. G. Redelman-Sidi, M.S. Glickman, and B.H. Bochner. The mechanism of action of BCG therapy for bladder cancer-a current perspective. Nat. Rev. Urol. 2014, 11, 153-162.
10. R.F. Han, and J.G. Pan. Can intravesical bacillus Calmette-Guérin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology, 2006, 67, 1216-1223.
11. A. Macedo, and C. Febra. Relation between BCG coverage rate and COVID-19 infection worldwide. Med Hypothesis, 2020 May 6;142:109816.
12. C. Ozdemir, U.C. Kucuksezer, and Z.U. Tamay. Is BCG vaccination affecting the spread and severity of COVID-19? Allergy. 2020;00:1-3.
13. A. Iwasaki, and N.D. Grubaugh. Why does Japan have so few cases of COVID-19? EMBO Molecular Medicine, 2020 May 8;12(5):e12481.
14. A. Miller, M.J. Reandelar, K. Fasciglione, et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. MedRxiv doi: https://doi.org/10.1101/2020.03.24.20042937
15. https://clinicaltrials.gov/ct2/results?term=bcg&cond=COVID&draw=1&rank=10#rowId9

Coronavirus (15) Dexamethasone: the world's first approved COVID-19 drug (e)

Yesterday in the daily coronavirus briefing, the UK government reported an encouraging finding that dexamethasone reduces the COVID-19 mortality rate, and authorised the use of this drug for severely ill COVID-19 patients who required oxygen, including those on mechanical ventilators.¹ Most of you must have read a lot about the preliminary results from the clinical trial RECOVERY (Randomized Evaluation of COVID-19 Therapy) led by the University of Oxford.² I am not going to repeat what the news has reported these two days. Here I would rather like to explain the mechanism of the drug and explain why it is important not to try to buy the drug and take it home for COVID-19 treatment.

Dexamethasone is a synthetic corticosteroid (steroid) among the most popular drugs being tested for COVID-19. It has been used since 1960 to treat people suffering from a variety of conditions relating to inflammation, such as some skin conditions, arthritis, asthma, and inflammatory bowel disease.

The drug suppresses inflammation by inhibiting the expression of many inflammatory mediators, the cells of the immune system. Severely ill COVID-19 patients who need oxygen suffer from an over-reaction of the immune system, called a cytokine storm, which causes lung injury and multi-organ failure, and can be deadly.³ The suppressive effect on the immune system by dexamethasone helps to calm down the cytokine storm. This explains why the drug can significantly reduce deaths in ventilated patients and the patients in need of oxygen.

The clinical trial result showed that the drug only works in severe cases while having little effect on COVID-19 patients with lesser symptoms of the disease. This is because the patients with less severity are not affected by over-reaction of the immune system. The application of the drug thus has no benefit for these patients.

It is also notable that the clinical trial RECOVERY used "low dose" of the dexamethasone for "up to 10 days" on the patients.² This is because previous experiences showed that higher cumulative doses and longer treatment durations of corticosteroids are more likely to develop osteonecrosis in SARS patients.⁴ In fact, in general practice, clinicians would avoid long-term prescription of the drug, and the drug tapered quickly if the patient is improving.⁵

The drug has no life-threatening side effects. However, patients with chronic use of the drug are usually monitored for mood changes, development of osteoporosis, weight gain, hyperglycemia, electrolyte changes, and depression.⁵ Moreover, the use of the drug is contraindicated if patients have systemic fungal infections, hypersensitivity to dexamethasone, or cerebral malaria.⁵

In addition to the side effects it can cause and the contraindication, the use of the drug in early treatment of patients infected with coronaviruses has shown association with a higher subsequent plasma viral load.^6,7 This seems to indicate that the drug's ability to reduce the immune response could also reduce the inflammatory response and prolong the viral load.

The drug is cheap and people can buy the drug on prescription for use with other conditions. However, we should not try to buy it and take it home for COVID-19 treatment, as it showed no effect on patients with no critical symptoms. Even for the severely ill patients, the right dose, the right timing, the right length of treatment, and the knowledge of the contraindications are important if the drug is to be beneficial to the patients.

References

1. "World first coronavirus treatment approved for NHS use by government" Department of Health and Social Care, UK, 16 June, 2020. https://www.gov.uk/government/news/world-first-coronavirus-treatment-approved-for-nhs-use-by-government

2. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. RECOVERY news, 16 June 2020. https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19

3. X. Zhang, Y. Tan, Y. Ling, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature, 2020 May 20. doi: 10.1038/s41586-020-2355-0

4. R. Zhao, H. Wang, X. Wang, et al. Steroid therapy and the risk of osteonecrosis in SARS patients: a dose-response meta-analysis. Osteoporos Int, 2017 Mar;28(3):1027-1034.

5. D.B. Johnson, M.J. Lopez, and B. Kelley. Dexamethasone. 2020 Apr 27. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. PMID: 29489240

6. N. Lee, K.C. Chan, S. Hui, et al. Effects of early corticosteroid treatment on plasma SARS-associatedCoronavirusRNA concentrations in adult patients. Journal of Clinical Virology, 31 (2004) 304-309.

7. Y.M. Arabi, Y. Mandourah, F. Al-Hameed, et al. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome. Am J Respir Crit Care Med., 2018; 197: 757-767.

Coronavirus (14) Popular drugs tested for effectiveness in COVID-19 treatment (d)

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.

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

Coronavirus (13) Popular drugs tested for effectiveness in COVID-19 treatment (c)

Continued from my blog post on 27th May.
8. Umifenovir
Umifenovir (Arbidol, Pharmstandard Group, Moscow, Russia) is a broad-spectrum antiviral drug similar to favipiravir, and has shown efficacy in Russia and China in the prophylactic (prevention) or treatment of infection by influenza viruses.^1,2 It is a viral entry inhibitor, working by interacting with the virus hemagglutinin and thus preventing fusion of the viral envelope with the target human cell membranes. The molecule also affects other stages of the virus life cycle, either by direct targeting viral proteins or virus-associated host factors.³ The drug is licensed only in China and Russia; it is not approved for use in other countries. It is not in the US FDA's list of approved drugs for prevention of influenza.⁴

Since 2004, umifenovir has been patented for its medicinal use as an antiviral agent against atypical pneumonia induced by SARS-CoV.³ An in vitro study showed that umifenovir efficiently inhibited SARS-CoV-2 infection with 50% maximal effective concentration (EC50) of 4.11uM, which is within the range of safe clinical dose.⁵ However, the drug is less effective than favipiravir in a comparative study on COVID-19 patients. The seven-day recovery rate for the umifenovir group was significantly lower than that for the favipiravir group (55.86% vs 71.43%, p= 0.0199). Patients with hypertension or diabetes also showed better improvement in the favipiravir group than in the umifenovir group.⁶

Umifenovir has recently been added to the Guidelines for the Diagnosis and Treatment of COVID-19 (sixth and seventh editions) in China. Many phase 4 clinical trials, mainly performed in China, are currently running for umifenovir in the treatment of COVID-19.^7,8,9

9. Remdesivir
Remdesivir (GS-5734) was developed by Gilead Sciences Inc. It is an adenosine analogue. It shuts down viral replication by inhibiting RNA-dependent RNA polymerase, and blocks the virus from making its genetic material. Research on the drug began in 2009 and antiviral profiling of the drug suggested it has the potential of a broad spectrum of antiviral activity. Before the outbreak of COVID-19, it was still an investigational product and had not been approved anywhere globally. Its safety and efficacy for any use had not been determined.¹⁰

The drug was first used to combat Ebola and related viruses but did not show effectiveness. In 2017, researchers at the University of North Carolina showed in in vitro and animal studies that the drug can inhibit the coronaviruses that cause SARS and MERS.¹¹ Promising results suggested it may have some effect in patients infected with SARS-CoV-2.

Remdesivir was given to the first COVID-19 patient diagnosed in the United States when his condition worsened. The man improved the next day.¹² A double-blind, randomized, placebo-controlled trial including 1,063 patients in hospitals around the world indicated that the drug shortened the length of illness from 15 days to 11 days.¹³

Gilead has initiated its own two phase 3 studies of the drug.¹⁰ Moreover, the drug is one of the candidates in WHO's megatrial SOLIDARITY and in the INSERM-sponsored DisCoVeRy trial in Europe.^14,15

The Department of Health and Social Care has approved the drug as the first medicine to treat COVID-19 in the UK. It is likely that those patients with the most severe cases of the disease will have priority in receiving the drug treatment. However, there is a concern over the side effects related to the liver and kidneys. Moreover, whether the manufacturer can provide enough supply for the exponential demand of the drug is another concern.¹⁶ Outisde the UK, the US and Japan are also using this drug to treat COVID-19 patients.^17,18

10. Sarilumab (Immune system inhibitors, anti-inflammatory drug)
Sarilumab (Kevzara®, Sanofi, New York, NY, USA and Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA) is approved for the treatment of rheumatoid arthritis in multiple countries. It is an antibody against the interleukin 6 (IL-6) receptor and can effectively block IL-6 signal transduction. IL-6 is one of the excessive cytokines produced as a result of COVID-19 infection and causes lung inflammation.¹⁹

A single group study of another IL-6 inhibitor similar to sarilumab, tocilizumab, with 21 severe, febrile hospitalized COVID-19 patients, showed fever returned to normal and improved oxygenation upon tocilizumab treatment.²⁰

Based on the above findings, the two developers of sarilumab, Sanofi and Regeneron, are in partnership with Northwell Health's Feinstein Institutes for Medical Research, to evaluate the effects of sarilumab on fever and the need for supplemental oxygen in a phase 2/3 trial. Preliminary analysis showed that sarilumab, similar to tocilizumab, rapidly lowered C-reactive protein, a key marker of inflammation.^20,21 However, sarilumab did not show notable clinical benefit versus placebo when combining the severe group (patients who required oxygen supplementation without mechanical or high-flow oxygenation) and the critical group (patients who required mechanical ventilation or high-flow oxygenation or required treatment in an intensive care unit). On the other hand, positive trends were reported for all outcomes in the critical group. They have now set a phase 3 trial with two amendments so that only the more advanced critical patients continue to be enrolled to receive treatment, and all new patients are to receive either higher-dose Kevzara or placebo.²¹

11. Colchicine
Colchicine is an anti-inflammatory drug used for rheumatic and non-rheumatic diseases such as gout, familial Mediterranean fever, and pericarditis (a condition in which the sac around the heart becomes inflamed).²² Colchicine prevents microtubule assembly and disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of cytokines, phagocytosis, and migration of neutrophils.²³

Due to its ability to suppress the generation of cytokines, it has been suggested that colchicine may be effective in relieving cytokine storm seen during SARS-CoV-2 infection. The drug thus has been widely tested in clinical trials in the world for its efficiency in severe COVID-19 patients of different levels.^24-26

However, there is a concern of causing of acute respiratory distress syndrome and multi-organ failure, the two common causes of death in COVID-19 patients, if an inappropriate dose of colchicine is used.^27,28

References

1. V.M. Gagarinova, G.S. Ignat'eva, L.V. Sinitskaia, et al. The new chemical preparation arbidol: its prophylactic efficacy during influenza epidemics. Zh. Mikrobiol. Epidemiol. Immunobiol. 1993;5:40-43. (Article in Russian, abstract available in English)
2. M.Z. Wang, B.Q. Cai, L.Y. Li, J.T. Lin, et al. Efficacy and safety of arbidol in treatment of naturally acquired influenza. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2004;26:289-293. (Article in Chinese, abstract available in English)
3. J. Blaising, S.J. Polyak, & E.I. Pecheur. Arbidol as a broad-spectrum antiviral: an update. Antivir. Res. 107, 84-94 (2014). 4. "FDA approved drugs for influenza" https://www.fda.gov/drugs/information-drug-class/influenza-flu-antiviral-drugs-and-related-information#ApprovedDrugs
5. X. Wang, R. Cao, H. Zhang, et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discovery, 6, Article number: 28 (2020).
6. C. Chen, Y. Zhang, J. Huang J, et al. Favipiravir versus arbidol for COVID-19: A randomized clinical trial. MedRxiv preprint doi: https://doi.org/10.1101/2020.03.17.20037432 this version posted April 15, 2020.
7. "Clinical study of Arbidol hydrochloride tablets in the treatment of pneumonia caused by novel coronavirus." ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04260594
8. "A prospective, randomized controlled clinical study of antiviral therapy in the 2019-nCoV pneumonia." ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04255017
9. "The clinical study of carrimycin on treatment patients with Covid-19." ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04286503
10. "Development of Remdesivir" https://www.gilead.com/-/media/gilead-corporate/files/pdfs/covid-19/gilead_rdv-development-fact-sheet-2020.pdf
11. T.P. Sheahan, A.C. Sims, R.L. Graham, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine. Vol. 9, Issue396, eaal3653.
12. M.L. Holshue, C. DeBolt, S. Lindquist, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382:929-936.
13. J.H. Beigel, K.M. Tomashek, L.E. Dodd, et al. Remdesivir for the treatment of Covid-19 - preliminary report. NEJM. 2020 May 22;NEJMoa2007764. doi: 10.1056/NEJMoa2007764.
14. ""Solidarity" clinical trial for COVID-19 treatments" WHO. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
15."Launch of a European clinical trial against COVID-19" https://presse.inserm.fr/en/launch-of-a-european-clinical-trial-against-covid-19/38737/
16. "Gilead's virus drug seen in short supply for Americans" Bloomberg News. https://www.bloomberg.com/news/articles/2020-05-11/gilead-s-covid-19-drug-seen-in-short-supply-for-americans.
17. "Gilead's investigational antiviral Remdesivir receives U.S. Food and Drug Administration emergency use authorization for the treatment of COVID-19" https://www.gilead.com/news-and-press/press-room/press-releases/2020/5/gileads-investigational-antiviral-remdesivir-receives-us-food-and-drug-administration-emergency-use-authorization-for-the-treatment-of-covid19
18. "Gilead announces approval of Veklury® (remdesivir) in Japan for patients with severe COVID-19" 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
19. W. Ahsan, S. Javed, M.A. Bratty, et al. Treatment of SARS-CoV-2: How far have we reached? Review. Drug Discoveries & Therapeutics. 2020; 14(2):67-72.
20. X. Xu, M. Han, T. Li, et al. Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXiv. http://www.chinaxiv.org/abs/202003.00026
21. "Sanofi and Regeneron provide update on U.S. Phase 2/3 adaptive-designed trial in hospitalized COVID-19 patients" https://www.sanofi.com/en/media-room/press-releases/2020/2020-04-27-12-58-00
22. Y.Y. Leung, L.L.Y. Hui, and V.B. Kraus. Colchicine-update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum., 2015, 45:341-350.
23. N. Dalbeth, T.J. Lauterio, and H.R. Wolfe. Mechanism of action of colchicine in the treatment of gout. Clin Ther., 2014, 36:1465-1479.
24. "Could the ancient drug colchicine help fight COVID-19?" MedicineNet, 23rd April, 2020. https://www.medicinenet.com/script/main/art.asp?articlekey=230649
25. S.G. Deftereos, G. Siasos, G. Gianopouolos, et al. The Greek study in the effects of colchicine in COVID-19 complications prevention (GRECCO-19 Study): rationale and study design. Hellenic J Cardio. 2020 Apr 3;S1109-9666(20)30061-0. doi:10.1016/j.hjc.2020.03.002.
26. "The effects of standard protocol with or without colchicine in Covid-19 infection" (NCT04360980) https://clinicaltrials.gov/ct2/show/NCT04360980
27. M. Maurizi, N. Delorme, M.C. Laprévote-Heully, et al. Acute respiratory distress syndrome in adults in colchicine poisoning. Ann Fr Anesth Reanim., 1986, 5:530-532.
28. M.C.Cure, A. Kucuk, and E. Cure. Colchicine may not be effective in COVID-19 infection; it may even be harmful? Letter to the editor. Clinical Rheumatology, 2020. https://doi.org/10.1007/s10067-020-05144-x

Coronavirus (12) Popular drugs tested for effectiveness in COVID-19 treatment (b)

Continued from my last blog post.

5. Corticosteroids (e.g. dexamethasone, hydrocortisone, methylprednisolone, prednisolone)

Corticosteroids are steroidal hormones that have anti-inflammatory functions, and are normally used to suppress inflammatory conditions resulting from immune system overdrive in fighting off infection. They were widely used in Hong Kong in the 2003 SARS epidemic.¹

The results of using corticosteroids on coronavirus infected patients were contradictory and mostly unfavourable. A study comparing 1287 steroid-treated and no-steroid-treated patients in Hong Kong showed that corticosteroid groups had a lower crude death rate.² However, a retrospective cohort study of SARS patients showed adverse outcomes (either ICU admission or mortality) following corticosteroid therapy.³ Early treatment of hydrocortisone in SARS patients was associated with a higher subsequent plasma viral load.⁴ Similarly, a delayed clearance of viral RNA from the respiratory tract was also observed in MERS patients with corticosteroid treatment.⁵ It seems that by reducing the inflammatory response, corticosteroids also reduce the rest of the immune response and prolong the viral load. Moreover, a meta-analysis synthesized from 10 trials suggested that higher cumulative doses and longer treatment durations of corticosteroids are more likely to develop osteonecrosis in SARS patients.⁶

In view of no unique reason existing to expect that COVID-19 patients will benefit from corticosteroids, and they might be more likely to be harmed with such treatment, a recent review in The Lancet suggested that corticosteroids should not be used for the treatment of COVID-19-induced lung injury or shock outside of a clinical trial.⁷ Based on the fact of lack of effectiveness and possible harm, WHO advises against the use of corticosteroids for COVID-19 unless they are indicated for another reason.⁸

There are, however, study results from several reports demonstrating that the timing, dosage, and duration of corticosteroid therapy are critical if this intervention is to be beneficial in patients.^2,9 In a systematic review and meta-analysis including 15 studies published since 2002 and a total of 5,270 patients infected with SARS-CoV, MERS-CoV or SARS-CoV-2, it is suggested that moderate corticosteroids can be used in patients with severe conditions to suppress the immune response and reduce symptoms.¹⁰

A UK-based clinical trial RECOVERY (Randomised Evaluation of COVid-19 thERapY) and a global REMAP-CAP trial collaborated together to test the effectiveness of dexamethasone in critically ill patients.¹¹

6. Favipiravir

Favipiravir (Avigan®, FUJIFILM Toyama Chemical Co., Ltd., Tokyo, Japan) is an approved influenza antiviral drug. It is a purine nucleic acid analogue and broad spectrum inhibitor of RNA-dependent RNA polymerase (RdRp) associated with viral replication. As the drug specifically blocks RNA polymerase, the mechanism is expected to have an antiviral effect on SARS-CoV-2 as this is a single-stranded RNA virus like the influenza virus.¹² Favipiravir has molecular mechanical activity similar to Remdesivir. While Remdesivir is intended for use in the most severe cases of COVID-19 and reduces their recovery time, favipiravir is tested in the hope that it may help a wider range of patients.

Ebola patients treated with favipiravir showed a trend toward improved survival.¹³ A retrospective analysis showed a higher overall survival rate and longer average survival time on Ebola patients with additional favipiravir treatment, in comparison with patients with the WHO-recommended supportive therapy. In addition, a higher percentage of Ebola patients who received favipiravir treatment had a more than 100-fold viral load reduction.¹⁴

A clinical trial (ChiCTR2000029600) conducted in Shenzhen recruiting 80 patients showed that 35 patients in the favipiravir arm demonstrated significantly shorter viral clearance time, compared with the 45 patients in the control arm (median 4 days vs. 11 days). X-ray chest image confirmed a higher rate of improvement in the favipiravir arm.¹⁵ For ordinary patients with COVID-19, the 7-day clinical recovery rate increased from 55.86% to 71.43% with favipiravir treatment. The time of fever reduction and cough relief also decreased significantly.¹⁶

The drug is currently in phase 3 development by the original manufacturer (NCT04358549).¹⁷ It may be added to the trial SOLIDARITY later by WHO.

Although the using of favipiravir for COVID-19 treatment sounds promising, the Health Minister of Japan, Katsunobu Kato, revealed on May 26 that his ministry has given up on the government's end-May target for approving the drug for the treatment of COVID-19, as no sufficient data to support its efficacy are yet available.¹⁸ In fact, favipiravir has a risk for teratogenicity and embryotoxicity.¹⁹ The mechanism that makes the drug effective against viruses also makes it destructive to fetuses with rapid cell growth.

7. Interferon beta (e.g. Betaferon (INF-β1b), Rebif (INF-β1a))

Human recombinant interferon beta (INF-β) was originally developed for chronic obstructive pulmonary disorder. Subcutaneous injections of INF-β have been used for the treatment of multiple sclerosis for more than 20 years.²⁰ The human body naturally produce INF-β as a defensive response to viruses.²¹ It is involved in regulating inflammation in the body and is known to improve the lung's condition and enhance the lung's ability to fight viral infections. A decrease in INF-β production is directly linked to increased susceptibility of people to develop severe respiratory diseases resulting from viral infections; SARS-CoV-2 infection can suppress the INF-β production in the body.²²

Interferon beta has shown antiviral effects in vitro and in marmosets infected with MERS.^23-26 However, the molecule generally failed to show significant improvement on humans with MERS and SARS infection.²⁷ On the other hand, a recent in vitro study showed that human recombinant INF-β1a inhibits SARS-CoV-2 virus load in cultured cells, at concentrations that are clinically achievable in patients, demonstrating the therapeutic potential of the molecules against COVID-19.²⁸ According to the researcher of the study, "the data may provide an explanation, at least in part, to the observation that approximately 80% of patients actually develop mild symptoms and recover. It is possible that many of them are able to mount IFN-β-mediated innate immune response upon SARS-CoV-2 infection, which helps to limit virus infection/dissemination at an early stage of disease."

The timing for INF-β administration and the application of the molecules to the right people is critical. An in vivo study demonstrated that INF-β administration shortly after infection protected mice from lethal MERS-CoV infection, by inhibiting virus replication and inflammatory cytokine production. On the other hand, delayed administration caused the failure to inhibit viral replication and had adverse events.²⁹ It is also important to apply INF-β treatment to patients only if they don't have comorbidities.^30,31

Due to its unspecific antiviral effects, the molecule is often evaluated, usually in combination with other drugs, before specific treatments are developed. For example, a combination of IFN-β with lopinavir/ritonavir was used against MERS-CoV and showed improvement in pulmonary function.³²

In clinical trials for COVID-19 treatment, IFN-β is usually used in combination with lopinavir/ritonavir. Subcutaneous IFN-β1a in combination with lopinavir/ritonavir is being tested in the WHO global megatrial Solidarity.³³ Subcutaneous IFN-β1b in combination with lopinavir/ritonavir and ribavirin was also tested in other clinical trials such as the open-label one performed in Hong Kong (NCT04276688), for the treatment of COVID-19.³⁴ The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days) than the control group (12 days).

An inhaled form of IFN-β1a, called SNG001, produced by Synairgen, is also being tested in a placebo-controlled trial led by Tom Wilkinson at the University of Southampton. The trial will use the drug much earlier in the course of the illness, to find out if the drug can protect the lungs and prevent the development of the severe lower respiratory tract illness.³⁵ The participants of the trial will receive either SNG001 or placebo, inhaled once daily for 14 days in their homes. Their general medical condition, levels of breathlessness, cough and sputum (mucus from the lungs) will be recorded every day, along with any safety information.

References

1. L.K. So, A.C. Lau, L.Y. Yam, et al. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet. 2003; 361: 1615-1617.

2. Y.C. Yam, C.W. Lau, Y.L. Lai, et al. Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong. Journal of Infection. (2007) 54, 28-39.

3. T.W. Auyeung, S.W. Lee, W.K. Lai, et al. The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study. J Infect. (2005) 51(2):98-102.

4. N. Lee, K.C. Chan, S. Hui, et al. Effects of early corticosteroid treatment on plasma SARS-associatedCoronavirusRNA concentrations in adult patients. Journal of Clinical Virology, 31 (2004) 304-309.

5. Y.M. Arabi, Y. Mandourah, F. Al-Hameed, et al. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome. Am J Respir Crit Care Med. 2018; 197: 757-767.

6. R. Zhao, H. Wang, X. Wang, et al. Steroid Therapy and the Risk of Osteonecrosis in SARS Patients: A Dose-Response Meta-Analysis. Osteoporos Int, 2017 Mar;28(3):1027-1034.

7. C.D. Russell, J.E. Millar & J.K. Baillie. Lancet. 2020; 395 (10223): 473-475.

8. Clinical management of COVID-19. Interim guidance, 27th May, 2020. World Health Organization.

9. Y. Wang, W.W. Jiang, Q. He, et al. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. MedRxiv, doi: https://doi.org/10.1101/2020.03.06.20032342

10. Z.W. Yang, J.L. Liu, Y.J. Zhou, et al. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect. 2020 Apr 10;S0163-4453(20)30191-2.

11. "Coordination of RECOVERY and REMAP-CAP trials" https://www.recoverytrial.net/files/professional-downloads/coordination-of-recovery-and-remap-cap.pdf

12. Y. Furuta, T. Komeno, & T. Nakamura. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 93, 449-463 (2017).

13. D. Sissoko, C. Laouenan, E. Folkesson, et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single-arm proof-of-concept trial in Guinea. Plos Med. 2016 Mar 1;13(3):e1001967.

14. C.Q. Bai, J.S. Mu, D. Kargbo,et al. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)-Sierra Leone, 2014. Clin. Infect. Dis. 63, 1288-1294 (2016).

15. Q. Cai, M. Yang, D. Liu, et al. Experimental treatment with Favipiravir for COVID-19: an open-label control study. Engineering. https://doi.org/10.1016/j.eng.2020.03.007

16. C. Chen, Y. Zhang, J. Huang, et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. bioRxiv preprint. https://doi.org/10.1101/2020.03.17.20037432

17. "Fujifilm commences Phase III trial of Avigan for Covid-19" Clinial Trials Area news. 1st April, 2020. https://www.clinicaltrialsarena.com/news/fujifilm-avigan-covid-19-trial-japan/)

18. "Japan approval for Avigan to treat COVID-19 delayed" The Pharma Letter. https://www.thepharmaletter.com/article/japan-approval-for-avigan-to-treat-covid-19-delayed

19. T. Nagata, A.K. Lefor, M. Hasegawa, et al. Favipiravir: A New Medication for the Ebola Virus Disease Pandemic. Disaster Med Public Health Prep, 2015 Feb;9(1):79-81.

20. D. Jakimovski, C. Kolb, M. Ramanathan, et al. Interferon ? for multiple sclerosis. Cold Spring Harb. Perspect. Med., 8 (2018), pp. 1-20

21. Y.J. Liu. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23 (2005), pp. 275-306.

22. E. Sallard, F.X. Lescure, Y. Yazdanpanah, et al. Type 1 interferons as a potential treatment against COVID-19. Antivir Res. 2020; 178:104791.

23. L.E. Hensley, E.A. Fritz, P.B. Jahrling, et al. INF-?1a and SARS coronavirus replication. Emerg. Infect. Dis., 10 (2004), pp. 317-319.

24. J.F.W. Chan, K.H. Chan, R.Y.T. Kao, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J. Infect. 67 (2013), pp. 606-616.

25. B.J. Hart, J. Dyall, E. Postnikova, et al. Interferon-? and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J. Gen. Virol., 95 (2014), pp. 571-577.

26. J.F. Chan, Y. Yao, M.L. Yeung, et al. Treatment with lopinavir/ritonavir or interferon-beta1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis, 2015 Dec 15;212(12):1904-1913.

27. L.J. Stockman, R. Bellamy and P. Garner. SARS: systematic review of treatment effects. PLoS Med., 3 (2006), pp. 1525-1531.

28. E. Mantlo, N. Bukreyeva, J. Maruyama, et al. Antiviral Activities of Type I Interferons to SARS-CoV-2 Infection. Antiviral Res. 2020 Apr 29;179:104811.

29. R. Channappanavar, A.R. Fehr, J. Zheng, et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J. Clin. Invest., 129 (2019), pp. 3625-3639.

30. J.A. Al-Tawfiq, H. Momattin, J. Dib, et al. Ribavirin and ingerferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an obsevtional study. Int. J. Infect. Dis. 20 (2014), pp. 42-46.

31. S. Shalhoub, F. Farahat, A. Al-Jiffri, et al. INF-a2a or INF-b1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study.J. Antimicrob. Chemother., 70 (2015), pp. 2129-2132.

32. T.P. Sheahan, A.C. Sims, S.R. Leist, et al. Comparative therapeutic efficacy of Remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020 Jan 10;11(1):222.

33. ""Solidarity" clinical trial for COVID-19 treatments." World Health Organization. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments

34. F.N. Hung, K.C. Lung, Y.K. Tso, et al. 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. The Lancet, 2020, Vol.395, 10238, p.1695-1704.

35. "University-led COVID19 drug trial expands into home testing" Medical Express. 27th May, 2020. https://medicalxpress.com/news/2020-05-university-led-covid19-drug-trial-home.html

Coronavirus (11) Popular drugs tested for effectiveness in COVID-19 treatment (a)

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.

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

Coronavirus (10) How existing drugs are chosen to test for effectiveness in COVID-19 treatment

Since the outbreak from Wuhan, COVID-19 has infected over 5 million people and caused the death of 350 thousand worldwide. There are no regulatory approved drugs specific for COVID-19 patients, despite the fact that much effort has been put into finding or developing effective drugs for the treatment of the disease, or vaccines to prevent the disease. Therefore, repurposing of existing drugs, which already have the regulatory approval or are in the late stages of clinical trials, is the main direction of clinical research for COVID-19 treatment nowadays. This blog post will explain the reason for this phenomenon and how these drugs are chosen.

To develop a new drug to be used for a disease, its functions against the disease need to be tested on cellular level, and then on animal modals. After that it has to undergo 3 phases of clinical trials to test the safety, effectiveness, efficacy, and side effects on humans, which usually takes years. Even after passing all the clinical trials, manufacturing and distributing the new drug at the scale needed to tackle this pandemic, can also be significantly challenging. On the other hand, the drugs currently being used to treat other illnesses have been carefully examined before and found to be safe to use. Moreover, as these drugs have existed for quite a while, they are cheap to produce, easy to manufacture, and are scalable. Furthermore, the dosage information is largely in hand. Therefore, they can be used immediately if they are proven to be effective for COVID-19 treatment.^1,2 

You may have heard of Remdesivir (a drug developed for Ebola), or Chloroquine / Hydroxychloroquine (malaria medications), quite frequently from the news recently. However, apart from those, there are dozens more existing drug candidates currently being tested for COVID-19, some as a single entity or some in combination, in over 1000 clinical trials worldwide as of 18th May from the data of Cytel's global COVID-19 clinical trial tracker.^3,4

As there are huge numbers of existing drugs or compounds, you may wonder how these are being selected to be tested for COVID-19 treatment. Ideally, the findings about 1) the genetic components and the structure of the virus; 2) the molecular mechanisms involving in the virus invasion to the host; and 3) the biological reactions, including the immune response, in COVID-19 cases, are useful to help looking for candidate drugs. For example, two anti-inflammatory drugs were selected by scientists in the UK for COVID-19 treatment as cytokine storm, resulting from the hyper-reaction of the host immune system, is observed in serious cases.⁵ However, the molecular mechanisms underlying the virus invasion is not much understood as the disease has newly emerged. This limits the finding of drugs to be tested.

A study conducted by a group of scientists from multiple disciplines, mainly from the San Francisco area, gives us a good example of how the selection of drugs and compounds is made for a newly emerged disease, when not many molecular mechanisms are known.⁶ The study first started by sequence analysis of available SARS-CoV-2 isolates, and identified 29 viral proteins to be translated and processed from the 14 open reading frames in the virus genome. Based on the analysis results, the scientists then cloned 26 of the 29 viral sequences into streptavidin-tagged expression vectors. Using the 26 tagged viral protein as baits, they were able to identify 332 high-confidence SARS-CoV-2-human protein-protein interactions in human embryonic kidney cells by affinity purification mass spectrometry.

By analysing these virus-human protein-protein interactions, the molecular mechanisms underlying the virus infection becomes clearer. These interactions unveiled the molecular pathways in protein trafficking, translation, transcription, and ubiquitination in the infected cells. Moreover, the interactome also unveiled the molecules involved in several innate immune signalling pathways. Any drugs/compounds able to intervene with the interactions could be candidates to be tested for treatment of COVID-19.

The finding of these interactions enable the scientists to identify 62 human proteins that are targeted by existing drugs or compounds: 29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds. These drugs and compounds were then examined with their antiviral activity. Preliminary results showed that protein biogenesis inhibitors (zotatifin, ternatin-4, and PS3061), and ligands of the Sigma1 and Sigma1 receptors (haloperidol, PB28, PD-144418 and hydroxychloroquine), are effective in reducing viral infectivity.*

Besides identifying drugs by first identifying molecular mechanisms underlying the viral infection from laboratory experiments, artificial intelligence (AI) has been started to be used in searching for drugs repurposed for a newly emerged pandemic.^7,8,9,10,11 By feeding in 1) databases of existing drugs or compounds, or 2) data on the molecular structures of the drugs and the virus, and 3) data on research findings of the molecular mechanisms of diseases or symptoms that may be involved, and by making use of the training/algorithm system for analysis, AI is able to help scientists to find candidate drugs without performing any laboratory work. However, as with the other method, selected drugs are still needed to be tested for their antiviral efficiency on a cellular level before proceeding to clinical trials.

According to Cytel's global COVID-19 clinical trial tracker, there are currently a dozen popular drugs being tested for their efficiency in the treatment of COVID-19. In my next blog post, I am going to introduce these drugs and their functions, and explain the reason of their being chosen for clinical studies.

*The main drawback of this study is the lack of an in vivo experiment to proof the in vitro findings of the interactome. The 26 viral proteins were ectopically expressed in modified embryonic kidney cells. Further verification of the expression of the viral proteins and those virus-human protein-protein interactions in the commonly infected cells should be performed in the future. Apart from this, the study was undertaken very nicely, providing quite a full picture of the molecular mechanisms underlying the virus invasion in just 2 to 3 months since the viral outbreaks.

References

1. "Repurposing existing drugs for COVID-19 a more rapid alternative to a vaccine, say researchers" Research news of the University of Cambridge. https://www.cam.ac.uk/research/news/repurposing-existing-drugs-for-covid-19-a-more-rapid-alternative-to-a-vaccine-say-researchers

2. S.P.H. Alexander, J. Armstrong, and A.P. Davenport, et al. A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development. IUPHAR review 29. British Journal of Pharmacology; 1 May 2020; DOI: 10.1111/bph.15094.

3. K. Thorlund, L. Dron, and J. Park, et al. A real-time dashboard of clinical trials for COVID-19. The Lancet, published online April 24, 2020. https://doi.org/10.1016/S2589-7500(20)30086-8.

4. Global coronavirus COVID-19 trial tracker. https://www.covid19-trials.com/

5. "National trial launched to find Covid-19 treatment" Addenbrook's Hospital news, 16th May, 2020. https://www.cuh.nhs.uk/news/communications/national-trial-launched-covid-19-treatment.

6. David E. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. 2020 Apr 30. doi: 10.1038/s41586-020-2286-9.

7. N.L. Bragazzi, H. Dai, G. Damiani, et al. How Big Data and Artificial Intelligence Can Help Better Manage the COVID-19 Pandemic. Int J Environ Res Public Health. 2020 May 2;17(9):E3176. doi: 10.3390/ijerph17093176.

8. McCall, B. COVID-19 and artificial intelligence: Protecting health-care workers and curbing the spread. Lancet Digit. Health 2020, 2, e166-e167.

9. P. Richardson, I. Griffin, C. Tucker, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020, 395, e30-e31.

10. Y. Ke, T. Peng, T.Yeh, et al. Artificial intelligence approach fighting COVID-19 with repurposing drugs. 2020 May 15. doi: 10.1016/j.bj.2020.05.001.

11. "AI VIVO identifies list of 31 drugs that show potential for Covid-19 treatment" Cambridge Independent, 22nd April, 2020. https://www.cambridgeindependent.co.uk/business/ai-vivo-identifies-list-of-31-drugs-that-show-potential-for-covid-19-treatment-9107179/