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

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