A Clinical Update on Employing Tocilizumab to Fight COVID-19

SARS-CoV-2 infection or COVID-19, currently regarded as ‘terror’ worldwide, has spread uncontrollably as a serious menace. Till date, limited effective medicines or treatments are available. The mortality and morbidity rates have increased considerably, which have been aggravated by acute respiratory distress syndrome (ARDS) and new and old cardiovascular injuries. To control COVID-19, many drugs have been taken into consideration, like ACE2 blockers, anti-inflammatory drugs, antibodies against IL-1 and anti-IL-6, Remdesivir, Dexamethasone, Hydroxychloroquine and vaccines. In this chapter, preference is given to Tocilizumab with the latest status of clinical research update available. Despite several clinical research attempts, some have yielded promising results, others are inconclusive.


Introduction
Since December 2019, the outbreak of the novel coronavirus (SARS-CoV-2) infection (i.e. , from Wuhan, China as a pandemic, has posed a serious threat towards mankind, treatment of which is still unknown [1]. In Jan 30, 2020, the novel coronavirus disease 2019 (COVID- 19), was declared as the Sixth public health emergency epidemic by the World Health Organization [WHO] [2]. Till date there is no single drug to control it. Despite Remdesivir being used extensively for the treatment, it is still under clinical trials [3] and not beyond question [4]. The elderly, immune-compromised or people having co-morbidities led to acute respiratory distress syndrome (ARDS), cardiovascular (CV) complications, and multi-organ failure [2,5]. Common symptoms of the disease include fever, cough, myalgia, malaise, breathlessness and diarrhea [2]. Tocilizumab (a humanized anti-IL-6 receptor antibody) is one of drugs used for the treatment of COVID-19 hospitalized patients [6]. This article summarizes all critical clinical trials to evaluate the efficacy of Tocilizumab.

About the molecule
Tocilizumab is an Interleukin-6 Receptor Inhibitor, having a molecular formula of [C6428H9976N1720O2018S42]. Its molecular mass is of [145.0 kDa], CAS number: [375823- . It is a recombinant humanized monoclonal antibody used in the treatment of inflammatory and autoimmune conditions like Rheumatoid arthritis, multiple myeloma and prostate cancer, nowadays used extensively for COVID-19 treatment [7][8][9][10][11].

Tocilizumab as drug
Tocilizumab, an immunosuppressive monoclonal antibody drug having the traditional name Actemra and Atlizumab, has been reported to be effective against COVID-19 in several countries such as China, France, Italy, Switzerland and Qatar Xiaoling [12,13]. The drug is known to treat patients with hyperinflammatory syndrome and acute respiratory failure [14]. The drug is sold in the European Union (EU) under the trade name RoActemra and in the United States as Actemra [15,16]. The drug was first approved in 2005 as an orphan drug in Japan, used in the treatment of Castleman's disease [17]. Nowadays, Tocilizumab has acquired license for EU, to be used alone or in combination with DMARDs [disease-modifying antirheumatic drugs]. This combined therapy is used in the treatment of rheumatic arthritis in adults, systemic form of juvenile idiopathic arthritis (sJIA) in children above 2 years and with the polyarticular form of juvenile idiopathic arthritis (pJIA) in children more than 2 years of age [17]. This drug displays a long elimination halflife. Several studies were conducted to find out whether the drug is useful or not.
In a single centre study in Brescia [Italy], having an gathering of 100 patients, 8 mg/kg [max 800 mg] of the drug was advised to be given to patients by two consecutive intravenous infusions 12 hr. apart. Significant clinical improvement was observed in this case [18]. In another study by Alattar et al. [19] at Quatar, 25 patients having COVID-19 were administered with Tocilizumab, one to three median doses of the drug individually [4.8 mg/kg]. Tocilizumab was associated with dramatic decline in inflammatory markers, radiological improvement and reduced ventilatory support requirements [19]. In a 61-year-old man with COVID-19 symptoms, with a history of kidney transplantation, 324 mg Tocilizumab was administered via subcutaneous route along with hydroxychloroquine that helped in prevention of the disease and did not require mechanical ventilation [20]. However, contrary reports do exist, that reports that Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with COVID-19 [21].

USFDA approval
The drug Actemra (tocilizumab, Genentech, Inc., South San Francisco, CA) was approved by USFDA to be used for the treatment of Rheumatoid Arthritis (RA), Giant Cell Arthritis (GCA), Polyarticular Juvenile Idiopathic Arthritis (PJIA), Systemic Juvenile Idiopathic Arthritis (SJIA) and Cytokine Release Syndrome (CRS) [22]. However, despite of recommendation of NIH on usage of Tocilizumab for COVID-19 treatment, it has not yet received approval of USFDA.

Dosage of tocilizumab for COVID-19 treatment
The use of Tocilizumab is recommended as per the US NIH guidelines only for clinical trial studies [23]. The preference is mainly given to hospitalized patients with increasing oxygen demand with or without elevated markers of systemic inflammation. As per the recommendations, Tocilizumab (single intravenous [IV] dose of tocilizumab 8 mg/kg actual body weight up to 800 mg) in combination with dexamethasone (6 mg daily for up to 10 days) is advised to be administered in certain hospitalized patients experiencing rapid respiratory decompensation due to COVID-19 [24].

Storage
This drug should be stored refrigerated at 2 to 8°C (36 to 46 F).

Plausible mechanism of tocilizumab against COVID-19
According to a study, by the team of Haiming Wei [25], after the SARS-CoV-2 infection, CD4 + T lymphocytes are activated to become pathogenic T helper cells, generating GM-CSF (Granulo Macrophage Colony Stimulating Factor]. This leads to severe inflammatory storm created by CD14 + CD16+ inflammatory monocytes with elevated expression of IL-6. These excessive immune cells usually invade the pulmonary circulation and cause damage to the immune system, thus leading to functional disability of lungs and mortality. Therefore, drugs like Tocilizumab are administered to prevent the cytokine storm. Tocilizumab has yielded effective results as an IL-6R antagonist. Excessive stimulation of IL-6 can cause CRS [Cytokine Release Syndrome] in hospitalized patients. The higher the level of CRS, higher is the serum peak concentration of IL-6. IL-6 binds to its receptor IL-6R and a complex is formed. IL-6R then binds to the signal transducer glycoprotein 130 (gp-130) to cause signal transduction. Two types of IL-6R are there, one is the Soluble form (sIL-6R) and the other is Membrane bound form [mIl-6R]. In classical signal transduction pathway, IL-6 binds to mIL-6R [transmembrane integral protein], and forms a complex, which then prohibits the connection of IL-6R with gp130 [integral membrane protein]. Thus no cytokine storm is produced. In the trans-signaling pathway, binding of Tocilizumab to sIl-6R, prevents the binding of IL-6R to gp130 [present on the membrane of monocytes, macrophages, dendritic cells] and thus hinders release of inflammatory storm. JAK/STAT tyrosine kinase system mediates one pathway, while Ras/mitogen-activated protein kinase (MAPK)/ NF-κB-IL-6 pathway mediates the other. Tocilizumab [humanized anti-IL-6R monoclonal antibody], is thus considered a potential drug in COVID-19 treatment [26, 27].

Other clinical considerations
Tocilizumab is contraindicated in immunocompromised individuals, those who use biologic immunomodulating drugs, and in patients having alanine aminotransferase >5 times the upper limit of normal; patients with gastrointestinal perforation; those having uncontrolled serious bacterial, fungal, or non-SARS-CoV-2 viral infection; absolute neutrophil count <500 cells/μL; platelet count <50,000 cells/μL. The drug should also be avoided in individuals having a known hypersensitivity to it [28]. It has been recommended to administer Dexamethasone [or an alternative corticosteroid of dosage equal to dexamethasone 6 mg] simultaneously in patients receiving Tocilizumab [9]. A patient's clinical response to dexamethasone is initially accessed before administering Tocilizumab [29]. The combination therapy yields an adverse effect in the form of severe and disseminated strongyloidiasis infestation. Therefore, Ivermectin should be used as a prophylactic treatment [30].

Side effects
The common side effects include respiratory tract infections, headache, hypertension, elevation in liver test. Rashes, erythema, oedema, itching can occur at the infection site [31]. Tuberculosis, sepsis and fungal infection are the associated infections that can occur. Hypersensitivity reactions, cancer, reactivation of herpes zoster, gastrointestinal perforation in patients with diverticulitis are also seen in some patients, though not significant [32].

Clinical trial status
The process of systemic review was followed and effectiveness of the drug analyzed from the NIH, US National Library of Medicine Clinical Trial Registry (ClinicalTrials.gov). At present (till May 2021), 81 clinical studies could be traced in the name Toclilizumab [until May 2021]. 33 studies have been excluded due to nonrelevance. 48 records are included in this study. Some of the studies have yielded promising initial results yet require more time for validation and declared to be effective or safe. Among the 48 trials done on Tocilizumab, 17 are in Recruiting stage, 12 trials have been concluded, 5 have been terminated, 1 has been withdrawn, 5 trials are in not yet recruiting stage and 6 are active but non recruiting. 1 among the 47 trials is in phase 1, 16 trials are in phase 2, 14 are in phase 3 trial. Analyzing the clinical trials from Table 1, it is evident that there is attempt to use Toclizumab alone or in combination with other drugs looks promising for the treatment of COVID 19 (Figure 1).

Comparing tocilizumab with other drugs involved in COVID-19 treatment
Several drugs employed for the treatment of COVID-19 through clinical trials are: Remdesivir, Tocilizumab, Baricitinib, Sarilumab and Hydroxychloroquine. In terms of clinical research output Remdesivir emerges as frontrunner, while Tocilizumab may be considered as a potential drug candidate against COVID-19. Despite the initial attempt of drug repurposing by using Hydroxychloroquine to treat COVID-19, there were limited encouraging results for which, its administration was removed from the line of treatment in various countries. A comparison between Tocilizumab and other drugs involved in the treatment of COVID-19 is presented in Table 2.

Summarizing prominent publications on tocilizumab related to COVID treatment
Apart from several clinical research outcomes (summarized in Table 1) there has been several publications revealing scientific information on the mechanism, application and prospect of the drug candidate Tocilizumab for COVID-19 treatment. There are more than 30 publications found in PubMed (https://pubmed.ncbi. nlm.nih.gov/) in the year 2021 among which few significant ones are summarized in following Table 3 The efficacy of the drug was unclear from this study compared to other observational studies. [154] 8 2021 Tocilizumab in COVID-19: some clarity amid controversy.
The recovery trial showed some evidence regarding the use of Tocilizumab in COVID-19 patients. Scientists found that only 31% of the population receiving Tocilizumab showed promises of recovery as compared to those receiving placebo.
Still, this drug therapy needs to be combined with other drugs for better outcomes. [155] 9 2021 Effectiveness of Tocilizumab in patients hospitalized with COVID-19.
Scientists found that Tocilizumab may be effective in diminishing the health hazards of patients with moderate to severe COVID-19associated pneumonia and elevated CRP level. Yet it needs to be administered to a large mass to fathom its efficacy. [156] 10 2021 Tocilizumab in hospitalized patients with severe Covid- 19 Pneumonia.
Scientists could not gather any significant clinical status or predict any lowering of mortality rate in comparison to placebo at 28 days.

Conclusion
Although the drug Tocilizumab has shown to reduce mortality and morbidity, still it cannot be referred to as an anti-COVID drug and may only be effective in patients having inflammation and lung damage caused by the coronavirus. Moreover the sensitivity of the drug limits its usage to a specific age and certain patients. Moreover, Tocilizumab is not-yet approved by the USFDA. This drug brings a ray of hope, as it's very much effective in mitigating immune damage, lung functional injuries and arterial oxygen saturation. Scientists therefore hope that this drug could be beneficial to a large mass of population in diminishing the adverse effects of the pandemic.