Tocilizumab|Uses|MOA|Side Effects

Tocilizumab is an interleukin-6 (IL-6) receptor antagonist used to treat Cytokine Release Syndrome (CRS), Systemic Juvenile Idiopathic Arthritis (sJIA), Giant Cell Arteritis (GCA), and Rheumatoid Arthritis (RA).

Tocilizumab is a recombinant humanized monoclonal antibody IL-6 receptor inhibitor used to treat inflammatory and autoimmune conditions. It was first described in the literature in 2003 when Chugai, a subsidiary of Roche began developing IL-6 inhibiting monoclonal antibodies. It is currently being investigated to treat severely ill patients with COVID-19.

Tocilizumab was granted FDA approval on 8 January 2010.

Tocilizumab Indication

Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome.

Rheumatoid arthritis

Tocilizumab is used for the treatment of moderate to severe rheumatoid arthritis, applied in combination with methotrexate, if other drugs like disease-modifying antirheumatic drugs (DMARDs) and TNF alpha blockers have proven to be ineffective or were not tolerated. It can be used as a monotherapy for patients who do not tolerate methotrexate. The drug slows down the progression of the disease and can improve physical function of patients.

Systemic juvenile idiopathic arthritis

The treatment of systemic juvenile idiopathic arthritis is similar to RA treatment: tocilizumab is combined with methotrexate unless the latter is not tolerated. General safety and effectiveness is established for children of two years and older.

In 2011 the US FDA approved tocilizumab for the treatment of the orphan disease, active systemic juvenile idiopathic arthritis (SJIA), a rare and severe form of arthritis affecting children.

Castleman’s disease

In Japan, tocilizumab is also approved for the treatment of Castleman’s disease, a rare benign tumor of B cells.

Neuromyelitis optica

Early case reports suggest tocilizumab might be effective in otherwise refractory neuromyelitis optica (NMO, Devic’s disease).

Giant cell arteritis

In May 2017, tocilizumab was FDA approved for giant cell (temporal) arteritis.

Cytokine release syndrome

On 30 August 2017, the FDA approved tocilizumab for cytokine release syndrome, a side effect of CAR-T cell therapies.

COVID-19

The pathogenesis of the acute pulmonary treatment injury related to COVID-19 is related to a severe hyperinflammatory state with high amounts of pro-inflammatory cytokines such as IL-6, IL-1, IL-2, and TNF-α. Preliminary trial data has suggested that tocilizumab may be effective in improving outcomes for patients severely affected by the SARS-CoV-2 virus; REMAP-CAP trial has provided sufficient evidence for it to be added to the approved list.

Tocilizumab Pharmacodynamics

Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions.6 Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index.6 Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity.

Tocilizumab Mechanism of action

Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts.6 IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and a-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin.4 IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation. Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation.

Tocilizumab Adverse effects

The most common adverse effects observed in clinical trials were

Upper respiratory tract infection (6-8%
Nasopharyngitis (4-7%)
Headache (3-7%)
Hypertension (3-6%)
ALT increased (1-6%)
Bronchitis (2-4%)
Rash (1-4%)
Dizziness (1-3%)
Mouth ulceration (1-2%)
Upper abdominal pain (2-3%)
Gastritis (1-2%)
Oral herpes simplex (<2%)
Stomatitis (<2%)
Gastric ulcer (<2%)
Increased weight (<2%)
Total bilirubin increased (<2%)
Leukopenia (<2%)
Peripheral edema (<2%)
Dyspnea (<2%)
Cough (<2%)
Conjunctivitis (<2%)

COVID-19

China’s National Health Commission included the use of tocilizumab in guidelines to treat coronavirus disease 2019 (COVID-19) patients. In March 2020, China approved tocilizumab for the treatment of inflammation in patients with the coronavirus SARS-CoV-2. As of June 2020, there is no evidence whether this treatment is effective. Chinese health officials say that only 21 patients have been asked to use this medicine. The same month, a randomized study, at 11 locations in China was conducted to compare favipiravir versus tocilizumab versus both.

On 11 March 2020, Italian physician Paolo Ascierto reported that tocilizumab appeared to be effective in three severe cases of COVID-19 in Italy. On 14 March 2020, three of the six treated patients in Naples had shown signs of improvement prompting the Italian Pharmacological Agency (AIFA) to expand testing in five other hospitals Roche and the WHO have each launched separate trials for its use in severe COVID-19 cases.

Tocilizumab was among the drugs noted as treatments for COVID-19 in a study of major hospitals in the U.S. that determined that abnormal liver tests were occurring in most hospitalized patients with COVID-19 and may be associated with poorer clinical outcomes. Several medications used in the treatments during the study were found to be associated with peak hospitalization liver transaminase elevations >5x ULN. Tocilizumab was significantly associated in the relationship between the drugs used to treat the disease and abnormal liver tests, which has prompted studies being conducted to determine whether the abnormal tests were due to the disease or to drug-induced liver injury, according to Michael Nathanson, director of the Yale Liver Center and co-author of the study.

Roche announced on July 29, 2020 that its randomized double-blind trial of tocilizumab in the treatment of pneumonia in COVID-19 patients had shown a reduction in hospitalization time in patients treated with tocilizumab. However, tocilizumab treatment did not meet its primary endpoint of improved clinical status of patients with COVID-19 associated pneumonia, nor its key secondary endpoint of reduced patient mortality.

In October 2020, another research was published that concluded that “tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19”.

In November 2020, press reports stated that early results from the REMAP-CAP trial conducted jointly by Imperial College London, the Intensive Care National Audit and Research Centre and Utrecht University had shown promising results in patients with severe COVID-19.

In January 2021, the REMAP-CAP trial released preliminary evidence that tocilizumab and sarilumab could reduce fatalities among severely ill Covid-19 patients. The drugs were added to the UK recommended list for COVID-19 treatment. The following month, the RECOVERY Trial revealed a similar result: 29% of the patients in the tocilizumab group died within 28 days compared with 33% in the usual care group, a statistically significant reduction of the risk of death on top of the reduction already given by dexamethasone. It also reduced the chance of a patient needing to go on a ventilator or dying from 38% to 33%. Researchers reported that tocilizumab and dexamethasone combined should cut death risk by about a third for patients on oxygen and halve it for those on a ventilator.

For more information please follow monograph of Tocilizumab

FDA Tocilizumab Monograph

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