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Tocilizumab

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Tocilizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetIL-6 receptor
Clinical data
Trade namesActemra, RoActemra
Other namesAtlizumab
AHFS/Drugs.comMonograph
MedlinePlusa611004
License data
Pregnancy
category
  • AU: C
Routes of
administration		Intravenous, subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life8–14 days during steady state (dependent on concentration)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6428H9976N1720O2018S42
Molar mass144987.06 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis, a severe form of arthritis in children. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.[4]

Tocilizumab was granted an emergency use authorization (EUA) for the treatment of COVID-19 in the United States in June 2021.[3][5][6]

Medical uses

The drug is administered by monthly intravenous infusions. An infusion takes about an hour.[7] An alternative formulation for subcutaneous injection was approved in October 2013.[8]

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.[9][10] The drug slows down the progression of the disease and can improve physical function of patients.[11]

Systemic juvenile idiopathic arthritis

The treatment of systemic juvenile idiopathic arthritis (SJIA) is similar to rheumatoid arthritis 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.[12] In 2011, the U.S. Food and Drug Administration (U.S. FDA) approved tocilizumab for the treatment of active systemic juvenile idiopathic arthritis.[13]

Castleman's disease

In Japan, tocilizumab is also approved for the treatment of Castleman's disease,[9][14] a rare benign tumor of B cells.

Giant cell arteritis

In May 2017, the FDA approved tocilizumab for giant cell (temporal) arteritis.[15]

Cytokine release syndrome

On 30 August 2017, the FDA approved tocilizumab for cytokine release syndrome, a side effect of CAR-T cell therapies.[16]

COVID-19

In September 2021, Indian pharmaceutical firm Hetero obtained emergency use approval from the country's health authority, Drugs Controller General of India (DCGI), to produce a generic version of Roche's drug tocilizumab to treat COVID-19 in adults. With the approval, the drug will be made available for treating hospitalised adults who are on systemic corticosteroids and need supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal oxygenation.[17] A 2021 meta-analysis of randomized controlled trials found that, while tocilizumab does not show significant benefits on survival, it could play a role in preventing progression to intensive care and mechanical ventilation.[18][dead link][unreliable source?]

On 1 December 2021, tocilizumab was granted a provisional approval by the Australian regulator, Therapeutic Goods Administration, for treatment of adults who are hospitalised with COVID-19, are receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation.[19]

Adverse effects

The most common adverse effects observed in clinical trials were upper respiratory tract infections (more than 10% of patients), nasopharyngitis (common cold), headache, and high blood pressure (at least 5%). The enzyme alanine transaminase was also elevated in at least 5% of patients, but in most cases without symptoms. Elevated total cholesterol levels were common.[20] Among the less common side effects were dizziness, various infections, as well as reactions of the skin and mucosae like mild rashes, gastritis and mouth ulcer. Rare but severe reactions were gastrointestinal perforations (0.26% in six months) and anaphylaxis (0.2%).[21]

Interactions

There are no certain interactions with other drugs. The blood plasma levels of simvastatin were reduced by 57% after a single dose of tocilizumab, but it is not known whether this is clinically relevant. A possible mechanism is that the elevated IL-6 levels of patients with rheumatoid arthritis suppress the biosynthesis of various cytochrome P450 enzymes, notably CYP1A2, CYP2C9, CYP2C19 and CYP3A4. Tocilizumab lowers IL-6 and thus normalises cytochrome levels, increasing the metabolization of simvastatin (and possibly other cytochrome metabolised drugs).[21]

Mechanism of action

Besides other functions, interleukin 6 (IL-6) is involved in the development of immunological and inflammatory reactions. Some autoimmune diseases like rheumatoid arthritis are associated with abnormally high IL-6 levels. Tocilizumab binds soluble as well as membrane bound interleukin-6 receptors, hindering IL-6 from exerting its pro-inflammatory effects.[21][22] It has been noted that the membrane bound form and soluble form of the IL-6 receptor may have different effects in the pathogenesis of rheumatoid arthritis with the soluble form being more implicated in disease progression.[23]

History

Interleukin 6 and its receptor were discovered and cloned at Osaka University, Japan, by Tadamitsu Kishimoto in the 1980s. In 1997, Chugai Pharmaceuticals began the clinical development of tocilizumab for the treatment of rheumatoid arthritis. Clinical studies for Castleman's disease and systemic juvenile idiopathic arthritis started in 2001 and 2002, respectively. Hoffmann–La Roche co-developed the drug due to a license agreement in 2003.[24]

Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for rheumatoid arthritis treatment.[25] In further studies, it was effective and generally well tolerated when administered either as monotherapy or in combination with conventional DMARDs in adult patients with moderate to severe rheumatoid arthritis.[26]

In June 2005, tocilizumab was approved in Japan for Castleman's disease.[9] In January 2009, the drug was approved by the European Medicines Agency (EMA) as RoActemra for the treatment of rheumatoid arthritis under the mentioned restrictions. On 11 January 2010, it was approved by the U.S. FDA as Actemra for the same purpose.[27] Tocilizumab was approved by Australia's Therapeutic Goods Administration on 27 May 2009[28] and was listed on the Pharmaceutical Benefits Scheme from 1 August 2010.[29] In New Zealand, tocilizumab was approved for distribution in July 2009,[30] and Pharmac approved subsidising it with special authority restrictions on 1 July 2013 for systemic juvenile idiopathic arthritis[31] and 1 July 2014 for rheumatoid arthritis.[32] The FDA approved tocilizumab for the treatment of systemic juvenile idiopathic arthritis for children from two years of age in April 2011, and the EMA followed in August the same year.

Tocilizumab is marketed by Chugai in some countries, especially in Japan and other Asian countries, and jointly by Chugai and Roche (Hoffmann–La Roche's holding company) in others, for example Great Britain, France and Germany.[24]

Research

The intensity of IL-6 in cancer cells from people with ovarian cancer is associated with poor prognosis, and in cell culture a different anti-IL-6 antibody (siltuximab) reduced IL-6 signaling and showed favorable effects in an animal model of the disease; however, the drug showed no clear effects when tested in a phase II clinical trial in people with advanced ovarian cancer.[33] The trial investigators later showed that in high-grade ovarian cancer cells, anti-IL6 antibodies reduced the activation of STAT3 (its major downstream transcription factor), leading to increased activity of the epidermal growth factor receptor (EGFR) pathway, which is thought to confer resistance to several cancer therapies.[34] The investigators then showed that inhibiting this pathway with the EGFR inhibitor gefitinib inhibited tumor growth in cell culture and animals of the disease, offering a potential rationale for combining anti-IL6 antibodies with gefitinib to treat advanced-stage ovarian cancer.[34]

Tocilizumab is being studied for pulmonary arterial hypertension (PAH).[35] Tocilizumab is currently under evaluation in a multicenter clinical trial (ALL-IN) for the prevention of acute cellular rejection in status post heart transplant patients.[36]

COVID-19

China's National Health Commission included the use of tocilizumab in guidelines to treat COVID-19 patients.[37] 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.[38] Chinese health officials say that only 21 patients have been asked to use this medicine.[39] The same month, a randomized study, at 11 locations in China was conducted to compare favipiravir versus tocilizumab versus both.[40]

On 11 March 2020, Italian physician Paolo Ascierto reported that tocilizumab appeared to be effective in three severe cases of COVID-19 in Italy.[41] 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.[42] Roche and the WHO have each launched separate trials for its use in severe COVID-19 cases.[43]

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.[44] 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.[45]

Roche announced on 29 July 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.[46][47]

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".[48]

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.[49][50]

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.[51] 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.[52][53]

In June 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for tocilizumab for the treatment of COVID-19 in hospitalized people aged two years of age and older who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[3][5][6]

Neuromyelitis optica

Early case reports suggest tocilizumab might be effective in otherwise refractory neuromyelitis optica (NMO, Devic's disease).[54][55][56][57]

Graves' ophthalmopathy

Two small studies found tocilizumab to be beneficial in endocrine ophthalmopathy (Graves' orbitopathy) that is refractory to corticosteroid treatment.[58][59]

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