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Tocilizumab, sold under the brand name Actemra among others, is an
immunosuppressive drug Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system. Classification Immunosuppressive drugs can be classifie ...
, used for the treatment of
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a recombinant humanized monoclonal antibody of the immunoglobulin IgG1 subclass against the interleukin-6 receptor (IL-6R). Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Interleukin 6 (IL-6) is a
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases,
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...
and
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by
Hoffmann-La Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...
. Tocilizumab was approved for medical use in the European Union in January 2009, and in the United States in January 2010.


Medical uses

In the United States, tocilizumab is indicated for the treatment of rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, cytokine release syndrome, and COVID19. In the European Union, tocilizumab is indicated for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, juvenile idiopathic polyarthritis, giant cell arteritis, cytokine release syndrome, and COVID19.


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 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. In 2011, the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) approved tocilizumab for the treatment of active systemic juvenile idiopathic arthritis.


Castleman's disease

In Japan, tocilizumab is also approved for the treatment of Castleman's disease, a rare
benign tumor A benign tumor is a mass of Cell (biology), cells (tumor) that does not Cancer invasion, invade neighboring tissue or Metastasis, metastasize (spread throughout the body). Compared to Cancer, malignant (cancerous) tumors, benign tumors generally ...
of
B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
s.


Giant cell arteritis

In May 2017, the FDA approved tocilizumab for giant cell 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

In June 2021, the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) issued an emergency use authorization (EUA) for tocilizumab for the treatment of COVID19 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 Extracorporeal membrane oxygenation (ECMO) is a form of extracorporeal life support, providing prolonged cardiac and respiratory system, respiratory support to people whose human heart, heart and human lung, lungs are unable to provide an adequa ...
(ECMO). The FDA approved tocilizumab for those indications in December 2022.


Adverse effects

The most common adverse effects observed in clinical trials were
upper respiratory tract infection An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore throat ...
s (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. 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 Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...
(0.2%).


Interactions

There are no certain interactions with other drugs. The blood plasma levels of
simvastatin Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease hyperlipidemia, elevated lipid levels. It is also used to decrease t ...
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 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
enzymes, notably CYP1A2, CYP2C9, CYP2C19 and
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
. Tocilizumab lowers IL-6 and thus normalises cytochrome levels, increasing the metabolization of simvastatin (and possibly other cytochrome metabolised drugs).


Mechanism of action

Besides other functions, interleukin 6 (IL-6) is involved in the development of immunological and inflammatory reactions. Some
autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s 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. 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.


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. Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for rheumatoid arthritis treatment. 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. In June 2005, tocilizumab was approved in Japan for Castleman's disease. In January 2009, the drug was approved by the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
(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. Tocilizumab was approved by Australia's Therapeutic Goods Administration on 27 May 2009 and was listed on the Pharmaceutical Benefits Scheme from August 2010. In New Zealand, tocilizumab was approved for distribution in July 2009, and Pharmac approved subsidising it with special authority restrictions in July 2013, for systemic juvenile idiopathic arthritis and in July 2014, for rheumatoid arthritis. 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 A holding company is a company whose primary business is holding a controlling interest in the Security (finance), securities of other companies. A holding company usually does not produce goods or services itself. Its purpose is to own Share ...
) in others, for example Great Britain, France and Germany.


Society and culture


Legal status

Tocilizumab was approved for medical use in the European Union in January 2009, and in the United States in January 2010.


Biosimilars

In September 2023, Tyenne became the first tocilizumab biosimilar authorized for medical use in the European Union, and in March 2024, became the first biosimilar with both
intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
and subcutaneous formulations to be approved in the United States. In April 2024, the Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tofidence, intended for the treatment of rheumatoid arthritis (RA), systemic juvenile idiopathic arthritis (sJIA), polyarticular juvenile idiopathic arthritis (pJIA) and coronavirus disease 2019 (COVID-19). The applicant for this medicinal product is Biogen Netherlands B.V. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Tofidence is a biosimilar medicinal product. Tofidence was authorized for medical use in the European Union in June 2024. Tyenne was approved for medical use in Canada in October 2024. In December 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Avtozma, intended for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, CAR-T cell-induced severe or life-threatening cytokine release syndrome and COVID-19. The applicant for this medicinal product is Celltrion Healthcare Hungary Kft. Avtozma is a biosimilar medicinal product.


COVID-19

Tocilizumab was approved for the treatment of COVID19 in the European Union in December 2021, and in the United States in December 2022. 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 tocilizumab to treat COVID19 in adults. In December 2021, tocilizumab was granted a provisional approval by the Australian regulator, Therapeutic Goods Administration, for treatment of adults. Tocilizumab was granted an emergency use authorization (EUA) for the treatment of COVID19 in the United States in June 2021. It was approved for the treatment of COVID19 in the European Union in December 2021, and in the United States in December 2022.


Research

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


COVID-19

There is good evidence tocilizumab can help reduce the need for mechanical ventilation for people in hospital with COVID19, and some evidence it can help prevent secondary infections. A 2021
meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
of
randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...
s 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 Mechanical ventilation or assisted ventilation is the Medicine, medical term for using a ventilator, ventilator machine to fully or partially provide artificial ventilation. Mechanical ventilation helps move air into and out of the lungs, wit ...
.


Neuromyelitis optica

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


Graves' ophthalmopathy

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


References


External links

* * * * * * * * {{Authority control Drugs developed by Genentech Drugs developed by Hoffmann-La Roche Immunosuppressants Orphan drugs Monoclonal antibodies Disease-modifying antirheumatic drugs