|Source||Humanized (from mouse)|
|Trade names||Actemra, RoActemra|
|Elimination half-life||8–14 days during steady state (dependent on concentration)|
|Chemical and physical data|
|Molar mass||144987.06 g·mol−1|
|(what is this?)|
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.
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 U.S. Food and Drug Administration (U.S. 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.
Giant cell arteritis
Cytokine release syndrome
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. 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%).
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).
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. 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.
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 (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 1 August 2010. In New Zealand, tocilizumab was approved for distribution in July 2009, and Pharmac approved subsidising it with special authority restrictions on 1 July 2013 for systemic juvenile idiopathic arthritis and 1 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) in others, for example Great Britain, France and Germany.
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. 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. 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.
Tocilizumab is being studied for pulmonary arterial hypertension (PAH). 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.
China's National Health Commission included the use of tocilizumab in guidelines to treat 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[update], 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 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.
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.
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).
- "Actemra- tocilizumab injection, solution, concentrate Actemra- tocilizumab injection, solution Actemra ACTPen- tocilizumab injection, solution". DailyMed. Retrieved 24 June 2021.
- "Coronavirus (COVID-19) Update: FDA Authorizes Drug for Treatment of COVID-19". U.S. Food and Drug Administration (FDA) (Press release). 24 June 2021. Retrieved 24 June 2021. This article incorporates text from this source, which is in the public domain.
- Markus Harwart (2008). "Die Entwicklung von Tocilizumab" [The development of tocilizumab] (in German). Krankenpflege-Journal. Retrieved 2016-04-30.
- "Tocilizumab Emergency Use Authorization (EUA)" (PDF). U.S. Food and Drug Administration (FDA). June 2021. This article incorporates text from this source, which is in the public domain.
- "Frequently Asked Questions on the Emergency Use Authorization for Actemra (tocilizumab) for Treatment of COVID-19" (PDF). U.S. Food and Drug Administration (FDA). July 2021. This article incorporates text from this source, which is in the public domain.
- Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 978-3-85200-196-8.
- "Genentech Gains FDA Approval for New Subcutaneous Formulation of Actemra for use in Adult Patients Living with Moderately to Severely Active Rheumatoid Arthritis". Genentech. 21 October 2013. Archived from the original on 8 September 2017.
- "RoActemra approved in Europe to treat patients suffering from Rheumatoid Arthritis" (Press release). Hoffmann–La Roche. 2009-01-21. Archived from the original on 2009-02-28. Retrieved 2009-01-05.
- "Assessment report for RoActemra" (PDF). European Medicines Agency.
- Roy Fleischmann; et al. (2009). "LITHE: Tocilizumab Inhibits Radiographic Progression and Improves Physical Function in Rheumatoid Arthritis (RA) Patients (Pts) at 2 Yrs with Increasing Clinical Efficacy Over Time". ACR. Cite journal requires
- Chaitow, J; De Benedetti, F; Brunner, H; et al. (2010). "Tocilizumab in Patients With Systemic Juvenile Idiopathic Arthritis: Efficacy Data From the Placebo-Controlled 12-Week Part of the Phase 3 TENDER Trial" (PDF). Arthritis & Rheumatism. 62 (Supplement 10): 1434.
- FDA Approves ACTEMRA® (tocilizumab) for the Treatment of Systemic Juvenile Idiopathic Arthritis (SJIA), South San Francisco, California: Genentech, April 15, 2011, archived from the original on 1 October 2018, retrieved July 20, 2015
- Matsuyama M, Suzuki T, Tsuboi H, Ito S, Mamura M, Goto D, et al. (2007). "Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease". Internal Medicine. 46 (11): 771–4. doi:10.2169/internalmedicine.46.6262. PMID 17541233.
- Komai T, Shoda H, Yamaguchi K, Sakurai K, Shibuya M, Kubo K, et al. (Dec 9, 2013). "Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report". Modern Rheumatology. 26 (2): 294–6. doi:10.3109/14397595.2013.861333. PMID 24313919. S2CID 21195912.
- Kieseier BC, Stüve O, Dehmel T, Goebels N, Leussink VI, Mausberg AK, et al. (March 2013). "Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses". JAMA Neurology. 70 (3): 390–3. doi:10.1001/jamaneurol.2013.668. PMID 23599943.
- Ayzenberg I, Kleiter I, Schröder A, Hellwig K, Chan A, Yamamura T, Gold R (March 2013). "Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy". JAMA Neurology. 70 (3): 394–7. doi:10.1001/jamaneurol.2013.1246. PMID 23358868.
- Araki M, Aranami T, Matsuoka T, Nakamura M, Miyake S, Yamamura T (July 2013). "Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab". Modern Rheumatology. 23 (4): 827–31. doi:10.1007/s10165-012-0715-9. PMC 3713263. PMID 22782533.
- "FDA Approves Actemra (tocilizumab) Subcutaneous Injection for Giant Cell Arteritis". Drugs.com.
- "FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome". US FDA. 30 August 2017.
- Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, et al. (October 2008). "Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study". Arthritis and Rheumatism. 58 (10): 2968–80. doi:10.1002/art.23940. PMID 18821691.
- Dinnendahl, V; Fricke, U, eds. (2010). Arzneistoff-Profile (in German). 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
- Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al. (January 2010). "Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study". Annals of the Rheumatic Diseases. 69 (1): 88–96. doi:10.1136/ard.2008.105197. PMC 3747519. PMID 19297346.
- Kallen KJ (November 2002). "The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1592 (3): 323–43. doi:10.1016/s0167-4889(02)00325-7. PMID 12421676.
- Markus Harwart (2008). "Die Entwicklung von Tocilizumab" [The development of tocilizumab] (in German). Krankenpflege-Journal. Archived from the original on 15 October 2018.
- "Jab hope for rheumatoid arthritis". October 27, 2008 – via news.bbc.co.uk.
- Oldfield V, Dhillon S, Plosker GL (2009). "Tocilizumab: a review of its use in the management of rheumatoid arthritis". Drugs. 69 (5): 609–32. doi:10.2165/00003495-200969050-00007. PMID 19368420. Archived from the original on 2013-01-16. Retrieved 2010-03-17.
- "Roche: FDA Approves Actemra For Rheumatoid Arthritis". The Wall Street Journal. 11 January 2010. Archived from the original on January 14, 2010.
- "Australian Drug Evaluation Committee 263rd meeting resolutions". Therapeutic Goods Administration. 27 May 2009. Archived from the original on 20 August 2009.
- "Anakinra (Kineret) to be deleted from the PBS". National Prescribing Service Limited. 1 August 2010. Archived from the original on 3 June 2012.
- Richards, Mark (20 July 2009). "Consent to the Distribution of New Medicines". New Zealand Gazette. 2009 (105): 2418. Retrieved 9 June 2015.
- "Approval of proposal involving pegfilgrastim and tocilizumab" (PDF). Pharmaceutical Management Agency. 24 May 2013. Retrieved 9 June 2015.
- "Decision to widen access to tocilizumab (Actemra) for rheumatoid arthritis in patients who are unable to be treated with methotrexate" (PDF). Pharmaceutical Management Agency. 14 May 2014. Retrieved 9 June 2015.
- Coward J, Kulbe H, Chakravarty P, Leader D, Vassileva V, Leinster DA, et al. (September 2011). "Interleukin-6 as a therapeutic target in human ovarian cancer". Clinical Cancer Research. 17 (18): 6083–96. doi:10.1158/1078-0432.CCR-11-0945. PMC 3182554. PMID 21795409.
- Milagre CS, Gopinathan G, Everitt G, Thompson RG, Kulbe H, Zhong H, et al. (April 2015). "Adaptive Upregulation of EGFR Limits Attenuation of Tumor Growth by Neutralizing IL6 Antibodies, with Implications for Combined Therapy in Ovarian Cancer". Cancer Research. 75 (7): 1255–64. doi:10.1158/0008-5472.CAN-14-1801. PMC 4384986. PMID 25670170.
- "Roche links with UK gov for ground-breaking PAH trial". PharmaTimes Media Ltd. 2016-01-06.
- Clinical trial number NCT03644667 for "Tocilizumab in Cardiac Transplantation" at ClinicalTrials.gov
- Miller, Roxanne Liu (March 4, 2020). "China approves use of Roche drug in battle against coronavirus complications". Reuters – via www.reuters.com.
- "China approves use of Roche arthritis drug for coronavirus patients". Reuters. 2020-03-04.
- "Coronavirus, farmaco per curare l'artrite reumatoide efficace su due pazienti con polmonite severa da Covid 19" [Coronavirus, drug to treat rheumatoid arthritis effective on two patients with severe pneumonia from Covid 19] (in Italian). Il fatto quotidiano. 2020-03-09.
- Wang, Guiqiang (March 17, 2020). "Favipiravir Combined With Tocilizumab in the Treatment of Corona Virus Disease 2019". National Library of Medicine. Cite journal requires
- "3 patients get better on arthritis drug - English". ANSA.it. March 13, 2020.
- "Coronavirus, via libera dell'Aifa al farmaco anti-artrite efficace su 3 pazienti e a un antivirale: test in 5 centri". www.ilmessaggero.it (in Italian). Retrieved 2020-03-14.
- "WHO and Roche launch trials of potential coronavirus treatments". SwissInfo.Ch.
- Hundt MA, Deng Y, Ciarleglio MM, Nathanson MH, Lim JK (July 2020). "Abnormal Liver Tests in COVID-19: A Retrospective Observational Cohort Study of 1827 Patients in a Major U.S. Hospital Network". Hepatology. 72 (4): 1169–1176. doi:10.1002/hep.31487. PMID 32725890. S2CID 220855183.
- Belli, Brita, Strong link found between abnormal liver tests and poor COVID-19 outcomes, Yale News, August 6, 2020
- "Roche provides an update on the phase III COVACTA trial of Actemra/RoActemra in hospitalized patients with severe COVID-19 associated pneumonia". www.roche.com. 29 July 2020. Retrieved 2020-08-18.
- Alijotas-Reig J, Esteve-Valverde E, Belizna C, Selva-O'Callaghan A, Pardos-Gea J, Quintana A, et al. (July 2020). "Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review". Autoimmunity Reviews. 19 (7): 102569. doi:10.1016/j.autrev.2020.102569. PMC 7252146. PMID 32376394.
- Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, et al. (October 2020). "Efficacy of Tocilizumab in Patients Hospitalized with Covid-19". The New England Journal of Medicine. 383 (24): 2333–2344. doi:10.1056/NEJMoa2028836. PMC 7646626. PMID 33085857.
- Sample, Ian (2020-11-19). "Rheumatoid arthritis drug appears to help Covid patients in ICU". The Guardian. ISSN 0261-3077. Retrieved 2020-11-19.
- "Initial data shows arthritis drug is effective in treating sickest Covid-19 patients". www.imperial.nhs.uk. Retrieved 2020-11-19.
- ""Product overview COVID-19 rapid evidence summary: Tocilizumab for COVID-19 Advice; NICE"". Retrieved 20 January 2020.
- Horby, Peter W.; Pessoa-Amorim, Guilherme; Peto, Leon; Brightling, Christopher E.; Sarkar, Rahuldeb; Thomas, Koshy; Jeebun, Vandana; Ashish, Abdul; Tully, Redmond; Chadwick, David; Sharafat, Muhammad; Stewart, Richard; Rudran, Banu; Baillie, J Kenneth; Buch, Maya H.; Chappell, Lucy C.; Day, Jeremy N.; Furst, Saul N.; Jaki, Thomas; Jeffery, Katie; Juszczak, Edmund; Lim, Wei Shen; Montgomery, Alan; Mumford, Andrew; Rowan, Kathryn; Thwaites, Guy; Mafham, Marion; Haynes, Richard; Landray, Martin J. (2021). "Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial". medRxiv. doi:10.1101/2021.02.11.21249258. S2CID 231879173. Retrieved 2021-02-11.
- Roberts, Michelle (2021-02-11). "Arthritis drug tocilizumab cuts deaths from Covid". BBC News. Retrieved 2021-02-11.
- "Tocilizumab". Drug Information Portal. U.S. National Library of Medicine.