Chemistry:Tocilizumab

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Short description: Immunosuppressive drug
Tocilizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetIL-6 receptor
Clinical data
Trade namesActemra, RoActemra
AHFS/Drugs.comMonograph
MedlinePlusa611004
License data
Pregnancy
category
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
 ☒N☑Y (what is this?)  (verify)

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID‑19. 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.[10]

Tocilizumab was approved for medical use in the United States in January 2010.[11][12]

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 COVID‑19.[3]

In the European Union, tocilizumab is indicated for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, juvenile idiopathic polyarthritis, giant cell arteritis, cytokine release syndrome, and COVID‑19.

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.[13][14] The drug slows down the progression of the disease and can improve physical function of patients.[15]

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.[16] In 2011, the US Food and Drug Administration (FDA) approved tocilizumab for the treatment of active systemic juvenile idiopathic arthritis.[17]

Castleman's disease

In Japan, tocilizumab is also approved for the treatment of Castleman's disease,[13][18] a rare benign tumor of B cells.

Giant cell arteritis

In May 2017, the FDA approved tocilizumab for giant cell (temporal) arteritis.[19]

Cytokine release syndrome

On 30 August 2017, the FDA approved tocilizumab for cytokine release syndrome, a side effect of CAR-T cell therapies.[20]

COVID-19

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).[21][22][23] The FDA approved tocilizumab for those indications in December 2022.[24]

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.[25] 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%).[26]

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).[26]

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.[26][27] 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.[28]

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.[29]

Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for rheumatoid arthritis treatment.[30] 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.[31]

In June 2005, tocilizumab was approved in Japan for Castleman's disease.[13] 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.[32] Tocilizumab was approved by Australia's Therapeutic Goods Administration on 27 May 2009[33] and was listed on the Pharmaceutical Benefits Scheme from 1 August 2010.[34] In New Zealand, tocilizumab was approved for distribution in July 2009,[35] and Pharmac approved subsidising it with special authority restrictions on 1 July 2013 for systemic juvenile idiopathic arthritis[36] and 1 July 2014 for rheumatoid arthritis.[37] 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.[29]

Society and culture

Legal status

Tocilizumab was approved for medical use in the United States in January 2010.[11][12]

COVID-19

Tocilizumab was approved for the treatment of COVID‑19 in the European Union in December 2021,[5] and in the United States in December 2022.[24]

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 COVID‑19 in adults.[38]

In December 2021, tocilizumab was granted a provisional approval by the Australian regulator, Therapeutic Goods Administration, for treatment of adults.[39]

Tocilizumab was granted an emergency use authorization (EUA) for the treatment of COVID‑19 in the United States in June 2021.[21][22][23] It was approved for the treatment of COVID‑19 in the European Union in December 2021,[5][40][41] and in the United States in December 2022.[24]

Research

Tocilizumab is being studied for pulmonary arterial hypertension (PAH).[42] 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.[43]

COVID-19

There is good evidence tocilizumab can help reduce the need for mechanical ventilation for people in hospital with COVID‑19, and some evidence it can help prevent secondary infections.[44]

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.[45][unreliable source?][46]

Neuromyelitis optica

Early case reports suggest tocilizumab might be effective in otherwise refractory neuromyelitis optica (NMO, Devic's disease).[47][48][49][50]

Graves' ophthalmopathy

Two small studies found tocilizumab to be beneficial in endocrine ophthalmopathy (Graves' orbitopathy) that is refractory to corticosteroid treatment.[51][52]

References

  1. ↑ 1.0 1.1 "Australian Product Information Actemra (tocilizumab)" (PDF). 2 September 2022. https://rss.medsinfo.com.au/ro/pi.cfm?product=ropactem11014. 
  2. ↑ "Actemra". 13 October 2022. https://covid-vaccine.canada.ca/actemra/product-details. 
  3. ↑ 3.0 3.1 "Actemra- tocilizumab injection, solution, concentrate Actemra- tocilizumab injection, solution Actemra ACTPen- tocilizumab injection, solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e5365ff-cb2a-4b16-b2c7-e35c6bf2de13. 
  4. ↑ 4.0 4.1 4.2 "Tofidence (tocilizumab-bavi) injection, for intravenous use". https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761354s000lbl.pdf. 
  5. ↑ 5.0 5.1 5.2 "RoActemra EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/roactemra. 
  6. ↑ "Tyenne Product information". 18 September 2023. https://ec.europa.eu/health/documents/community-register/html/h1754.htm. 
  7. ↑ "Tyenne EPAR". 2 October 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/tyenne. 
  8. ↑ "FDA Approves Biogen's Tofidence (tocilizumab-bavi), a Biosimilar Referencing Actemra" (Press release). Biogen Inc. 29 September 2023. Archived from the original on 30 September 2023. Retrieved 1 October 2023 – via GlobeNewswire.
  9. ↑ "Tyenne: Pending EC decision". 21 July 2023. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/tyenne. 
  10. ↑ Markus Harwart (2008). "Die Entwicklung von Tocilizumab" (in de). Krankenpflege-Journal. http://www.krankenpflege-journal.com/rheuma/768-die-entwicklung-von-tocilizumab-medizinischer-fortschritt-auf-basis-einer-erfolgreichen-kooperation-von-chugai-und-roche.html. 
  11. ↑ 11.0 11.1 "Drug Approval Package: Actemra (Tocilizumab) Injection BLA 125276". 9 March 2010. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125276s000TOC.cfm. 
  12. ↑ 12.0 12.1 "Drug Approval Package: Actemra (tocilizumab) Solution for Subcutaneous Injection NDA #125472". 17 July 2014. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125472Orig1s000TOC.cfm. 
  13. ↑ 13.0 13.1 13.2 "RoActemra approved in Europe to treat patients suffering from Rheumatoid Arthritis" (Press release). Hoffmann–La Roche. 21 January 2009. Archived from the original on 28 February 2009. Retrieved 5 January 2009.
  14. ↑ "Assessment report for RoActemra". European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000955/WC500111086.pdf. 
  15. ↑ "LITHE: tocilizumab inhibits radiographic progression and improves physical function in rheumatoid arthritis (RA) patients (Pts) at 2 yrs with increasing clinical efficacy over time.". Arthritis Rheum. (ACR) 60 (10): S238-9. October 2009. https://acr.confex.com/acr/2009/webprogram/Paper15221.html. Retrieved 1 August 2020. 
  16. ↑ "Tocilizumab in Patients With Systemic Juvenile Idiopathic Arthritis: Efficacy Data From the Placebo-Controlled 12-Week Part of the Phase 3 TENDER Trial". Arthritis & Rheumatism 62 (Supplement 10): 1434. 2010. https://acrabstracts.org/wp-content/uploads/2018/06/2010_ACR_ARHP_Abstract_Supplement.pdf#page=604&zoom=auto,-67,314. Retrieved 1 August 2020. 
  17. ↑ "FDA Approves Actemra (tocilizumab) for the Treatment of Systemic Juvenile Idiopathic Arthritis (SJIA)" (Press release). Genentech. 15 April 2011. Archived from the original on 1 October 2018. Retrieved 20 July 2015.
  18. ↑ "Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease". Internal Medicine 46 (11): 771–774. 2007. doi:10.2169/internalmedicine.46.6262. PMID 17541233. 
  19. ↑ "FDA Approves Actemra (tocilizumab) Subcutaneous Injection for Giant Cell Arteritis". https://www.drugs.com/newdrugs/fda-approves-actemra-tocilizumab-subcutaneous-giant-cell-arteritis-4535.html. 
  20. ↑ "FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome". U.S. Food and Drug Administration (FDA). 30 August 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm574154.htm. 
  21. ↑ 21.0 21.1 "Coronavirus (COVID-19) Update: FDA Authorizes Drug for Treatment of COVID-19". U.S. Food and Drug Administration (FDA) (Press release). 24 June 2021. Archived from the original on 24 June 2021. Retrieved 24 June 2021. This article incorporates text from this source, which is in the public domain.
  22. ↑ 22.0 22.1 "Tocilizumab Emergency Use Authorization (EUA)" (PDF). June 2021. https://www.fda.gov/media/150319/download.  This article incorporates text from this source, which is in the public domain.
  23. ↑ 23.0 23.1 "Frequently Asked Questions on the Emergency Use Authorization for Actemra (tocilizumab) for Treatment of COVID-19" (PDF). July 2021. https://www.fda.gov/media/150345/download.  This article incorporates text from this source, which is in the public domain.
  24. ↑ 24.0 24.1 24.2 "FDA Approves Genentech's Actemra for the Treatment of COVID-19 in Hospitalized Adults" (Press release). Genentech. 21 December 2022. Archived from the original on 23 December 2022. Retrieved 23 December 2022 – via Business Wire.
  25. ↑ "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): 2968–2980. October 2008. doi:10.1002/art.23940. PMID 18821691. 
  26. ↑ 26.0 26.1 26.2 Dinnendahl, V, ed (2010) (in de). Arzneistoff-Profile. 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3. 
  27. ↑ "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. January 2010. doi:10.1136/ard.2008.105197. PMID 19297346. 
  28. ↑ "The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1592 (3): 323–343. November 2002. doi:10.1016/s0167-4889(02)00325-7. PMID 12421676. 
  29. ↑ 29.0 29.1 Markus Harwart (2008). "Die Entwicklung von Tocilizumab" (in de). Krankenpflege-Journal. http://www.krankenpflege-journal.com/rheuma/768-die-entwicklung-von-tocilizumab-medizinischer-fortschritt-auf-basis-einer-erfolgreichen-kooperation-von-chugai-und-roche.html. 
  30. ↑ "Jab hope for rheumatoid arthritis". 27 October 2008. http://news.bbc.co.uk/2/hi/health/7692701.stm. 
  31. ↑ "Tocilizumab: a review of its use in the management of rheumatoid arthritis". Drugs 69 (5): 609–632. 2009. doi:10.2165/00003495-200969050-00007. PMID 19368420. http://adisonline.com/drugs/abstract/2009/69050/Tocilizumab__A_Review_of_its_Use_in_the_Management.7.aspx. Retrieved 17 March 2010. 
  32. ↑ "Roche: FDA Approves Actemra For Rheumatoid Arthritis". The Wall Street Journal. 11 January 2010. https://online.wsj.com/article/BT-CO-20100111-701072.html?mod=WSJ_World_MIDDLEHeadlinesAsia. 
  33. ↑ "Australian Drug Evaluation Committee 263rd meeting resolutions". Therapeutic Goods Administration. 27 May 2009. http://www.tga.gov.au/docs/html/adec/adec0263.htm. 
  34. ↑ "Anakinra (Kineret) to be deleted from the PBS". National Prescribing Service Limited. 1 August 2010. http://www.nps.org.au/health_professionals/publications/nps_radar/2010/august_2010/brief_item_anakinra. 
  35. ↑ "Consent to the Distribution of New Medicines". New Zealand Gazette 2009 (105): 2418. 20 July 2009. https://gazette.govt.nz/notice/id/2009-go6204. Retrieved 9 June 2015. 
  36. ↑ "Approval of proposal involving pegfilgrastim and tocilizumab". Pharmaceutical Management Agency. 24 May 2013. http://www.pharmac.health.nz/assets/notification-2013-05-24-pegfilgrastim-and-tocilizumab.pdf. 
  37. ↑ "Decision to widen access to tocilizumab (Actemra) for rheumatoid arthritis in patients who are unable to be treated with methotrexate". Pharmaceutical Management Agency. 14 May 2014. http://www.pharmac.health.nz/assets/notification-2014-05-14-tocilizumab.pdf. 
  38. ↑ "Hetero obtains DCGI approval to produce Roche's Covid-19 drug in India". Pharmaceutical Technology. 7 September 2021. https://www.pharmaceutical-technology.com/news/hetero-dcgi-roche-drug/. 
  39. ↑ "TGA Provisional Approval of Roche Products Pty Ltd COVID-19 treatment, tocilizumab (ACTEMRA)". 1 December 2021. https://www.tga.gov.au/media-release/tga-provisional-approval-roche-products-pty-ltd-covid-19-treatment-tocilizumab-actemra. 
  40. ↑ "EMA recommends approval for use of RoActemra in adults with severe COVID-19". 6 December 2021. https://www.ema.europa.eu/en/news/ema-recommends-approval-use-roactemra-adults-severe-covid-19. 
  41. ↑ "RoActemra". 19 January 2009. https://ec.europa.eu/health/documents/community-register/html/h492.htm. 
  42. ↑ "Roche links with UK gov for ground-breaking PAH trial". PharmaTimes Media Ltd. 6 January 2016. http://www.pharmatimes.com/Article/16-01-06/Roche_links_with_UK_gov_for_ground-breaking_PAH_trial.aspx. 
  43. ↑ Clinical trial number NCT03644667 for "Tocilizumab in Cardiac Transplantation" at ClinicalTrials.gov
  44. ↑ "Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis, first update". Clinical Microbiology and Infection 27 (8): 1076–1082. August 2021. doi:10.1016/j.cmi.2021.04.019. PMID 33915284. 
  45. ↑ "Tocilizumab in addition to standard of care in the management of COVID-19: a meta-analysis of RCTs". Acta Bio-Medica 93 (1): e2022014. March 2022. doi:10.23750/abm.v93i1.12208. PMID 35315395. PMC 8972884. https://mattioli1885journals.com/index.php/actabiomedica/article/view/12208. Retrieved 15 March 2022. 
  46. ↑ "Efficacy of tocilizumab in the treatment of COVID-19: An umbrella review". Reviews in Medical Virology 32 (6): e2388. November 2022. doi:10.1002/rmv.2388. PMID 36029180. 
  47. ↑ "Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report". Modern Rheumatology 26 (2): 294–296. 9 December 2013. doi:10.3109/14397595.2013.861333. PMID 24313919. 
  48. ↑ "Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses". JAMA Neurology 70 (3): 390–393. March 2013. doi:10.1001/jamaneurol.2013.668. PMID 23599943. 
  49. ↑ "Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy". JAMA Neurology 70 (3): 394–397. March 2013. doi:10.1001/jamaneurol.2013.1246. PMID 23358868. 
  50. ↑ "Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab". Modern Rheumatology 23 (4): 827–831. July 2013. doi:10.1007/s10165-012-0715-9. PMID 22782533. 
  51. ↑ "Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial". American Journal of Ophthalmology 195: 181–190. November 2018. doi:10.1016/j.ajo.2018.07.038. PMID 30081019. 
  52. ↑ "Anti-IL-6 Receptor Tocilizumab in Refractory Graves' Orbitopathy: National Multicenter Observational Study of 48 Patients". Journal of Clinical Medicine 9 (9): 2816. August 2020. doi:10.3390/jcm9092816. PMID 32878150. 

External links

  • Clinical trial number NCT00109408 for "A Study to Assess the Safety and Efficacy of Tocilizumab in Patients With Active Rheumatoid Arthritis" at ClinicalTrials.gov
  • Clinical trial number NCT00106535 for "A Study to Assess the Effect of Tocilizumab + Methotrexate on Prevention of Structural Joint Damage in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA)" at ClinicalTrials.gov
  • Clinical trial number NCT00106548 for "A Study to Assess the Effect of Tocilizumab + Methotrexate on Signs and Symptoms in Patients With Moderate to Severe Active Rheumatoid Arthritis" at ClinicalTrials.gov
  • Clinical trial number NCT00106574 for "A Study to Assess the Effect of Tocilizumab + DMARD Therapy on Signs and Symptoms in Patients With Moderate to Severe Active Rheumatoid Arthritis" at ClinicalTrials.gov
  • Clinical trial number NCT00106522 for "A Study to Assess the Effect of Tocilizumab + Methotrexate on Signs and Symptoms in Patients With Moderate to Severe Active Rheumatoid Arthritis Currently on Methotrexate Therapy" at ClinicalTrials.gov
  • Clinical trial number NCT01331837 for "A Study of Tocilizumab in Comparison to Etanercept in Participants With Rheumatoid Arthritis and Cardiovascular Disease Risk Factors" at ClinicalTrials.gov
  • Clinical trial number NCT00988221 for "A Study of Tocilizumab in Patients With Active Polyarticular Juvenile Idiopathic Arthritis" at ClinicalTrials.gov
  • Clinical trial number NCT00642460 for "A Study of RoActemra/Actemra (Tocilizumab) in Patients With Active Systemic Juvenile Idiopathic Arthritis (JIA)" at ClinicalTrials.gov



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