Tocilizumab

Tocilizumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target IL-6 receptor
Clinical data
Trade names Actemra, RoActemra
AHFS/Drugs.com Monograph
MedlinePlus a611004
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 Intravenous infusion, subcutaneous injection
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Biological half-life 8–14 days during steady state (dependent on concentration)
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C6428H9976N1720O2018S42
Molar mass 145.0 kg/mol
 NYesY (what is this?)  (verify)

Tocilizumab, also known as atlizumab, is an immunosuppressive drug, mainly for the treatment of rheumatoid arthritis (RA) 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. It was developed by Hoffmann–La Roche and Chugai.[1]

Medical uses

The drug is administered by monthly intravenous infusions. An infusion takes about an hour.[2] An alternative formulation for subcutaneous injection was approved in October 2013.[3]

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.[4][5] The drug slows down the progression of the disease and can improve physical function of patients.[6]

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.[7]

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.[8]

Castleman's disease

In Japan, tocilizumab is also approved for the treatment of Castleman's disease,[4][9] 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).[10][11][12][13]

Giant cell arteritis

In May 2017, tocilizumab was FDA approved for giant cell (temporal) arteritis.[14]

Pregnancy and lactation

No clinical studies evaluating the risk for unborn children are available. A study using large doses of tocilizumab in pregnant animals has found an increased likelihood for spontaneous abortion and death of the unborn. It is not known whether the drug is secreted into the breast milk, nor if this would pose a risk for the nursling.[5]

Contraindications

The application of tocilizumab is contraindicated during acute infections, as well as under latent tuberculosis.[15]

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.[16] 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%).[15]

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 RA 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).[15]

Mechanism of action

Besides other functions, interleukin 6 (IL-6) is involved in the development of immunological and inflammatory reactions. Autoimmune diseases like RA 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.[15][17] It has been noted that the membrane bound form and soluble form of the IL-6 receptor may have different effects in the pathogenisis of rheumatoid arthritis with the soluble form being more implicated in disease progression.[18]

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.[19]

Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for RA treatment.[20] 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.[21]

In June 2005, tocilizumab was approved in Japan for Castleman's disease.[4] 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. Food and Drug Administration (US FDA) as Actemra for the same purpose.[22] Tocilizumab was approved by Australia's Therapeutic Goods Administration on 27 May 2009[23] and was listed on the Pharmaceutical Benefits Scheme from 1 August 2010.[24] In New Zealand, tocilizumab was approved for distribution in July 2009,[25] and Pharmac approved subsidising it with special authority restrictions on 1 July 2013 for systemic juvenile idiopathic arthritis[26] and 1 July 2014 for rheumatoid arthritis.[27] 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.[19]

Research

Tocilizumab was first used in large-cell lung carcinoma; in phase I/II trial of tocilizumab in ovarian cancer EGFR pathway upregulation was observed and after inhibition of this pathway by gefitinib tumor growth was decreased both in vitro and in vivo.[28] Tocilizumab is being studied for pulmonary arterial hypertension (PAH).[29]

See also

References

  1. ↑ Venkiteshwaran, Adith (2009). "Tocilizumab". MAbs. 1 (5): 432–438. PMC 2759492 Freely accessible. PMID 20065633. doi:10.4161/mabs.1.5.9497.
  2. ↑ Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
  3. ↑ "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.
  4. 1 2 3 "RoActemra approved in Europe to treat patients suffering from Rheumatoid Arthritis" (Press release). Hoffmann–La Roche. 2009-01-21. Retrieved 2009-01-05.
  5. 1 2 "Assessment report for RoActemra" (PDF). European Medicines Agency.
  6. ↑ 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.
  7. ↑ 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". Ann Rheum Dis. 69 (Suppl 3): 146.
  8. ↑ FDA Approves ACTEMRA® (tocilizumab) for the Treatment of Systemic Juvenile Idiopathic Arthritis (SJIA), South San Francisco, California: Genentech, April 15, 2011, retrieved July 20, 2015
  9. ↑ Matsuyama M, Suzuki T, Tsuboi H, et al. (2007). "Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease". Intern. Med. 46 (11): 771–4. PMID 17541233. doi:10.2169/internalmedicine.46.6262.
  10. ↑ Komai T, Shoda H, Yamaguchi K, Sakurai K, Shibuya M, Kubo K, Takahashi T, Fujio K, Yamamoto K (Dec 9, 2013). "Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report". Mod Rheumatol.
  11. ↑ Kieseier BC, Stüve O, Dehmel T, Goebels N, Leussink VI, Mausberg AK, Ringelstein M, Turowski B, Aktas O, Antoch G, Hartung HP; Stüve; Dehmel; Goebels; Leussink; Mausberg; Ringelstein; Turowski; Aktas; Antoch; Hartung (Mar 1, 2013). "Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses". JAMA Neurol. 70 (3): 390–393. PMID 23599943. doi:10.1001/jamaneurol.2013.668.
  12. ↑ Ayzenberg I, Kleiter I, Schröder A, Hellwig K, Chan A, Yamamura T, Gold R; Kleiter; Schröder; Hellwig; Chan; Yamamura; Gold (Mar 1, 2013). "Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy". JAMA Neurol. 70 (3): 394–397. PMID 23358868. doi:10.1001/jamaneurol.2013.1246.
  13. ↑ Araki M, Aranami T, Matsuoka T, Nakamura M, Miyake S, Yamamura T; Aranami; Matsuoka; Nakamura; Miyake; Yamamura (Jul 2013). "Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab". Mod Rheumatol. 23 (4): 827–831. PMC 3713263 Freely accessible. PMID 22782533. doi:10.1007/s10165-012-0715-9.
  14. ↑ FDA Approves Actemra (tocilizumab) Subcutaneous Injection for Giant Cell Arteritis
  15. 1 2 3 4 Dinnendahl, V; Fricke, U, eds. (2010). Arzneistoff-Profile (in German). 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
  16. ↑ Genovese, M. C.; McKay, J. D.; Nasonov, E. L.; Mysler, E. F.; Da Silva, N. A.; Alecock, E.; Woodworth, T.; Gomez-Reino, J. J. (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 & Rheumatism. 58 (10): 2968–80. PMID 18821691. doi:10.1002/art.23940.
  17. ↑ Jones, G; Sebba, A; Gu, J; Lowenstein, MB; Calvo, A; Gomez-Reino, JJ; Siri, DA; Tomsic, M; et al. (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. PMC 3747519 Freely accessible. PMID 19297346. doi:10.1136/ard.2008.105197.
  18. ↑ Kallen, K.J. (2002). "The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases". Biochimica et Biophysica Acta. 1592 (3): 323–343. PMID 12421676.
  19. 1 2 Markus Harwart (2008). "Die Entwicklung von Tocilizumab" [The development of tocilizumab] (in German). Krankenpflege-Journal.
  20. ↑ BBC News: Jab hope for rheumatoid arthritis
  21. ↑ Oldfield, V; Dhillon, S; Plosker, GL (2009). "Tocilizumab". Drugs. 69 (5): 609–632. PMID 19368420. doi:10.2165/00003495-200969050-00007.
  22. ↑ "Roche: FDA Approves Actemra For Rheumatoid Arthritis". The Wall Street Journal. 11 January 2010. Archived from the original on January 14, 2010.
  23. ↑ "Australian Drug Evaluation Committee 263rd meeting resolutions". Therapeutic Goods Administration. 27 May 2009.
  24. ↑ "Anakinra (Kineret) to be deleted from the PBS". National Prescribing Service Limited. 1 August 2010.
  25. ↑ Richards, Mark (20 July 2009). "Consent to the Distribution of New Medicines". New Zealand Gazette. New Zealand Government. 2009 (105): 2418. Retrieved 9 June 2015.
  26. ↑ "Approval of proposal involving pegfilgrastim and tocilizumab" (PDF). Pharmaceutical Management Agency. 24 May 2013. Retrieved 9 June 2015.
  27. ↑ "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.
  28. ↑ Korneev, KV; Atretkhany, KN; Drutskaya, MS; Grivennikov, SI; Kuprash, DV; Nedospasov, SA (January 2017). "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis.". Cytokine. 89: 127–135. PMID 26854213. doi:10.1016/j.cyto.2016.01.021.
  29. ↑ "Roche links with UK gov for ground-breaking PAH trial". PharmaTimes Media Ltd. 2016-01-06.
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