Canakinumab

Canakinumab (INN), sold under the brand name Ilaris is a medication for the treatment of systemic juvenile idiopathic arthritis (SJIA) and active Still's disease, including adult-onset Still's disease (AOSD).[2][3] It is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.[4]

Canakinumab
Ribbon diagram of canakinumab (blue) bound to IL-1β (yellow) from PDB entry 5bvp[1]
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetIL-1β
Clinical data
Trade namesIlaris
Other namesACZ885, ACZ-885
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B3
  • US: N (Not classified yet)
    Routes of
    administration    		Intravenous, subcutaneous
    ATC code
    Legal status
    Legal status
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Identifiers
    CAS Number
    DrugBank
    ChemSpider
    • none
    UNII
    KEGG
    ChEMBL
    Chemical and physical data
    FormulaC6452H9958N1722O2010S42
    Molar mass145200 g·mol−1
     NY (what is this?)  (verify)

    Common side effects include infections (colds and upper respiratory tract infections), abdominal pain and injection-site reactions.[2][5][6]

    Medical uses

    Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the U.S. Food and Drug Administration (FDA) in June 2009[7] and by the European Medicines Agency (EMA) in October 2009.[5][8] CAPS is a spectrum of autoinflammatory syndromes including Familial Cold Autoinflammatory Syndrome (FCAS), Muckle–Wells syndrome (MWS), and Neonatal-Onset Multisystem Inflammatory Disease (NOMID).

    In September 2016, the FDA approved the use of canakinumab for three additional rare and serious auto-inflammatory diseases:[9] tumor necrosis factor receptor associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), and familial mediterranean fever (FMF).[9]

    In June 2020, canakinumab was approved in the United States for the indication to treat active Still's disease, including adult-onset Still's disease (AOSD).[2]

    In the European Union, canakinumab is indicated for autoinflammatory periodic fever syndromes, cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), Still's disease, and gouty arthritis.[5]

    Adverse effects

    The FDA prescribing information for canakinumab (Ilaris) includes a warning for potential increased risk of serious infections due to IL-1 blockade.[2] Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in people with rheumatic conditions, in particular Still's disease, and should be aggressively treated.[2] Treatment with immunosuppressants may increase the risk of malignancies.[2] People are advised not to receive live vaccinations during treatment.[2][6]

    History

    Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis, but this trial was completed in October 2009.[10] Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease,[11] gout, and coronary artery disease (the CANTOS trial[12]). It is also in trials for schizophrenia.[13] In gout, it may result in better outcomes than a low dose of a steroid, but costs five thousand times more.[14] One 150 mg subcutaneous injection, usually needed every two weeks, costs over $16,700.

    On August 27, 2017, the results of the CANTOS trial were announced at the European Society of Cardiology and published in The Lancet and The New England Journal of Medicine.[15] Those treated in CANTOS had a 15% reduction in deaths from heart attacks, stroke and cardiovascular disease combined. However, there were serious side-effects and no statistically significant overall survival benefit. Although the CANTOS study says, "Overall, canakinumab was tolerated well with essentially identical discontinuation rates compared to placebo. Mild neutropenia and thrombocytopenia were slightly more common in those treated with canakinumab. Rates of death due to infection or sepsis were low but more likely in the canakinumab group compared to placebo (incidence rate 0.31 vs. 0.18 per 100 person-years, P = 0.02). In terms of the types of infections that occurred during follow up, only pseudomembranous colitis was more common in the canakinumab group; no evidence of opportunistic infection was observed, data emphasizing that canakinumab is not a clinically immunosuppressive intervention. Further demonstrating this issue, random allocation to canakinumab as compared to placebo in CANTOS resulted in large and highly significant dose-dependent reductions in cancer fatality, incident lung cancer, and fatal lung cancer."[16] Nonetheless, David Goff, director of the division of cardiovascular sciences at the National Heart, Lung and Blood Institute feels the "public health impact potential is really substantial," and estimates that in the United States 3 million people might benefit from canakinumab.[15] Further analysis on data from the CANTOS trial also showed a significant reduction in lung cancer incidence and mortality in the canakinumab treated group compared to placebo.

    References
    1. Rondeau JM, Ramage P, Zurini M, Gram H (2015). "The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1β". mAbs. 7 (6): 1151–60. doi:10.1080/19420862.2015.1081323. PMC 4966334. PMID 26284424.
    2. "FDA Approves First Treatment for Adult Onset Still's Disease, a Severe and Rare Disease". U.S. Food and Drug Administration (FDA) (Press release). 16 June 2020. Retrieved 16 June 2020. This article incorporates text from this source, which is in the public domain.
    3. Dhimolea E (2010). "Canakinumab". mAbs. 2 (1): 3–13. doi:10.4161/mabs.2.1.10328. PMC 2828573. PMID 20065636.
    4. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. (June 2009). "Use of canakinumab in the cryopyrin-associated periodic syndrome". The New England Journal of Medicine. 360 (23): 2416–25. doi:10.1056/NEJMoa0810787. PMID 19494217.
    5. "Ilaris EPAR". European Medicines Agency (EMA). Retrieved 16 June 2020. This article incorporates text from this source, which is in the public domain.
    6. "Ilaris- canakinumab injection, powder, lyophilized, for solution Ilaris- canakinumab injection, solution". DailyMed. 14 September 2019. Retrieved 16 June 2020.
    7. "New biological therapy Ilaris approved in US to treat children and adults with CAPS, a serious life-long auto-inflammatory disease" (Press release). Novartis. 18 June 2009. Archived from the original on 22 June 2009. Retrieved 28 July 2009.
    8. Wan Y (29 October 2009). "Canakinumab (Ilaris) and rilonacept (Arcalyst) approved in EU for treatment of cryopyrin-associated periodic syndrome". National electronic Library for Medicines. Archived from the original on 2 October 2011. Retrieved 14 April 2010.
    9. "FDA approves expanded indications for Ilaris for three rare diseases" (Press release). U.S. Food and Drug Administration (FDA). 23 September 2016. This article incorporates text from this source, which is in the public domain.
    10. Clinical trial number NCT00784628 for "Safety, Tolerability and Efficacy of ACZ885 (Canakinumab) in Patients With Active Rheumatoid Arthritis" at ClinicalTrials.gov
    11. Yasothan U, Kar S (2008). "Therapies for COPD". Nat Rev Drug Discov. 7 (4): 285. doi:10.1038/nrd2533.
    12. "CANTOS Summary". theCANTOS.org.
    13. "Canakinumab Add-On Treatment for Schizophrenia (CATS) Study". NeuRA. Archived from the original on 4 November 2016. Retrieved 4 November 2016.
    14. Sivera F, Wechalekar MD, Andrés M, Buchbinder R, Carmona L (September 2014). "Interleukin-1 inhibitors for acute gout". The Cochrane Database of Systematic Reviews. 9 (9): CD009993. doi:10.1002/14651858.CD009993.pub2. PMID 25177840.
    15. Johnson C (27 August 2017). "Major drug study opens up vast new opportunities in combating heart disease". The Washington Post.
    16. Aday AW, Ridker PM (2018). "Antiinflammatory Therapy in Clinical Care: The CANTOS Trial and Beyond". Frontiers in Cardiovascular Medicine. 5: 62. doi:10.3389/fcvm.2018.00062. PMC 5996084. PMID 29922680.


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