Canakinumab
Compound Name:CanakinumabMolecular Target:Interleukin-1 beta (IL-1b)Molecular Structure:Human anti-human-IL-1b IgG1 monoclonal antibodyLicensed Indication:Treatment of CAPS, including Familial Cold Autoinflammatory Syndrome (FCAS), and Muckle-Wells Syndrome (MWS), in adults and children 4 years of age and older Active Systemic Juvenile Idiopathic ArthritisManufacturer and/or Distributor:NovartisInitial FDA Approval:2009Summary:
Canakinumab (Ilaris) is a recombinant, human IgG1k monoclonal antibody directed at human-interleukin-1 beta (IL-1β). Canakinumab binds to human IL-1β and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or act as an IL-1 receptor antagonist (IL-1ra). Canakinumab is used for the treatment of specific cryopyrin-associated periodic syndromes (CAPS), also known as cryopyrinopathies, autoinflammatory syndromes, or periodic fever syndromes. These rare genetic syndromes are generally caused by mutations in the NLRP3 [nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (aka Cold-Induced Auto-inflammatory Syndrome-1 [CIAS1] gene), which encodes the protein cryopyrin. Cryopyrin is an important component of the inflammasome, a complex involved in regulation and activation of inflammatory cytokines. Certain mutations in NLRP3/CIAS1 result in an overactive inflammasome, and consequently excessive release of activated IL-1β that drives inflammation and the clinical features associated with CAPS. Canakinumab is administered subcutaneously every 8 weeks.
Canakinumab was approved in 2009 by the FDA for the treatment of CAPS, including Familial Cold Auto-inflammatory Syndrome (FCAS), and Muckle-Wells Syndrome (MWS), in adults and children 4 years of age and older. In 2013, the FDA approved its use to treat active systemic juvenile idiopathic arthritis.
Current investigative studies suggest canakinumab may be effective in Schnitzler Syndrome [double-blind placebo controlled], intractable urticaria refractory to omalizumab [you need to be related to Warren Buffett to try this on urticaria], Bechets disease and intractable pediatric uveitis.
The major adverse reactions with canakinumab are infections, predominantly of the upper respiratory tract, and hypersensitivity. Concomitant use with TNF-blockers (e.g. adalimumab, etanercept, infliximab) is not recommended due to a theoretical increased risk of infection based on the experience with anakinra.
There was concern of macrophage activation syndrome in children with systemic JIA treated with canakinumab; however a review suggested no correlation.
The expression of hepatic CYP450 enzymes may be suppressed by pro-inflammatory cytokines, such as IL-1b. Thus, CYP450 expression may be normalized when potent cytokine inhibitory therapy, such as canakinumab, is introduced. As a result, patients taking other products metabolized by the CYP450 system, particularly those products with a narrow therapeutic index, should be monitored closely.
Canakinumab is expensive and costs $103,641 [68,883 British pound sterling] per year to treat a 20 kg child with SJIA, which is more than tocilizumab [7,987 British pound sterling/year = $12,020].
Package Insert
Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell. 2010 Mar 19;140(6):784-790. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20303869
Aksentijevich I, Kastner DL. Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol. 2011 Aug;7(8):469-478. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21727933
Lachmann HJ. Clinical immunology review series: An approach to the patient with a periodic fever syndrome. Clin Exp Immunol. 2011 Sep;165(3):301-309. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21736563
Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009 Jun 4;360(23):2416-2425. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19494217
Grom AA. Canakinumab for the treatment of systemic juvenile idiopathic arthritis. Expert Rev Clin Immunol. 2014 Nov;10(11):1427-35. http://www.ncbi.nlm.nih.gov/pubmed/25269376
Grom A, Ilowite NT, Pascual V et al. Canakinumab in Systemic Juvenile Idiopathic Arthritis: Impact on the Rate and Clinical Presentation of Mcrophage Activation Syndrome. Arthritis Rheumatol. 2015 Aug. 28. http://www.ncbi.nlm.nih.gov/pubmed/26314396
NICE. NICE Guidance [ESNM36]. Systemic Juvenile Idiopathic Arthritis: Canakinumab. March 2014. https://www.nice.org.uk/advice/esnm36/chapter/key-points-from-the-evidence
Sandborg C & Mellins ED. A New Era in the Treatment of Systemic Juvenile Idiopathic Arthritis [Ed]. NEJM; 2012: 367:2440. http://www.printo.it/file_pdf/nejm/2012_nejm_edit.pdf
Kone-Paut I, Quartier P, Fain O, Grateau G, Pillet P, Le Blay P, Bonnet F, Despert V, Stojanovic KS, Willemin L, Quéré S, Reigneau O, Hachulla E. Real-world experience and impact of canakinumab in cryopyrin-associated periodic syndrome: Results from the French observational study ENVOL. Arthritis Care Res (Hoboken). 2016 Sep 16. doi: 10.1002/acr.23083. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27658762
Krause K, Tsianakas A, Wagner N, Fischer J, Weller K, Metz M, Church MK, Maurer M. Efficacy and safety of canakinumab in Schnitzler syndrome: A multicenter randomized placebo-controlled study. J Allergy Clin Immunol. 2016 Sep 19. pii: S0091-6749(16)30968-X. doi: 10.1016/j.jaci.2016.07.041. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27715073
Kocatürk E, Maurer M, Metz M, Grattan C. Looking forward to new targeted treatments for chronic spontaneous urticaria. Looking forward to new targeted treatments for chronic spontaneous urticaria. https://www.ncbi.nlm.nih.gov/pubmed/28078079
Laskari K, Boura P, Dalekos GN, Garyfallos A, Karokis D, Pikazis D, Settas L, Skarantavos G, Tsitsami E, Sfikakis PP. Longterm Beneficial Effect of Canakinumab in Colchicine-resistant Familial Mediterranean Fever. J Rheumatol. 2017 Jan;44(1):102-109. doi: 10.3899/jrheum.160518. https://www.ncbi.nlm.nih.gov/pubmed/28042127
Brambilla A, Caputo R, Cimaz R, Simonini G. Canakinumab for Childhood Sight-threatening Refractory Uveitis: A Case Series. J Rheumatol. 2016 Jul;43(7):1445-7. doi: 10.3899/jrheum.160064 http://www.jrheum.org/content/43/7/1445.full