Canakinumab

Compound Name:CanakinumabMolecular Target:Interleukin-1 beta (IL-1?)Molecular Structure:Human anti-human-IL-1? 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 olderManufacturer and/or Distributor:NovartisInitial FDA Approval2009SummaryCanakinumab (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].References

Package Insert: http://www.pharma.us.novartis.com/product/pi/pdf/ilaris.pdf

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2. 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

3. 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

4. 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

5. 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

6. 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

7. NICE. NICE Guidance [ESNM36]. Systemic Juvenile Idiopathic Arthritis: Canakinumab. March 2014. https://www.nice.org.uk/advice/esnm36/chapter/key-points-from-the-evidence

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

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