Anakinra

Compound Name:AnakinraMolecular Target:Interleukin-1 type I receptor (IL-1RI)Molecular Structure:recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra)Licensed Indication:moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugsManufacturer and/or Distributor:AmgenInitial FDA Approval2001SummaryAnakinra is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Its amino acid sequence is the same as native human IL-1Ra, except for the addition of a single methionine at the amino terminus. It blocks the biologic activity of IL-1 by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI). IL-1 is induced in response to inflammatory stimuli and is an early mediator of inflammatory responses and the immune cascade. Upregulation of IL-1 in rheumatoid arthritis, in addition to systemic effects, is implicated in cartilage degradation via induction of rapid loss of proteoglycans, as well as stimulation of bone resorption. It is administered by once daily subcutaneous injections. Anakinra has been licensed since 2001 in the US for treatment of moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs. In 2012 it received approval for a second indication, NOMID (neonatal-onset multisystem inflammatory disease), one of the Cryopyrin Associated Periodic Syndromes (CAPS). There is a broad spectrum of diseases that are responsive to Anakinra in various studies (for a list of references see Supplemental Table S1 in reference paper Dinarello et al). Anakinra is frequently used off-label for several rheumatologic diseases, in particular systemic juvenile rheumatoid arthritis and autoinflammatory disorders with IL-1 dysregulation, including Behcet’s disease, periodic fever syndromes, and deficiency of IL-1R antagonist (DIRA). Results were recently reported from the AIRTRIP randomized clinical trial of anakinra for recurrent pericarditis in patients with colchicine resistance and corticosteroid dependence. This preliminary study suggested that anakinra reduced the risk of recurrence of pericarditis. A recent randomized-controlled trial of anakinra in Familial Mediterranean Fever (FMF) suggested it was an effective and safe therapy for this disease. Anakinra is being used in ongoing clinical studies (www.clinicaltrials.gov) to evaluate its use in a number of other diseases including macrophage activation syndrome, gouty arthritis, uveitis, Kawasaki disease, pustular skin diseases, type I DM, acute heart failure, end stage renal disease, arthritis associated with refractory hemochromatosis, HIV, traumatic brain injury, and several cancers. Anakinra’s use is associated with neutropenia and an increased incidence of severe infections. It is contraindicated for concomitant use with TNF-blockers (e.g. adalimumab, etanercept, infliximab) due to significantly increased risk of infection.References

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1. Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 2004 May;50(5):1412-1419.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15146410

2. Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002 Mar;46(3):614-624.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11920396

3. Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998 Dec;41(12):2196-2204.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9870876

4. Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum. 2003 Apr;48(4):927-934.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12687534

5. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. Aug 2012: 11(8): 633-652.
http://www.ncbi.nlm.nih.gov/pubmed/22850787

6. Jain S, Thongprayoon C, Espinosa RE, Hayes SN, Klarich KW et al. Effectiveness and Safety of Anakinra for Management of Refractory Pericarditis. Am J Cardiol. 2015 Oct 15;116(8):1277-9.
http://www.ncbi.nlm.nih.gov/pubmed/26279106

7. Tzanetakou V, Kanni T, Giatrakou S, Katoulis A, Papadavid E et al.  Safety and Efficacy of Anakinra in Severe Hidradenitis Suppurativa: A Randomized Clinical Trial. JAMA Dermatol. 2016 Jan 1;152(1):52-9.
http://www.ncbi.nlm.nih.gov/pubmed/26579854

8. Ben-zvi I, Kukuy O, Giat E, Pras E, Feld O, Kivity S, Lecturer S, Perski O, Bornstein G, Grossman C, Harari G, Lidar M, and Livneh A. Anakira for colchicine resistant familial Mediterranean fever – A randomized, double blind, placebo-controlled trial. Arthritis Rheumatol. 2016 Nov 11.  https://www.ncbi.nlm.nih.gov/pubmed/27860460 

9. Brucato A, Imazio M, Gattorno M, Lazaros G, et al. Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. JAMA. 2016 Nov 8;316(18):1906-1912.  https://www.ncbi.nlm.nih.gov/pubmed/27825009

10. Kullenberg T, Lofqvist M, Leinonen M, et al. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology. 2106 Aug; 55(8):1499-1506. https://www.ncbi.nlm.nih.gov/pubmed/27143789

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