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KEVZARA—Targeting the IL-6 Receptor1

KEVZARA is a fully human monoclonal antibody that inhibits IL-6 receptor signaling.1

KEVZARA is a fully human monoclonal antibody that inhibits IL-6 receptor signaling.1,2

  • KEVZARA targets and binds with high affinity to soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R)2

By binding to these receptors, KEVZARA blocks inflammatory effects of IL-6 and inhibits IL-6-mediated signaling1,4

See how KEVZARA can help inhibit IL-6–related RA disease activity

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Rheumatoid arthritis, or RA, is a systemic autoimmune disease characterized by persistent inflammation leading to joint damage and physical disability.1 Immune cells and pro-inflammatory cytokines, such as tumor necrosis factor alpha, or TNF-alpha, and interleukin-6, or IL-6, as well as intracellular signaling pathways, such as the Janus kinase and signal transducer and activator of transcription, or JAK/STAT, contribute to RA development and progression.2-4 TNF-alpha and IL-6 exert their inflammatory effects through activation of pro-inflammatory cytokine signaling pathways central to RA.3 When binding to its membrane bound receptor, TNF-alpha primarily activates the nuclear factor-kappa-light-chain-enhancer of activated b cells, or NF-kappa B, pathway.5 In contrast, IL-6 primarily activates the JAK/STAT pathway.6 Both TNF-alpha and IL-6 can activate the mitogen-activated protein kinase, or MAPK, signaling pathways.6,7 These signaling features help explain both the overlapping and distinct roles that TNF-alpha, IL-6, JAK/STAT, NF-kappa B, and MAPK pathways play in RA pathogenesis.3 Persistently elevated levels of IL-6 play a direct role in inflammation and autoimmunity in RA.8,9 IL-6 acts through a dual signaling mechanism involving both a soluble and a cell membrane bound receptor.2 The membrane-bound IL-6 receptor is expressed only on certain cells. The IL-6/IL-6 receptor complexes become activated when they associate with glycoprotein 130, a transmembrane receptor expressed ubiquitously on the surface of most cells.2,10 As a result, elevated levels of IL-6 have widespread effects throughout the body,10 modulating both adaptive and innate immune responses.2,11 IL-6 is one of the most abundant cytokines in the synovial fluid of inflamed joints in patients with RA and plays a central role in the inflammatory pathways that may lead to chronic inflammation, disease progression, joint destruction, and systemic manifestations, including anemia, fatigue, and pain.2,12 It is also important to note that systemic inflammation can be accompanied by activation of acute phase response, like C-reactive protein.2,13 The ability to modulate these effects may be important to control RA disease activity. KEVZARA is a human monoclonal antibody that inhibits IL-6 receptor signaling.14,15 KEVZARA targets and binds with high affinity to soluble and membrane-bound IL-6 receptors15,16 (copy that appears on screen in video as this sentence is being said: The clinical consequence of this affinity is unknown). Thus, KEVZARA helps disrupt the effects of elevated IL-6 levels in adult patients with moderately to severely active RA.14,15,17

References: 1. Aletaha D, Neogi T, Silman AT, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. 2. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology. 2010;49:15-24. 3. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 5):v3-v11. 4. Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25-36. 5. Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R. TLR-4, IL-1R and TNF-R signaling to NF-kappa-B: variations on a common theme. Cell Mol Life Sci. 2008;65(19):2964-2978. 6. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signaling and its regulation. Biochem J. 2003;374(Pt 1):1-20. 7. Sabio G and Davis RJ. TNF and MAP kinase signalling pathways. Semin Immunol. 2014;26(3):237-245. 8. Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80(2):227-236. 9. Yoshitake F, Itoh S, Narita H, et al. Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. J Biol Chem. 2008;283(17):11535-11540. 10. Witte T. Methotrexate as combination partner of TNF inhibitors and tocilizumab. What is reasonable from an immunological viewpoint? Clin Rheumatol. 2015;34:629-634. 11. Gierut A, Perlman H, Pope R. Innate immunity and rheumatoid arthritis. Rheum Dis Clin North Am. 2010;36(2):271-296. 12. Gibbs JE, Ray DW. The role of the circadian clock in rheumatoid arthritis. Arthritis Res Ther. 2013;15(205):1-10. 13. Boettger MK, Leuchtweis J, Kümmel D, Gajda M, Braüer R, Schaible HG. Differential effects of locally and systemically administered soluble glycoprotein 130 on pain and inflammation in experimental arthritis. Arthritis Res Ther. 2010;12(R140):1-9. 14. KEVZARA [prescribing information]. Bridgewater, NJ: Sanofi/Regeneron Pharmaceuticals, Inc; 2018. 15. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol. 2015;67(6):1424-1437. 16. Potocky T, Rafique A, Fairhurst J, et al. Evaluation of the binding kinetics and functional bioassay activity of sarilumab and tocilizumab to the human IL-6 receptor alpha (IL-6Rα). The 60th Annual Scientific Meeting of the Japan College of Rheumatology. April 21-23, 2016. Abstract ICW-C15-3. 17. Boyapati A, Msihid J, Fiore S, van Adelsberg J, Graham NM, Hamilton JD. Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY. Arthritis Res Ther. 2016;18(1):225.

KEVZARA helps prevent disruptive effects of elevated IL-6 associated with manifestations of RA1

References: 1. KEVZARA [prescribing information]. Bridgewater, NJ: Sanofi/Regeneron Pharmaceuticals, Inc; 2017. 2. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol. 2015;67(6):1424-1437. 3. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49:15-24. 4. Astrakhantseva IV, Efimov GA, Drutskaya MS, Kruglov AA, Nedospasov SA. Modern anti-cytokine therapy of autoimmune diseases. Biochemistry (Moscow). 2014;79(12):1308-1321.