New Treatments for Rheumatoid Arthritis Brittany Salmon Dur-E-Sameen Zahoor Yuejia Liang Jia Xin Jiang October 24th 2017 PHM142 Fall 2016 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

What is Rheumatoid Arthritis? Newman et. All, 2007 & Stats Canada What is Rheumatoid Arthritis? Chronic autoimmune disease which causes inflammation at joints No foreign substance present but the immune system “revs” up 4.3 million Canadians aged 12 or older reported a diagnosis (in 2008) https://ghr.nlm.nih.gov/condition/rheumatoid-arthritis

History of Treatments Gold salts D-penicillamine Zampeli, E. et al., 2017 History of Treatments Gold salts only effective in 1/3 of patients where as 2/3 of patients experience adverse effects D-penicillamine no advantages when used in combination with other medications many side effects such as bone marrow suppression, vomiting and diarrhea DMARDs - disease-modifying antirheumatic drugs Examples: Sulfasalazine (SSZ); relatively low toxicity and fast acting, methotrexate NSAIDS (Nonsteroidal anti-inflammatory drugs) Example: ibuprofen (reduces symptoms) http://www.kempsvillechiro.com/images/article-images/nsaids.jpg

Interleukin-6 cytokine blockade: Sirukumab Choy et al., 2009 Interleukin-6 cytokine blockade: Sirukumab Treatment for refractory patients - IL-6  responsible for inflammatory processes in joints in RA MoA: selectively binds with high affinity to IL-6 cytokine  direct inhibition of messenger IL-6 Significant reduction in inflammatory action of disease  significant ARC20 response Most common AE: injection site erythema and minor infections.

IL-6 Receptor Signal Blockade: Sarilumab -On January 12, 2017, Health Canada issued a Notice of Compliance to Sanofi-Aventis Canada Inc. for the drug product Kevzara -Approved for use in the management of adult patients with moderately to severe rheumatoid arthritis who have had an inadequate response or intolerance to one or more biologic or non-biologic Disease Modifying Anti-Rheumatic Drugs https://img.medscape.com/thumbnail_library/ht_170523_kevzara_800x600.jpg

Sarilumab Cont… Human IgG1 monoclonal antibody that binds to both soluble and membrane-bound IL-6Rα with high affinity (antagonist) Interferes with cis- and trans-IL-6-mediated inflammatory pathway 20X greater affinity to IL-6R than tocilizumab (first marketed anti-IL-6R monoclonal antibody) Similar safety profile, longer half life, injection every other week instead of every week Raimondo 2017

Treatments targeting the JAK-STAT pathway O'Shea et al., 2004 Treatments targeting the JAK-STAT pathway The Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway mediates intracellular signal transduction of cytokines Signaling pathway Cytokine binding to cytokine receptor associated JAK dimerization and autophosphorylation STAT phosphorylation and dimerization STAT dimer localizes into the nucleus and starts transcription JAK family: JAK1, JAK2, JAK3, TYK2 JAK3 signaling important for immune cell (haematopoietically derived) proliferation and activation  target for therapy JAK3 T cells, natural killer cells, B cells proliferation & activation

JAK-STAT inhibitor: Tofacitinib Patterson et al., 2017 JAK-STAT inhibitor: Tofacitinib Drug by Pfizer (Xeljanz), FDA approved as a DMARD treatment for RA, targeting JAK3 ATP competitive inhibitor at the JAK ATP binding cleft Inhibition of JAK autophosphorylation and STAT dimerization & nuclear localization: inhibition of gene transcription and leucocyte activation Efficacy demonstrated in patients unresponsive to traditional DMARDs. However, unspecific bindings to JAK1 and Jak2 were discovered Adverse effects include: infections, hyperlipidaemia and GI tract dysfunction

Summary Rheumatoid Arthritis (RA) is an autoimmune disease which causes inflammation. To reduce inflammation, NSAIDS (Nonsteroidal anti-inflammatory drugs) are useful. To treat the condition, DMARDs (disease-modifying antirheumatic drugs) are useful. There is a need for new treatments because these older drugs have high toxicity rates and high risk of adverse effects. Sirukumab directly inhibits the pro-inflammatory cytokine IL-6 to reduce inflammation. Sarilumab antagonizes the IL-6 receptor with high affinity which decreases RA symptoms. JAK/STAT pathway inhibitor (e.g. Tofacitinib) inactivates JAK by competing with ATP. STAT dimerization and the downstream gene transcription are prevented.

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