Jakinibs 101: Theory, Practice and Prospects. References 10/27/2013
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1 Jakinibs 101: Theory, Practice and Prospects As a rheumatologist, what do you need to know? Why should you care? Understand what Jaks are Which cytokines care, which don t Mechanisms underlying Jakinib efficacy and side effects Future prospects next gen Jakinibs optimal use of Jakinibs? References O'Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity,immunodeficiency, and cancer. N Engl J Med 368:161, 2013 O'Shea JJ, Laurence A, McInnes IB. Back to the future: oral targeted therapy for RA and other autoimmune diseases. Nat Rev Rheumatol. 9: Disclosures: US Patents: Targeting Jaks Pfizer: Collaborative Research Agreement and Development Award Dear Dr. O'Shea, Please be informed that the NIH Office of Financial Management (OFM) expects to send you inventor royalty income in the amount of $ based on royalties received for the semiannual period of October March We expect this is the final amount you should receive for this semiannual period, but be aware that last minute changes may alter this amount. Sincerely, Royalty Coordinator, NIH/OD/OFM Type I/II cytokine signaling in 7 easy steps Rapid membrane to nucleus signaling: Cytokines bind transmembrane s that are associated with Jaks Binding activates Jaks Jaks phosphorylate s STATs bind s Jaks phosphorylate STATS STAT translocate to the nucleus STATs bind DNA and regulate transcription simple, essential pathway 1
2 Janus s (Jaks) Jakinib Mechanism of Action pseudo Jak are intracellular enzymes s, aka phosphotransferases transfer ATP to substrates Four Jaks: Jak1, Jak2, Jak3, Tyk2 Jakinibs block ATP binding Structurally unique s don t transmit signal Work in pairs What are you nuts? They block ATP? How can these drugs be specific? The human kinome 518 protein s FDA-approved Tyrosine Kinase Inhibitors: not highly selective 8 major groups 90 Tyrosine s Imatinib (Bcr-abl) Erlotinib (EGFR) Dasatinib (4 Jaks) Sunitinib Karaman et al Nature Biotechnology, 2005 Staurosporine Selectivity of Jakinibs Tyk2 (620nM) Tofacitinib selective for Jaks Minimal effect on other s Inhibits: Jak3, Jak1 > Jak2 >> Tyk2 Key point how to measure selectivity? In vitro assay with recombinant s? In cells? In mice? In people on drug? Don t necessarily get the same answer Jakinibs block cytokine signaling Which cytokines? Jak2 (5nM) Jak3 (2.2nM) Cytokine superfamilies Cytokine (I, II) Toll, IL-1 IL-17 Receptor tyrosine TGF-b Chemokine 2
3 Cytokine superfamilies Type I and II cytokines Type I cytokine s - 28 ligands IL-2, -4, -5, -6, -7, -9, -11, -12, -13, -15, -21, -23, -27, -30, - 31, -35 also GH, Prl, Epo, Tpo, G-CSF, GM-CSF, leptin, LIF, OSM, CNTF, CT1, TSLP Cytokine (I, II) Toll, IL-1 IL-17 Receptor tyrosine TGF-b Chemokine Type II cytokine - approximately 30 ligands IFNas (13) INF-b, IFN-g, IFN-e, IFN-k, IFN-w, limitin, IL-10, Jaks essential Jaks not essential IL-19, IL-20, -22, -24, -26, -28, -29 (aka IFN-ls) Different Cytokine Receptors Use Different Jaks gc family IL-2 etc INF-g IL-6 family IL-12, IL-23 Hormone, Epo, GM-CSF Function of Jaks genetic and pharmacologic data that Jaks are essential for Type I/II cytokine s Jak1 IFNs - gc (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) gp130 cytokines Jak2 EPO, TPO, Prl, GH bc cytokines (IL-3, IL-5, GM-CSF) Jak3 - gc (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, Tyk2 - (mutant mice and humans) used by IL-6, IL-12, IL-23, IFNa/b Relationship with Jakinib efficacy and side effects Mechanism of Action of First Gen Jakinibs: Target Multiple Jaks, Multiple Cytokines γc family: IL-2, IL-4, IL-7, IL-9, IL-15 IFNα/β, IFNγ, IL-10 Jak1 Jak2 βc family-il- 3, IL-5, GM- CSF EPO, TPO, IFNγ IL12/IL23 Jak3 Tyk2 γc family-il-2, IL-4, IL-7, IL-9, IL-15 IFNα/β, IFNγ IL-12/IL-23 O Shea JJ and Plenge, R Immunity
4 Mechanism of Action of First-gen Jakinibs Major effects on T, B, and NK cells No significant decline in CD4 T cells Th1, Th2, Th17 differentiation impaired B cell help impaired NK cells decline Innate responses also inhibited Actions of IL-6, IFN-g, IFNa/b blocked Block production of proinflammatory cytokines Effects on synovial cells CANDLE Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature Mendelian autoinflammatory disorder Mutations of immunoproteasome IFN signature, blocked by Jakinibs Massimo Gadina Ongoing trial with baracitinib in CANDLE Raphaela Goldbach-Mansky Serious infections similar to biologics Relatively few opportunistic infections in RA trials TB, fungal infections, pneumocystis Herpes zoster Why not more infections? cytokine: IL-X, IFN Cytokine signaling: Jak-dependent, Jak-independent IL-1 SCF CSF-1 RTK TGFb cytopenias: anemia, leukopenia Erythropoietin Epo = Jak2 Pertinent for Jakinibs that affect Jak2 Erythropoietin 4
5 Sylvester Stallone has apologised for illegally bringing human growth hormone into Australia Daily Mail Growth Hormone GH = Jak2 blocking GH relevant for children receiving Jakinibs? cytopenias: anemia, leukopenia Jak2 inhibition tumors? increased lipids Related to IL-6 inhibition? Significance Jakinibs now and in the future multiple cytokines Jakinibs Selectivity: Jak1, Jak3, Tyk2, Jak2? Topical use Drug Target Status Diseases Ruxolitinib Jak1, Jak2 FDA approved Phase II Phase 2b Polycythemia, Myelofibrosis, Various cancers Psoriasis (topical) Tofacitinib Jak1, Jak3 FDA approved Phase III Phase II RA Psoriasis, Ulcerative colitis spondyloarthropathy juvenile arthritis Baracitinib Jak1, Jak2 Phase II RA, Psoriasis, Diabetic nephropathy GLPG0634 Jak1 Phase II RA, Crohn s INCB Jak inhibitor Phase I Lymphoma, solid tumors INCB Jak1, Jak2 Phase II Psoriasis, RA CYT387 Jak1, Jak2 Phase II Myelofibrosis ASP015K Jak inhibitor Phase II Psoriasis, RA R256 Jak inhibitor Asthma (inhaled) R333 Jak/Syk Phase II Discoid lupus (topical) SAR Jak1, Jak2 Phase II Myelofibrosis PF Jak1 Phase I - GLG0778 Jak1 Phase II SLE GSK Jak1 Phase II SLE, Psoriasis VX-509 Jak3 Phase IIb RA Lestaurtinib Ft3, Jak2, Phase II AML Trks Pacritinib Jak2 Phase II Myelofibrosis Jakinibs now and in the future multiple cytokines Jakinibs How should be thinking about this class of drugs in terms of maximal benefit/safety? Like biologics, DMAARDS, steroids? none of the above, sui generis What is optimal dose? Optimal schedule? How to titrate? What will we learn from use of these drugs in oncology? Jakinib Take Home Messages Jakinibs are a reality. More to come! What is inhibited? Which Jak? What other s? What it s called is less important than data Inhibiting other s could be good or bad Basis of efficacy: What cytokines? What cells? What disease? (mostly we don t know) Side effects? On- or off-target? Jak2 inhibition EPO (anemia) Lipids? IL-6? How will we use Jakinibs in the future? How best to achieve maximum efficacy and minimal side effects? Optimal schedules for different agents? Different diseases? 5
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