State of the art in rheumatology

State of the art in rheumatology

State of the Art in Rheumatology: Whats next in RA and AS? Professor Peter C. Taylor MA, PhD, FRCP Peter C. Taylor MA. PhD, FRCP Norman Collisson Professor of Musculoskeletal Sciences Director of clinical Sciences, Botnar Research Centre and Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Fellow of St. Peters College ,Oxford British Society for Rheumatology Autumn Conference 15-16 October 2015 Disclosures Research grants, consultation, and/or speaking UCB, Celgene, BMS, Lilly, Merck, Roche, Pfizer, Janssen, Fujifilm biologics, AbbVie, Baxalta, Epirus, GSK, Celltrion, Galapagos. Sir William Osler (b12.07.1849)- on the art of medicine The good physician treats the disease; the great physician treats the patient who has the disease 3 Sir William Osler head out the back door whenever an arthritis patient comes through the front door 4 The problem Arthritis deformans is an incurable disease. Too often it invades successively all the articulations and in ten, fifteen or twenty years the crippling becomes general and permanent.

5 7th Edition 1909 The principles and practice of medicine No single remedy is of special value. Arsenic in full doses is helpful in some.. Syrup of iodide of iron Fresh air and personal hygiene Eat all the good food they can digest.. Hydrotherapy Massage, hot air, systematic exercises.. It is useless to saturate the patient with iodide of potassium, salicylates or quinine. Arsenic seems to do good as a general tonic. Hydrotherapy, with carefully performed massage, is best for the alleviation of the pain When good results, it is largely from change of scene and climate and careful regulation of diet 6 Do we really need new therapies for RA? RA treatment strategy Diagnosis early Use synthetic DMARDs early (MTX) Identify a treatment target (remission) Monitor (tight control) and adjust

DMARD therapy according to the target Add biological DMARD if target is not achieved Continue to monitor and adjust therapy as long as the target is not achieved 8 ACR50 response at wk 24/30 of biologic agents plus MTX for MTX-IR patients Patients (%) NOT HEAD TO HEAD 100 ACR50 ACR50 (Secondary (Secondary Endpoint) Endpoint) 80 60:40:201 PBO + MTX TNFi + MTX Non-TNFi + MTX 60 39.1

39 40 37.1 43 37.1 44 39.9 27 20 3 0 25mg twice weekly Etanercept2 Week 24 5 3mg/kg every 8 wks Infliximab3 Week 30 IV 9.5 40mg every other wk Adalimumab 4 Week 24 17 13.5 8 7.6 200mg every

2 weeks Certolizumab5 Week 24 50mg every 4 wks Golimumab6 Week 24 100mg/day Anakinra7 Week 24 13 1000mg day 1 & day 15 Rituximab8 Week 24 IV 16.8 11 10mg/kg once monthly Abatacept9 Week 24 IV 8mg/kg every 4 wks Tocilizumab10 Week 24 IV ACR, American College of Rheumatology; IR, inadequate responder; PBO, placebo; TNFi, tumour necrosis factor inhibitor. *p<0.001; p<0.01; p=0.005; p<0.0001. 1. Burmester GR et al. Rheumatology. 2013;10(2):77-88. 2. Weinblatt ME et al. N Engl J Med. 1999;340(4):253-259. 3. Maini R et al. Lancet. 1999;354(9194):1932-1939. 4. Keystone EC et al. Arthritis Rheum. 2004;50(5);1400-1411. 5. Keystone E et al. Arthritis Rheum. 2008;58(11):3319-3329. 6. Keystone EC et al. Ann Rheum Dis. 2009;68(6):789-796. 7. Cohen S et al. Ann Rheum Dis. 2004;63(9):10621068. 8. Edwards JCW et al. N Engl J Med. 2004;350(25):2572-2581. 9. Kremer JM et al. Ann Intern Med. 2006;144(12):865-876. 10. Smolen JS et al. Lancet. 2008;371(9617):987-997. 9 ACR50 response at wk 24 for anti-TNFs + MTX in MTX-nave patients NOT HEAD TO HEAD

PBO + MTX TNFi + MTX 100 Patients (%) 80 69 67 60 54 40 40 29 40 46 43 32 32 20 0 GO-BEFORE1 (Golimumab) ERA2a (Etanercept) TEMPO3b (Etanercept) ASPIRE4,c

(Infliximab) PREMIER5,d (Adalimumab) Etanercept was taken in combination with PBO; bThe TEMPO study investigated combination therapy with MTX+etanercept vs MTX+placebo in patients who were not MTX-nave.cWeek;54 dWeek 52 *p=0.042; p<0.01; p0.001. a 1. Emery P et al. Arthritis Rheum. 2009;60(8):2272-2283. 2. Bathon JM et al. N Eng J Med. 2000;343(22):1586-1593. 3. Enbrel US Prescribing Information. New York, NY: Pfizer Inc; 2013. 4. Remicade US Prescribing Information. Horsham, PA: Janssen Biotech, Inc; 2013. 5. Keystone EC et al. J Rheumatol. 2014;41(2):235-243. 10 Limited persistence, even on TNF inhibitors Persistence Rate TNFi switching status 12 months (95%CI) 24 months (95%CI) First TNFi 72% (70%-75%) 57% (54%-60%) Second TNFi 60% (55%-64%) 42% (37%-47%) Third TNFi 63% (54%-70%)

42% (33%-51%) Greenberg JD et al. Ann Rheum Dis. 2012;71(7):1134-1142 11 Radiographic progression (mTSS) at wk 52/54 with biologics and MTX in MTX-IR and DMARD-IR patients with RA NOT HEAD TO HEAD Modified Total Sharp/van der Heijde score. DMARD-IR patients. c Genant-modified Sharp Score. a b 8.0 6.9 7.0 Mean Change From Baseline PBO + MTX TNFi + MTX Non-TNFi + MTX 6.0 mTSS/SHS, modified Total Sharp/van der Heijde score. *p<0.0001; p<0.001; p=0.01. 5.0 4.0 3.0 2.8 2.0 2.6 1.7 1.3

1.0 0.1 0.0 -1.0 2.8 2.7 0.4 1.1 0.93 0.53 0.25 0.8 0.2 -0.54 Etanercept1,a,b Week 52 Infliximab2 Week 54 Adalimumab3 Certolizumab4 Golimumab5 Week 52 Week 52 Week 52 Anakinra6 Week 52 Abatacept7 Week 52 Tocilizumab8,c Week 52

1. Klareskog L et al. Lancet. 2004; 263(9410):675-681. 2. Remicade Prescribing Information. Horsham, PA: Janssen Biotech; 2013. 3. Humira Prescribing Information. North Chicago, IL: AbbVie; 2013. 4. Keystone E et al. Arthritis Rheum. 2008;58(11):3319-3329. 5. Emery P et al. Arthritis Rheum. 2011;63(5):1200-1210. 6. Kineret Prescribing Information. Stockholm, Sweden: Swedish Orphan Biovitrum AB; 2012. 7. Kremer JM et al. Ann Intern Med. 2006;144(5):865-876. 8. Kremer JM et al. Arthritis Rheum. 2011;63(3):609-621 12 Access to innovative biologic treatments for RA in Europe: 1998-2008 LIMITED BY COST! A decade after their introduction Only 11% of EU patients could access biologics by 2008 Etanercept Infliximab Adalimumab Anakinra Rituximab Abatacept 1. Kobelt G, Kasteng F. http://www.efpia.eu/../ACCESS TO RA TREATMENTS - Rheumatoid Arthritis in Europe October 2009.pdf [Accessed June 2015] 13 Biosimilars: The solution? But they are not generics Follow-on products of traditional chemical pharmaceuticals are exact chemical copies These are true generics Follow-on products of innovator biological pharmaceuticals are only similar copies There are no biogenerics There are only similar products, i.e. biosimilars Figure 1 Figure 1. Clark (2003) Antibody engineering IgG effector mechanisms. Available at: http://www.path.cam.ac.uk/~mrc7/igs/mikeimages.html. Accessed November 2014 14 Manufacturing of biologics is complex, VL

3 VH CH1 CH2 CH3 Ck 1 2 Tumor necrosis factor (TNF) Anti-TNF genes/DNA Production cell line 5 4 Protein DNA 6 Perfusion bioreactor 9 Y mRNA 8 Monoclonal antibody 7 YYY Y Y Y

Purification Due Due to to the the manufacturing manufacturing process process and and molecular molecular complexity, complexity, itit is is extremely extremely difficult difficult to make an exact copy of a biologic, especially a monoclonal antibody to make an exact copy of a biologic, especially a monoclonal antibody 1. Kuhlmann M et al. Nephrol Dial Transplant. 2006;21(Suppl 5):v4v8. 2. Misra M. Indian J Pharmacol. 2012;44:1214. 3. European Commission. 2013. What you Need to Know about Biosimilar Medicinal Products. Available at: http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf. Accessed 23 October 2014 15 There are varying degrees of bio similarity The parent compound. Similar, yet very different. Permission to use image obtained from Peter Taylor 16 Biological product complexity: Example: Showing a few modifications

pyro-E O O D D D O O G G pyro-E Pyro-Glu (2) D Deamidation (3 x 2) Methionine oxidation (2 x 2) Glycation (2 x 2) D D High mannose, G0, G1, G1, G2 (5) Sialylation (5) G G K K (9,600)2 108 C-term Lys (2) 2 x 6 x 4 x 4 x 5 x 5 x 2 = 9,600 potential variants

Adapted from: Steven Kozlowski. 2014. US FDA Perspectives on Biosimilar Biological Products. Available at: https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski%20-%20Biomanufacturing%20Summit.pdf. Accessed 23 October 2014 17 A small change can make a big difference Example: Immune effector function of an antibody molecule Adapted from: Clark, M (1997), Chemical Immunology;65:88-110 & Clark, M (1997) Antibody Engineering IgG Effector Mechanisms. Available at: http://www.path.cam.ac.uk/~mrc7/pdb/index.html Accessed October 2014 18 A small change can make a big difference Example: Immune effector function of an antibody molecule Asn (297) 1 Glc NAc 4 1 Glc NAc 4 1 Man 2 1 Glc NAc 4

1 Gal 3,6 2 Man 2 1 Glc NAc 4 1 Gal 3,6 2 Neu Ac/Gc Man Neu Ac/Gc Adapted from: Clark, M (1997), Chemical Immunology;65:88-110 & Clark, M (1997) Antibody Engineering IgG Effector Mechanisms. Available at: http://www.path.cam.ac.uk/~mrc7/pdb/index.html Accessed October 2014 19 A small change can make a big difference Example: Immune effector function of an antibody molecule ImmuneEffector Function 120 Glycoengineeredantibody(only26% fucosylated) Cell Lysis(%)

100 80 Wildtypeantibody(100%fucosylated) 60 40 20 Glycoengineerednegativecontrol antibody 0 0 10 20 30 40 50 AntibodyConc. (ng/ml) Adapted from: Clark, M (1997), Chemical Immunology;65:88-110 & Clark, M (1997) Antibody Engineering IgG Effector Mechanisms. Available at: http://www.path.cam.ac.uk/~mrc7/pdb/index.html Accessed October 2014 20 A small change can make a big difference Example: Immune effector function of an antibody molecule Presence or absence of one sugar residue (fucose) can affect the biological activity (killing of target cells) Changes in immune effector function may influence potency, but also may affect the safety of the drug Adapted from: Clark, M (1997), Chemical Immunology;65:88-110 & Clark, M (1997) Antibody Engineering IgG Effector Mechanisms. Available at: http://www.path.cam.ac.uk/~mrc7/pdb/index.html Accessed October 2014 21 and biological tests provides complete

understanding Primary structure e.g.: Higher order structure e.g.: LC-MS intact mass LC-MS subunits Peptide mapping NMR CD spectroscopy FT-IR Impurities e.g.: CEX, cIEF acidic/basic variants LC glycation Peptide mapping deamidation, oxidation, mutation, glycation SEC/FFF/AUC aggregation Post translat. modif. e.g.: Biological activity e.g.:

Binding assay ADCC assay CDC assay NP-HPLC-(MS) N-glycans AEX N-glycans MALDI-TOF N-glycans HPAEC-PAD N-glycans MALDI-TOF O-glycans HPAEC-PAD sialic acids RP-HPLC sialic acids Combination of attributes e.g.: MVDA, mathematical algorithms >100 attributes, understanding goes beyond sum of individual data Berkowitz SA, et al. Nat Rev Drug Discov 2012; 11(7): 527540 Anti-TNF biosimilars update: the most advanced products with published data. Many more on the way! Originator Biosimilar Developed by Status Infliximab CT-P13 Celltrion (Remsima)/ Hospira (Inflectra) Ph I (AS), Ph III (RA); marketed in EU, Korea, Japan, Turkey and filed in US BOW015

Epirus (partner: Ranbaxy Laboratories) Infimab marketed in India; Ph III (RA) planned for EU/US PF-06438179 Pfizer Ph III (RA) SB4 Samsung Bioepis (partner: Biogen Idec) Ph III RA; accepted for EMA review HD203 Hanwha (partner: Merck) Ph III RA; marketed in Korea GP2015 Sandoz Ph III (PsO) ABP501 Amgen Ph III (RA & PsO) GP2017 Sandoz Ph III (PsO) Exemptia

Zydus Cadila Ph III (RA); marketed in India Etanercept Adalimumab 23 Novel therapies tested in inflammatory disease IL-61 Sarilumab Sirukumab Clazakizumab GM-CSF Mavrilimumab11 MOR10312 Namilumab13 IL-17 Secukinumab2 Brodalumab3 Ixekizumab4 Novel Therapi es JAK5 Tofacitinib Baricitinib GLPG0634 VX-509 Vaccinations TNF Kinoid6 Rheumavax7 IL-12/IL-232 Ustekinumab Briakinumab PDE4, B cell, T-cell costimulation,

adhesion molecules, Anti-IL20 Apremilast,8 vedolizumab,9 ofatumumab,10 1. Smolen JS et al. Ann Rheum Dis. 2014;73(3):492-509. 2. Mudigonda P et al. Derm Online J. 2012;18(10):1-10. 3. Papp KA et al. N Engl J Med. 2012;366(13):11811189. 4. Leonardi C et al. N Eng J Med. 2012;366(13):1190-1199. 5. Clark JD et al. [Epub ahead of print January 23, 2014]. J Med Chem. doi: 10.1021/jm401490p. 6. Vandepapelire P et al. Gastroenterol. 2011;140:S1-S192.abstract 743. 7. Ranjeny T et al. Arthritis Rheum. 2011;63(suppl 10):2430. 8. Palfreeman AC et al. Drug Design Devel Ther. 2013;7:201-210. 9. McLean LP et al. Immunotherapy. 2012;4(9):883-898. 10. Rosman Z et al. BMC Medicine. 2013;11:1-12. doi:10.2217/imt.12.85. 11. Burmester GR, et al. Ann Rheum Dis. 2013;72(9):1445-1452. 12. Behrens F et al. [Epub ahead of print February 17, 2014].Ann Rheum Dis. doi:10.1136/annrheumdis2013-204816. 13. Takeda pipeline. 2011 Available at: http://www.takeda.com/investor-information/results/pdf/2011/qr2011_full_d10_en.pdf. Accessed May 2014 24 Targeting inflammatory pathways: IL-6 as an example Currently (November 2014), tocilizumab is approved by the EMA and FDA for use in RA, and tofacitinib is approved by the FDA for use in RA Target Target the the ligand ligand IL-6 Target Target the the receptor receptor gp130 IL-6R Cell Surface JAK STAT STAT STAT P P P

P STAT Nucleus Target Target signalling signalling STAT Transcription P P 25 Ahmed, et al. Mol Cancer Ther. 2007;6:2386-2390 Anti-IL-6: Review of recent data Currently (November 2014), sirukumab is not approved for use in RA or lupus Sirukumab ACR50 ACR50 response response at at Week Week 12 12 * 27 27 * 23 ** 19

24 *p<0.05; **p=0.01 vs. placebo SI 2 1 5 3 1 100 90 80 70 60 50 40 30 20 10 0 P ACR50 response (%) Fully human anti-IL-6 monoclonal antibody, currently undergoing Phase III trials in RA and Phase II in Lupus Phase II dose ranging study in RA: Sirukumab Sirukumab was was efficacious efficacious and and generally generally well well tolerated tolerated in in patients

patients with with active active RA RA despite despite MTX MTX Hsu, et al. Ann Rheum Dis. 2012;71(Suppl3):188 26 Targeting inflammatory pathways: IL-6 as an example Currently (November 2014), tocilizumab is approved by the EMA and FDA for use in RA, and tofacitinib is approved by the FDA for use in RA Sirukumab IL-6 Sarilumab (& Tocilizumab) Olokizumab gp130 IL-6R JAK STAT STAT STAT P P Tofacitinib Baricitinib GLPG0634 VX-509 P

P STAT Nucleus Target the receptor STAT Transcription P P Ahmed, et al. Mol Cancer Ther. 2007;6:2386-2390 27 Anti-IL-6: Review of recent data Currently (November 2014), sarilumab is not approved for use in RA Sarilumab ACR20 response (%) First fully human monoclonal antibody directed against the IL-6 receptor, currently undergoing Phase III trials in RA MOBILITY Part A Study 100 90 80 70 60 50 40 30 20 10 0 Phase II study in patients with moderate to severe active RA ACR20 ACR20 response response at

at Week Week 12 12 67 65 49 46 Placebo 62 * 72 100 mg Q2W 150 mg Q2W 100 mg QW 200 mg Q2W 150 mg QW *p<0.05 vs. placebo Sarilumab Sarilumab in in combination combination with with MTX MTX significantly significantly improved improved signs signs and and symptoms symptoms of of RA RA Huizinga, et al. Ann Rheum Dis. 2012;71(Suppl3):60 28 Anti-IL-6 pathway: Implications for clinical practice Increasing choice of IL-6 inhibitors targeting ligand or receptor Potential for differential responses and kinetics of response

between agents? Potential for differences in safety? Competition for market share drives improved costcompetitiveness? 29 Targeting inflammatory pathways: IL-6 as an example Currently (February 2013), tocilizumab is approved by the EMA and FDA for use in RA, and tofacitinib is approved by the FDA for use in RA Target the ligand IL-6 Target the receptor gp130 IL-6R Cell Surface JAK P P Target Target signalling signalling Jak inhibitors STAT STAT STAT P P STAT

Nucleus STAT Transcription P P Ahmed, et al. Mol Cancer Ther. 2007;6:2386-2390 30 X-ray crystal structure confirms that ATP and tofacitinib bind at the ATP binding site ATPgS bound to JAK3 Tofacitinib bound to JAK3 Chrencik, et al. J Mol Biol. 2010; 400:413-433. 31 JAK inhibitors: proposed selectivities described by manufacturers Tofacitinib1 Specificity for JAK1 and JAK3 over JAK2 Decernotinib 3 Specificity for JAK3 Baricitinib2 Specificity for JAK1 and JAK2 Filgotinib 4 Specificity for JAK1 TYK2 JAK1 JAK3

FUNCTION Growth/maturation of lymphoid cells Differentiation/ homeostasis of T cells, NK cells B-cell class switching Inflammation JAK1 TYK2 JAK1 JAK2 JAK1 JAK2 Nave T-cell differentiation Antiviral Inflammation T-cell homeostasis Inflammation Antitumor Inflammation Antimycobacterial Antiviral Granulopoiesis JAK2

TYK2 JAK2 JAK2 Innate immunity Erythropoiesis Differentiation/ proliferation of Th17 cells Megakaryocyte/ platelet production Inflammation Myelopoiesis Growth Mammary development Reprinted (adapted) with permission from Clark JD et al. [Epub ahead of print January 23, 2014]. J Med Chem. doi: 10.1021/jm401490p Copyright 2014, American Chemical Society. NK, natural killer; STAT, signal transducer and activator of transcription; TKY2, tyrosine kinase 2. Tofacitinib is not approved by EMA. 1. Clark JD et al. [Epub ahead of print January 23, 2014]. J Med Chem. doi: 10.1021/jm401490p. 2. Smolen JS et al. Arthritis Rheum. 2012;64(suppl 10):490. 3. Hoock T et al. Arthritis Rheum.2011;63(suppl 10):1136. 4. Vanhoutte F, et al. Ann Rheum Dis. 2013; 72(suppl 3):242. 32 A wide range of different cytokines exert their effect via the JAK family Adapted from OShea JJ, et al. Nature Reviews Rheumatology 2013; 9(3):173182 33 Proportion of TNF-IR, DMARD-IR and MTX-nave patients with ACR50 response 100 Week 12 Week 24

Week 24 Week 24 Week 12 Week 24 Adalimumab Tofacitinib 5 mg BID Response Rates (%) 80 Tofacitinib 10 mg BID PBO 40 27.8 26.5 35.5 33.3 20 0 Patient: N= 132 133 131 315 318 159 ORAL Step1,2

ORAL Sync2,3 TNF-IR DMARD-IR + Nonbiologic DMARDs *p<0.0001;avs baseline; p0.001; p<0.001. Tofacitinib is not approved by EMA. Tofacitinib Regimen: + MTX 36.7 34.7 12.6 8.4 . 56.2 46.6 60 43.7 27.6 32.4 12.3 204 201 108 204 ORAL Standard2,4

36.8 31.1 12.5 8.4 321 316 160 27.2 243 245 122 373 397 186 ORAL Scan2,5 ORAL Solo2,6 ORAL Start2,7 MTX-IR MTX-IR DMARD-IR MTX-nave + MTX + MTX

Monotherapy Monotherapy 1. Burmester GR et al. Lancet. 2013;382(9865):451-460. 2. Pfizer Inc. 2012. Tofacitinib for Treatment of Rheumatoid Arthritis. Available at: http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM302960.pdf Accessed 23 October 2014. 3. Kremer J et al. Ann Intern Med. 2013;159(4):253-261. 4. van Vollenhoven R et al. N Engl J Med. 2012;367(6):508-519. 5. van der Heijde D et al. Arthritis Rheum. 2013;65(3):559-570. 6. Fleischmann R et al. N Engl J Med. 2012;367(6):495-507. 7. Lee EB et al. Arthritis Rheum. 2012;64(suppl 10):2486 34 TNF-IR, DMARD-IR and MTX-nave RA patients Percentage Percentage of of Patients Patients Achieving Achieving DAS28DAS284(ESR) 4(ESR) 3.2 3.2 Patients With DAS28-4(ESR) <3.2 (%) 100 Week 12 Week 24 Week 24 80 Adalimumab Tofacitinib 5 mg BID adalimumab 60 Tofacitinib 10 mg BID PBO 28.4 20.8 14.3

1719.3 119 125 ORAL Step1,2 120 16 14.3 12.5 4 5 0N= 38.2 27.8 MTX 40 20 Week 24 Week 12 204 201 108 ORAL Standard2-4 17 5.3

3 204 316 309 ORAL Scan2,5 156 14 232 229 ORAL Solo2,6 114 373 397 186 ORAL Start2 TNF-IR MTX-IR MTX-IR DMARD-IR MTX-nave Patient: Tofacitinib + MTX + MTX + MTX Monotherapy Monotherapy Regimen: ESR, erythrocyte sedimentation rate.

*p<0.05; p<0.0001; p0.001; p0.05; p<0.001. Tofacitinib is not approved by EMA. Tofacitinib 5 mg is approved in over 20 markets around the world for the treatment of moderate-to-severe RA. Tofacitinib 5 mg and 10 mg is approved in Switzerland and Russia. MTX-nave data from ORAL Start trial was not recorded for marketing authorization. 1. Burmester GR et al. Lancet. 2013; 382(9865):451-460. 2. . Pfizer Inc. 2012. Tofacitinib for Treatment of Rheumatoid Arthritis. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM302960.pdf Accessed 23 October 2014 3. van Vollenhoven R et al. N Engl J Med. 2012;367(6):508-519. 4. van Vollenhoven R et al. Arthritis Rheum. 2012;64(suppl 10):1297. 5. van der Heijde D et al. Arthritis Rheum. 2013;65(3):559-570. 6. Fleischmann R et al. N Engl J Med. 2012;367(6):495-507.. 35 Baricitinib in MTX-IR patient with RA ACR ACR at at Week Week 12 12 Responders (%) 100 40 30 57 60 40 20 0 78 75 80 DAS28-CRP DAS28-CRP <2.6 <2.6 at at Week Week 12 12

37 54 22 41 35 23 31 12 10 17 40 20 20 14 15 1 mg (n=49) 2 mg (n=52) 10 4 8 2 PBO (n=98) 1 mg (n=49) ACR20

2 mg (n=52) ACR50 4 mg (n=52) 8 mg (n=50) 0 PBO (n=98) 4 mg (n=52) 8 mg (n=50) ACR70 CRP, C-reactive protein. *p<0.05 vs placebo. Keystone E, Taylpr PC et al. Ann Rheum Dis. 2015 Feb;74(2):333-40. . Taylor PC et al. EULAR June 12-15, 2013; Madrid, Spain; Abstract #OP0047 36 Targeting the GM-CSF Pathway Currently (November 2014), none of the biologics mentioned below are approved for use in RA MOR103 Namilumab GM-CSF Target Target the the ligand ligand

Mavrilimumab GM-CSFR Cell Surface JAK STAT STAT STAT P P P P STAT Nucleus Target Target the the receptor receptor STAT Transcription P P 37 Ahmed, et al. Mol Cancer Ther. 2007;6:2386-2390 GM-CSF as a Target for Inflammation and Pain Granulocyte macrophage colony stimulating factor (GMCSF) as a therapeutic target for inflammation and pain. Inhibition of GM-CSF during inflammation (joints in RA) may inhibit differentiation, adhesion, chemotaxis and activation of

multiple inflammatory and immune cells (monocytes, macrophages, neutrophils, dendritic cells [DC]) and their respective precursors, and therefore reduce the production of inflammatory cytokines (IL1, TNF, IL-23 and IL-6). These cytokines are relevant in shaping the response of Tcells, causing differentiation and production of IL-17 and GMAdapted from Van Nieuwenhuijze A et al. Mol Immunol CSF. 2013;56:675-682 . 38 Mavrilimumab + MTX in Moderate to Severe RA Percent of Patients Phase II study, moderate-to-severe RA pts MTX IR (N=239). Of 239 patients, 6 were excluded from ITT population (ITT N=233: 75 placebo [PBO] and 158 mavrilimumab [MAV]) ACR Responses at Week 12 100 80 69.2 56.1 60 40 * 40.0 41.0 41.0 23.1 20 0 PBO + MTX

* 29.3 12.0 ACR20 MAV 10mg 30.8 * * 20.5 4.0 5.1 ACR50 MAV 30 mg 9.8 7.7 17.9 ACR70 MAV 50mg MAV 100mg Response rate differences in ACR were seen from week 4 and increased during the treatment period. The 100 mg dose demonstrated significant benefit vs PBO in DAS28 remission, as well as ACR20, 50 and 70 responses Changes in CRP were observed as early as week 2 *p<0.05 EARTH Study Burmester GR et al. Ann Rheum Dis 2013;72:1445-1452. 39 MOR103 in Moderate to Severe RA Mean change from BL in DAS28 score Multicenter, randomized, double-blind, dose escalation trial of IV MOR103. Of 93

randomized and treated patients, 85 completed the trial 4 treatment groups, PBO, 0.3, 1.0 and 1.5 mg/Kg of MOR103 IV at baseline and days 8, 15 and 22. Follow-up visits at weeks 4, 5, 6, 8, 10, 13 and 16. primary outcome was safety Weeks Behrens F et al. Ann Rheum Dis online first published on February 17, 2014 as 10.1136/annrheumdis-2013-204816. 40 Targeting spleen tyrosine kinase Rituximab B Cell receptor B Cell surface CD20 SYK Target Target signalling signalling BTK PI3K Signalling leads to activation of B cells PKC NFKB 41 Parekh, et al. Semin Cancer Biol. 2011;21(5):335-346 SYK inhibitor: Fostamatinib monotherapy data OSKIRA-4: OSKIRA-4: Change Change in in proportion proportion of of patients patients with with ACR20

ACR20 response response Adalimumab 40 mg Taylor PC et al. Ann Rheum Dis. 2014 Jul 29. [Epub ahead of print] 42 SYK inhibitor: Recent fostamatinib Phase lll data ACR20 ACR20 responder responder rates rates at at Week Week 24 24 in in Phase Phase III III Fostamatinib dose OSKIRA 1 MTX-R + Fosta OSKIRA 2 DMARD-IR + fosta OSKIRA 3 MTX + Fosta after one anti-TNF failure 100mg bid 49% p<0.001 39.6% p<0.001 36.2% p=0.004 100mg bid/150mg od 44% p=0.006

39.6% p<0.001 27.8% p=0.168 Placebo 34% 24.5% 21.1% OSKIRA-1 failed to meet co-primary endpoint of change in mTSS at Week 24* The safety and tolerability findings were generally consistent with earlier studies^ *Rigel Pharmaceuticals Inc. 2014 Rigel will resume responsibility for Fostamatinib. Available at: http://ir.rigel.com/phoenix.zhtml?c=120936&p=irolnewsArticle&ID=1826622&highlight= Accessed November 2014 43 Vaccinations: The future of RA treatment? Currently (November 2014), TNF kinoid is not approved for use in RA and Crohns disease TNF-alpha Kinoid Patients % A vaccine targeting TNF avoids treatment resistance by eliciting a natural immune response through the production of polyclonal antibodies against multiple epitopes of TNF. Currently undergoing Phase II trials in RA Shown promising results in Phase I/II trials in Crohns disease: 100 80 60 40 20 0 81 19 Semerano, et al. Expert Opin Biol Ther. 2011;11(4):1-6

44 What are the unmet needs for AS patients? Therapies that are: Effective! Safe Well tolerated Convenient an oral DMARD that works! Cost effective so that it its use is not restricted to the minority of sufferers with the worst disease Something to fill the gap between NSAIDs and biologic anti-TNFs? Something better than anti-TNFs? 45 Factors contributing to AS pathophysiology Ankylosing spondylitis is associated with genetic polymorphisms in genes involved in immunological pathways, antigen processing, T cell activation and apoptosis, and cytokines or cytokine receptors TNF inhibition validates TNF as mediator of symptoms and signs in AS The IL-23-Th17 axis has been implicated by data showing that patients with AS have an elevated frequency of CD4+ T cells expressing IL-17 and IL-22 In AS patients with higher greater disease activity, the percentage of T cells expressing programmed death-1 (PD-1) is significantly lower than in those with lower scores, suggesting that the defective T cell apoptosis may contribute to the spinal radiologic changes PBMC from patients with AS are deficient in production of IL-10, an anti-inflammatory 46 van der Heijde et al. Ann Rheum Dis. 2010;69:949. activity and radiographic damage (ASDAS) Variable Previous mSASSS (0-72) ASDAS ASDAS disease activity states - Moderate vs inactive (1.3 and <2.1 vs <1.3) - High vs inactive (2.1 and 3.5 vs <1.3)

- Very high vs inactive (>3.5 vs <1.3) Model with ASDAS continuous Multivariable regression 1 Progression rate per 2-year interval (95% CI) (N = 183) 1.03 (1.01; 1.05) 0.72 (0.41; 1.04) Model with ASDAS categorical Multivariable regression 2 Progression rate per 2year interval (95% CI) (N = 183) 1.03 (1.01; 1.05) 0.57 (-0.56; 1.69) 0.91 (-0.17; 1.99) 2.31 (1.11; 3.51) *All models are time-lagged (2 years of time lag) and auto-regressive (i.e. adjusted for mSASSS in the 2-years before). reflect progression in mSASSS units over 2 years. Not included in the model Neither HLA-B27, nor the medication (NSAIDs, NSAID score or biologics), or the presence of EAM (individually or all combined) confounded the relationship between each of the disease activity measures and mSASSS Essers I et al, Rheumatology (Oxford). 2015 Apr;54(4):633-40. 47 TNF blockade has good symptomatic efficacy in SpA * 60 % ASAS40

50 47 45 48 44 39 40 30 20 12 14 13 15 16 Golimumab4 Placebo Certolizumab5 Placebo pegol 10 0 Infliximab1 Placebo Etanercept2 Placebo Adalimumab3 Placebo *Different studies. No head to head comparison van der Heijde D, et al. Arthritis Rheum 2005;52:58291; 2Davis JC, et al. Ann Rheum Dis 2005;64:155762; 3van der Heijde D, et al. Arthritis Rheum 2006;54:213646

4 Inman RD, et al. Arthritis Rheum 2008;58:340212; 5Landew R, et al. Ann Rheum Dis 2014;73:3947 1 48 of Certolizumab pegol in axSpA and nraxSpA RAPID-axSpA Study: 200 mg Certolizumab pegol s.c. EOW vs 400 mg Certolizumab pegol s.c. every four weeks vs placebo Landew R, et al. Ann Rheum Dis 2014;73:3947 49 Anti-TNF over 2 years does not inhibit radiographic progression in AS 50 Uncoupling of inflammation and new bone formation TNF brake hypothesis Active inflammation suppresses new bone formation by upregulating DKK-1 DKK-1 inhibits bone formation by blocking the Wnt pathway TNF-inhibition downregulates DKK-I, releasing the Wnt pathway to make bone Diarra, D et al. Nat Med. 2007. Feb;13(2):156-63. 51 Bisphosphonates Vs. Infliximab in Ankylosing Spondylitis Treatment (Background: Pamidronate successfully used in the treatment of AS) 6-month, open-label study: 60 active AS patients, neridronate (100 mg/month IV) or infliximab (5 mg/kg) in 1:1 ratio At six months: Significant and comparable reduction in both groups in BASDAI (NER -1.72 vs INF-1.62), and VAS axial pain BASFI significantly reduced at 3 & 6 months in NER; and at 3, but not 6 months in INF group Lumbar spinal BMD significantly increased in NER but

not INF ESR/CRP only reduced in infliximab group Conclusion: High iv doses of neridronate (an amino-bisphosponate) 52 Viapiana O. et al. Rheumatology 2014;53:90-94 . Do TNF-blockers need to be given continuously? 7 6 5 4 3 2 1 0 Baseline week 6 week 24 week 54 week 102week 156 Relapse 24 weeks 48 weeks BASDAI Baraliakos X, et al. Arthritis Res Ther 2005;7:R43944 BASFI BASMI 53 Do TNF-blockers need to be given continuously? Withdrawa l of aTNF 7 6 5 4 3 2 1 0 Baseline week 6 week 24 week 54 week 102week 156 Relapse 24 weeks 48 weeks BASDAI

Baraliakos X, et al. Arthritis Res Ther 2005;7:R43944 BASFI BASMI 54 Do TNF-blockers need to be given continuously? Withdrawa l of aTNF 7 Restart 6 5 4 3 2 1 0 Baseline week 6 week 24 week 54 week 102week 156 Relapse 24 weeks 48 weeks BASDAI Baraliakos X, et al. Arthritis Res Ther 2005;7:R43944 BASFI BASMI 55 Treat to target algorithm in SpA Main target Active SpA Adapt therapy according to disease activity

Adapt therapy if state is lost Use measures of clinical disease activity and acute phase reactants as needed Alternative target Sustained Remission Remission Adapt therapy according to disease activity Smolen JS, et al. Ann Rheum Dis 2014;73:616 Use measures of clinical disease activity and acute phase reactants as needed Low disease activity Sustained low disease activity Adapt therapy if state is lost 56 Treat to target algorithm in SpA Main target Active SpA

Adapt therapy according to disease activity Adapt therapy if state is lost Use measures of clinical disease activity and acute phase reactants as needed Alternative target Sustained Remission Remission Adapt therapy according to disease activity Smolen JS, et al. Ann Rheum Dis 2014;73:616 Use measures of clinical disease activity and acute phase reactants as needed Low disease activity Sustained low disease activity Adapt therapy if state is lost 57 Anti-TNF treatment in axSpA: early initiation leads to better treatment

outcomes Patient 1: 24 years, CRP 0.7, HLA-B27+ve, BASFI 4.8 BASFI Probability for partial remission after 6 months 12% 25% 35% 23% 43% 55% >2.0 0.62.0 8% 17% 25% 16% 32% 43% 6% 14% 20% 12% 26% 36% 0.6

8% 17% 25% 16% 32% 43% >2.0 5% 12% 18% 10% 23% 32% 4% 9% 14% 8% 18% 26% HLA-B27 neg. Vastesaeger N, et al. Ann Rheum Dis 2011;70:973-81 0.62.0 CRP (mg/dL)

AGE >40 AGE 40 >6. 4.54.54.5 >6.5 4.5 5 6.5 6.5 0.6 HLA-B27 pos. 58 Anti-TNF treatment in axSpA: early initiation leads to better treatment outcomes Patient Patient2: 1:42 24years, years,CRP CRP2.7, 0.7,HLA-B27ve, HLA-B27+ve,BASFI BASFI7.0 4.8 BASFI Probability for partial remission after 6 months 12% 25% 35% 23% 43% 55%

>2.0 0.62.0 8% 17% 25% 16% 32% 43% 6% 14% 20% 12% 26% 36% 0.6 8% 17% 25% 16% 32% 43% >2.0 5% 12%

18% 10% 23% 32% 4% 9% 14% 8% 18% 26% HLA-B27 neg. Vastesaeger N, et al. Ann Rheum Dis 2011;70:973-81 0.62.0 CRP (mg/dL) AGE >40 AGE 40 >6. 4.54.54.5 >6.5 4.5 5 6.5 6.5 0.6 HLA-B27 pos. 59 early response leads to better treatment

outcomes Probability at year 8 100% Dropout BASDAI 50 Non-responder 80% BASDAI 50 Responder 60% Partial Remission 40% OR=1.27, 95% CI: 1.01.6, p=0.06 20% OR=1.85, 95% CI: 1.26.0, p=0.002 0% OR=2.73, 95% CI: 1.26.0, p=0.012 0 1 2 3 4 BASDAI at week 12 Baraliakos X, et al. Rheumatology (Oxford) 2011;50:16909 60 Duration of remission after halving Etanercept dose in AS: A randomized, prospective, long-term, follow-up study First phase (2005-09): n=78 open-label study, biologicnave active AS patients treated with ETN 50 mg/Wk Second phase: Jan 2010:

55% were in remission (BASDAI<4, no iritis, arthritis, dactylitis, normal CRP), randomized to ETN 50 mg/wk (n=21) or 50 mg/QOW (n=22) in open label possible in 50% AS patients Remission Follow Most can be up: maintained remission on up toin22 months 100 90 90 86 80 70 60 ETN 50 QW ETN 50 QOW 50 40 30 20 10 0 Remission % half dose Cantini F. et al. Biologics. 2013;7:16. 61

IL-6 blockade in axSpA Does it work? 62 Assessment of short-term efficacy of tocilizumab in AS : Results of RCT trial BUILDER-1: DBRPCT, AS patients TNFi nave, Part 1: TCZ 8 mg/kg or PL X 12 wks, Part 2 (beginning after part 1 enrollment ended), new pts TCZ 4 or 8 mg/kg or PL X 24 wks (Phase III) BUILDER-2: TNFi IR AS pts, same doses of TCZ (Phase III) 102 randomized in BUILDER-1 Part 1; 99 (48 TCZ, 51 PL) 10 ASAS20 at 12 weeks Sieper J, et al. Ann Rheum Dis 2014;73:95100 40 35 30 37 p=0.28 BUILDER-1 Part-1 27 25 20 15 Tocilizumab Placebo 10 5

0 % of patients with ASAS20 @ Wk 12 20 & exploratory endpoints did not differ CRP levels dropped, indicating IL-6 blockade Other parts of the study cancelled 63 Ankylosing Spondylitis: Products in Development Product Name Description Organization Stage Secukinumab1 IL-17 inhibitor Novartis/Alcon Phase 3 Ixekizumab1 IL-17 inhibitor Eli Lilly Phase 3 Apremilast1 PDE4 inhibitor Celgene Phase 3 Tofacitinib1 JAK-3 inhibitor Pfizer

Phase 2 Ustekinumab2, IL-12/23 inhibitor Janssen Phase 2 Actonel2,3 Pyridinyl bisphosphonate Sanofi Phase 2 Infliximab biosimilar1 TNF-alpha inhibitor Celltrion Phase 1/2 Infliximab biosimilar1 TNF-alpha inhibitor Pfizer Phase 1 1. Ankylosing Spondylitis (Bekhterevs Disease) Pipeline Review, H2 2013 (Global Markets Direct). 2. Clinicaltrials.gov.. 3. Actonel prescribing information. 64 % ASAS20 Responders IL-17A inhibition with secukinumab in AS Arrows indicate infusions. Baeten D, et al. Lancet 2013;382:170513

Weeks 65 Anti-IL17A ameliorates active AS Baeten D et al. Lancet 2013 ; 382:1705-13 66 % of patients Ustekinumab in 20 patients with active AS 100 Results at Week 24 75 80 75 75 65 55 60 40 20 0 50 35 30 20 ASAS 40 ASAS 20 ASAS PRBASDAI ASDAS 50 CII ASDAS

(>=1.1) ASDAS MI (>=2) inactive disease PASS (<1.3) PhASS CII, clinically important improvement; MI, major improvement; PASS, patient acceptable symptom state; PhASS, physician acceptable symptom state. 67 ddubnyy D, et al. Ann Rheum Dis 2014;73:81723 ASAS40 with other biologics in axSpA 70% Chart Title 60% 50% TNFinhibitor 40% 30% 20% Placebo 10% 0% Anakinra Rituximab Abatacept Secukinumab Apremilast Tocilizumab Rituximab Anakinra (anti-CD20), Abatacept (anti-IL1), n=20, (T-Zell-Modulator), TNF-naiv auch

Tocilizumab TNF-Versager Secukinumab (100mg n=30, (anti-IL6), s.c.) auch (2 Infusionen (anti-IL17), n=51, TNF-Versager Apremilast TNF-naiv n=24 1000mg) (n= (10mg/kg) TNF-naiv (8mg/kg) 17) (30mg Ustekinumab (10mg/kg) BID p.o.) (anti-IL1) 100mg s.c n=20 TNF-naive Week 24 (anti-CD20) each 1g i.v. n=20 TNF-failure+ TNF-naive Week 24 (T-Zell-Modulator) 10mg/kg i.v. n=30 TNF-failure+ TNF-naive Week 24 (anti-IL6R) 8mg/kg i.v.

n=51 TNF-naive Week 12 (anti-IL17) 2x 10mg/kg n=24 TNF-failure + TNF-naive Week 6 (PDE-inhibitor) 30mg BID p.o. n=17 TNF-naive Week 12 Ustekinumab (IL12/23-inhibitor.) 3x 90mg s.c. (BL, W4, W16) n=20 TNF-naive Week 24 68 ASAS40 with other biologics in axSpA 70% Chart Title 65% 60% 50% TNFinhibitor 40% 30% 20% 21% 30%

25% 24% 7% 10% 12% Placebo 0% Anakinra Rituximab Abatacept Tocilizumab Secukinumab Apremilast Ustekinumab Anakinra Rituximab (anti-IL1), (anti-CD20), n=20, Abatacept n=20, TNF-naiv (T-Zell-Modulator), auch(100mg TNF-Versager Tocilizumab s.c.) n=30, (2 Infusionen auch Secukinumab (anti-IL6), TNF-Versager n=51, 1000mg) (anti-IL17), TNF-naiv (10mg/kg) Apremilast

n=24 (8mg/kg) TNF-naiv (n= 17) (10mg/kg) (30mgUstekinumab BID p.o.) (anti-IL1) 100mg s.c n=20 TNF-naive Week 24 (anti-CD20) each 1g i.v. n=20 TNF-failure+ TNF-naive Week 24 (T-Zell-Modulator) 10mg/kg i.v. n=30 TNF-failure+ TNF-naive Week 24 (anti-IL6R) 8mg/kg i.v. n=51 TNF-naive Week 12 (anti-IL17) 2x 10mg/kg n=24 TNF-failure + TNF-naive Week 6 (PDE-inhibitor) 30mg BID p.o. n=17 TNF-naive Week 12

(IL12/23-inhibitor.) 3x 90mg s.c. (BL, W4, W16) n=20 TNF-naive Week 24 69 Summary and conclusions Biologic therapy has an important role in managing our RA and AS patients Our approach to management has changed substantially since approval of the first anti-TNF Data supporting both the long term efficacy and safety of biologics should be considered when making treatment decisions T2T approaches are likely to improve long term outcomes However, rapid advances in understanding the pathobiology have led to new therapeutic target identification Clinical trials to validate these targets are underway But the relative benefit:risk profiles and cost effectiveness remain to be seen 70

Recently Viewed Presentations

  • CSC 552.201 - Advanced Unix Programming, Fall, 2008

    CSC 552.201 - Advanced Unix Programming, Fall, 2008

    Establish remaining activities. Transition Establish final product for release. Establish user readiness & acceptance. Establish support Deployment Additional points on RUP & SEI RUP has Entry and Exit Criteria Entry Criteria are requirements when entering a stage in the process...
  • Strengthening the Animal/ Human Bond

    Strengthening the Animal/ Human Bond

    Offer diverse and inventive listening tools and resources to support the broadest range of needs. ... Now is the time to leverage the opportunity to reach a similarly vast segment of the pet owner population and support the calling of...
  • Ethics Training for Baltimore County Public Schools&#x27; Employees

    Ethics Training for Baltimore County Public Schools' Employees

    Learn about the Ethics Code Policies to which all board employees are subject; Learn about your responsibilities under the policies, and . Learn about financial disclosure forms and how they are handled by the Panel.
  • Miscellaneous Nose Topics Dr. Vishal Sharma Contents 1.

    Miscellaneous Nose Topics Dr. Vishal Sharma Contents 1.

    Introduction. Leakage of cerebrospinal fluid from nose. Denotes presence of fistulous communication b/w sub-arachnoid space & nasal cavity. Paradoxical CSF rhinorrhoea:leak of CSF from nose but defect present in mastoid or middle ear roof.
  • Corpus Annotation: Framework and Exercises

    Corpus Annotation: Framework and Exercises

    But it is not sufficient — cannot handle multiple correct choices, and works only pairwise Krippendorff's alpha, Kappa variations…; see (Krippendorff 07; Bortz 05 in German) Tolerances: When is the agreement no longer good enough? — why the 90% rule?
  • Implement Health and Safety Procedures

    Implement Health and Safety Procedures

    For example, every training module without exception. may include an OHS element addressing the specific OHS issues for the particular training module. Establishing an effective OHS training program requires the business to set broad objectives for the training. Possible objectives...
  • Business Rental Presentation Erin Kramarich Director of Business

    Business Rental Presentation Erin Kramarich Director of Business

    Early Start. Deliveries for Early Monday Morning. Delivered on Friday afternoon between 4-6 PM. $10 per day charge ($20 Max) for the weekend. If travel is commencing earlier (Sunday for example)
  • The Legal Landscape for LBGT Individuals, Couples and ...

    The Legal Landscape for LBGT Individuals, Couples and ...

    Equality Virginia Day of Action January 29, 2013 The Fine Print This presentation is a very limited review of a broad subject, has been shortened to fit in the time allowed and to omit material repetitive from other presentations, is...