What I Have Learned Over the Years - Keystone s Top 10 -

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1 What I Have Learned Over the Years - Keystone s Top 10 - Edward Keystone, MD FRCP(C) Professor of Medicine University of Toronto, CANADA Ontario Rheumatology Association Meeting Muskoka, Canada Sunday, May 25, 9:00 AM 10:00 AM

2 Objectives To learn the appropriate therapeutic approach with conventional DMARDs To learn about new therapeutic strategies with biologics to reduce our taxes. To understand the influence of patient-derived outcomes on clinical response and reaching therapeutic targets

3 Edward Keystone, MD FRCP(C) Disclosures 3 Sources of Funding for Research: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, F. Hoffmann-La Roche Inc, Janssen Inc, Lilly Pharmaceuticals, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB. Consulting Agreements/Advisory Board Membership: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, F. Hoffmann-La Roche Inc, Genentech Inc, Jannsen Inc, Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, UCB Speaker Honoraria Agreements: Abbott Laboratories, Astrazeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen Financial Interests/Stock Ownership: None Discussion of Off-Label, Investigational, or Experimental Drug Use: None Revised Nov 19, 2013

4 4 I Loved My Instructions For This Lecture

5 5 Make It Practical! Make It Funny!

6 NO Pressure! 6

7 7 Keystone s Top Strategies with conventional therapies actually work better than expected. 2. Pre-clinical studies of biologics do not always reflect clinical outcomes 3. Efficacy of all biologics are amazingly similar. 4. IL-6 is the driver of anemia of chronic disease 5. Radiographic inhibition by biologics: things aren t always what they seem 6. Patient-derived outcomes are the major determinants of therapeutic outcomes 7. Tax dollars can be saved with dose reduction of biologics 8. Tax dollars cannot be saved with biologics in MTX-IRs 9. Tax dollars can be saved using combination MTX + biologic in early RA 10. Selling the pharm can be career limiting

8 8 Keystone s Top 10: # 1 Appropriate Strategies With Conventional Therapies Work Better Than Expected

9 Use of Triple Rx 9

10 In MTX-Naïve Patients 10

11 % Patients with Good* Response Triple Therapy All three drugs Sulfasalazine and hydroxychloroquine Methotrexate 24/31 (77%) 14/35 (40%) 12/36 (33%) 0 P=.003 by log-rank test Months * Good = 50% improvement in modified Paulus criteria O'Dell JR, et al. N Engl J Med. 1996;334:1287.

12 But What About In MTX-Inadequate Responders?

13 Treatment Strategies in MTX-IRs: Results of Switching Active Therapies in Inadequate Responders -The RACAT Trial- O Dell et al, N Engl J Med 2013; DOI: /NEJMoa

14 RACAT Trial Trial Schematic O Dell et al, N Engl J Med 2013; DOI: /NEJMoa /Supplement

15 Proportion With Outcome (%) RACAT Trial 24 Weeks P = Triple Etanercept P = DAS DAS O Dell et al, N Engl J Med 2013; DOI: /NEJMoa

16 DAS RACAT Trial DAS28 By Strategy - Divided by Switch P < For improvement After switch in both groups AA AB BA BB Week

17 Proportion With Outcome (%) RACAT Trial 48 Weeks P = P = Triple Etanercept DAS DAS O Dell et al, N Engl J Med 2013; DOI: /NEJMoa

18 Take Home Message The proportion of patients failing to achieve a good DAS28 response in MTX-IRs with the addition of HCQ + SSZ was the same as with ETN The efficacy of triple therapy after failure of MTX/etanercept has been demonstrated for the first time. Switching therapy with Etanercept or triple therapy inadequate responders leads to similar outcomes clinically and radiographically.

19 Use of SubQ MTX 19

20 Head-to-head, Randomised, Crossover Study Of Oral Vs Subcutaneous Methotrexate In Patients With RA: Drug-exposure Limitations Of Oral Doses > 15 Mg May Be Overcome With Subcutaneous Administration 20 Schiff M et al, Ann Rheum Dis 2014

21 21 AUC of Oral vs SubQ MTX Schiff, M. et al, Ann Rheum Dis 2014; 0:1-3; doi: /annrheumdis

22 CATCH COHORT Survival of Initial SC MTX vs Oral MTX in ERA 22 Hazlewood G et al, Arth Rheum 2013, Vol 65 (S10), 627)

23 Take Home Message Current Dogma: SQ MTX should be used in case of unresponsiveness or evidence of toxicity of oral MTX My Dogma: SQ MTX should be considered as first line Rx in early RA alone or in combination with other DMARDs

24 Thank You, Carter! 24

25 25 Keystone s Top 10: # 2 Reading The Pre-Clinical Literature Helps Before Embarking On Biologic Studies in Humans

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30 Lessons Learned From T-cell Depletion High expectation bias need for early placebo in early phase trials Systemic CD4 depletion does not equate to HIV in non-infected individuals Maybe someone should read the literature before embarking on human studies.

31 31 Keystone s Top 10: # 3 The Response Of All Biologics Are Amazingly Similar

32 Patients Responding (%) Anti-TNFs in MTX-IRs - ACR 24 Weeks- 80 ACR20 ACR50 ACR MTX q8+MTX 10q8+MTX 3 0 MTX 15 ETN+MTX 10 3 MTX qow +MTX MTX MTX Infliximab (ATTRACT 1 ) Etanercept (Weinblatt 2 ) Adalimumab (DEO19 3 ) GLM100+MTX GLM50+MTX Golimumab (GO-FORWARD 4 ) CZP400+MTX CZP200+MTX Certolizumab pegol (RAPID 1 5 ) 1. Maini R, et al. Lancet 1999; 2. Weinblatt ME, et al. NEJM 1999; 3.Keystone E, et al. Arth and Rheum 2004; 4. Keystone E, et al. Ann Rheum Dis. 2009; 5. Keystone EC, et al. Arthritis Rheum 2008

33 Rules for Biologic & Small Molecule Response in DMARD-IRs ACR 20 60% ACR % ACR 70 20%

34 Patients Responding (%) Biologic Therapy in Anti-TNF-IRs ACR 24 weeks Abatacept (ATTAIN 1 ) Rituximab (REFLEX 2 ) Tocilizumab (RADIATE 3 ) Golimumab (GO-AFTER 4 ) 1. Genovese MC et al., N Engl J Med 2005;353: Cohen SB et al., ARTHRITIS & RHEUMATISM Vol. 54, No. 9, September 2006, pp Emery P et al., Ann Rheum Dis 2008;67; Smolen J et al., Ann Rheum Dis 2008; 67:50.

35 Rules for Biologic & Small Molecule Response in TNF-Irs ACR 20 50% ACR % ACR 70 12%

36 Take Home Message Clinical responses of all biologics/small molecules examined to date after failure of MTX or a TNFi are the same. Amazing!

37 37 Keystone s Top 10: # 4 IL-6 Is The Driver of Anemia of Chronic Disease

38 38 IL-6 Causes Anaemia Of Chronic Inflammation By Inducing Hepcidin Production By Hepatocytes Hepcidin inhibits: Release of iron from macrophages (reticuloendothelial block) 1,2 Absorption of dietary iron (iron deficiency) 1,2 Inflammation IL-6 Hepcidin Macrophage iron release Macrophage Hepatocytes Intestinal iron absorption 1. Andrews NC. J Clin Invest 2004; 113: ; 2. Nemeth E, et al. J Clin Invest 2004; 113:

39 Haemoglobin (g/dl) Tocilizumab Has The Potential To Reverse Chronic Anaemia (OPTION & TOWARD) Placebo + DMARDs TCZ 8 mg/kg + DMARDs Baseline Hb <LLN 140 = = Baseline Hb LLN Time (weeks) LLN level = 120 for females and 130 for males Time (weeks) 39 Smolen JS, et al. Lancet. 2008;371: Genovese M, et al. Arthritis & Rheumatism. 2008;58:

40 Take Home Message Tocilizumab might be the better alternative in those patients who have developed significant anemia of chronic disease. But, little data with other biologics except golimumab where modest effect seen 40

41 41 Keystone s Top 10: # 5 Things Aren t Always What They Seem With Radiographic Outcomes

42 % Patients Aspire Trial Radiographic Remission Is Easier to Achieve Than Clinical Remission % Remission % Not Progressing MTX Alone INF 3 mg/kg + MTX INF 6 mg/kg + MTX Breedveld FC, et al. ACR 2004, Abstract L5. St.Clair W et al. Arthritis Rheum. 2004;50: Klareskog L, et al. Ann Rheum Dis 2005;64(suppl III):59.

43 % Patients Tempo Trial Relationship Between Clinical Remission & Radiographic Remission % Remission % Not Progressing MTX Alone Etanercept Etanercept + MTX Breedveld FC, et al. ACR 2004, Abstract L5. St.Clair W et al. Arthritis Rheum. 2004;50: Klareskog L, et al. Ann Rheum Dis 2005;64(suppl III):59.

44 Premier 44 Early Combination Treatment Randomization 104-week double-blind, active-controlled phase Adalimumab 40 mg eow + MTX* (n=268) 799 patients MTX weekly* (n=257) Adalimumab 40 mg eow (n=274) Week 0 *Escalated over 8 wks to 20 mg/wk, as needed and as tolerated Primary endpoint assessed Breedveld F, Arth Rheum 2006, 54:36-37

45 Mean Change From Baseline 45 Premier Change In Total Sharp Score MTX Alone Adalimumab Adalimumab + MTX *P<0.001 for ADA + MTX vs MTX and ADA alone ** P<0.001 for ADA alone vs MTX alone. Breedveld F, Arth Rheum 2006, 54:36-37

46 TSS 46 PREMIER Change In 2 Years Adalimumab + MTX Ada Alone MTX Alone Cumulative Probability Emery P et al, J Rheum 2009: 7,

47 % of Patients PREMIER Probability Of Radiographic 2 Years >4 ΔTSS >10 ΔTSS >20 ΔTSS * Ada + MTX Ada Alone MTX Alone n = *p<0.05 vs. MTX alone; p<0.01 vs. MTX alone; p<0.001 vs. MTX alone. Emery P et al, J Rheum 2009: 7,

48 48 Another Example Where Mean Change In TSS Can Lead You Astray

49 49 Etanercept (ETN) Plus MTX Combination Therapy Resulted in Better Clinical & Radiographic Outcomes Than ETN Monotherapy Even in Patients with Active RA despite MTX Treatment: 52-Week Results from JESMR Study Radiographic Progression for 52 Weeks MTX should be continued at the commencement of ETN therapy even in RA patients who had shown an inappropriate response to MTX as evidenced by changes in radiographic progression. Kameda H, et al. J Rheumatol 2011, 38:

50 Etanercept (ETN) Plus MTX Combination Therapy Resulted in Better Outcomes Than ETN Monotherapy: Results from JESMR STUDY 50 Cumulative Probability of van der Heijde-Sharp Score (0-52 Weeks) MTX should be continued at the commencement of ETN therapy even in RA patients who had shown an inappropriate response to MTX as evidenced by changes in radiographic progression. Kameda H, et al. J Rheumatol 2011, 38:

51 DAM-HAQ Aggregate Trial Data What Does Progression of Joint Damage Mean for Physical Function? 51 Correlation of DAM-HAQ w ith Joint Damage 0.8 r= unit TSS = 0.1 units HAQ based on irreversible joint damage (DAM HAQ) TSS Smolen JS et al, Ann Rheum Dis 2010, 69:

52 What Does A Change in TSS Mean For Physical Function in Late RA? ~ 25 unit change in TSS = Noticeable change in physical function caused by joint damage

53 53 Take Home Message It s easier to halt radiographic progression than achieve clinical remission. The mean change in TSS is determined by a small subset of radiographic progressors for which biologics are particularly important. The probability of radiographic progression is a more important outcome than the change in TSS. A substantial change in TSS is required to cause disability.

54 Change from baseline in Genant scores LITHE Trial Tocilizumab: Change From Baseline In 52 Weeks 25 Placebo + MTX TCZ 4mg/kg+MTX TCZ 8 mg/kg + MTX RRP No RP No RRP Cumulative percent (n)

55 Change GO-FORWARD Total vdhs Score: Week 24 TSS Change from baseline p= p= p= Mean Median IQR p= PBO + MTX (n=133) GLM 100 mg + PBO GLM 50 mg + MTX (n=89) GLM + MTX combined GLM 100 mg + MTX (n=89) Emery P et al. ACR 2009, OP640.

56 Change GO-BEFORE Total vdhs Score: Week 52 TSS Change from baseline p= p= p=0.025 Mean Median IQR p= PBO + MTX GLM 100 mg + PBO 0.00 GLM 50 mg + MTX GLM 100 mg + MTX GLM + MTX combined Centocor Inc., data on file.

57 Mean Change (SE) from Baseline in mtss Structure Preservation: Results in Two Studies Placebo/MTX p< Tofacitinib 5 mg BID Tofacitinib 10 mg BID p= p=0.038 p=0.079 N= MTX-naïve MTX-IR Month 6 data from studies 1069 and 1044; SE: Standard Error; mtss: modified Total Sharp Score; MTX, methotrexate; IR, inadequate responder; BID, twice daily 57

58 58 Take Home Message Many patients with severe RA in clinical trials failing MTX do not exhibit clinically relevant radiographic progression. Patients with less severe disease in clinical practice are even less likely to progress radiographically. It is increasingly difficult to demonstrate significant differences between biologics/small molecules in MTX- IRs with more moderate disease. It is increasingly difficult for a biologic/sm to exhibit efficacy in inhibiting structural damage relative to PBO within clinical trials.

59 Overall Take Home Message Things Aren t Always What They Seem With Radiographic Outcomes With Biologic Rx 59

60 60 Keystone s Top 10: # 6 Patient-derived Outcomes In A Composite Are Major Determinants of the Therapeutic Response & Target Achieved

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62 Attract Study 62 Patient-derived Outcomes Significantly Influence ACR20 Response* Pain HAQ Pt Global CRP Phys Global TJC SJC Infliximab MTX Alone Furst D et al, Arth Rheum 44:S80, 2001

63 Baseline Patient Derived Outcomes Influence Timing of 3 or 6 Months 63 Baseline Akhavan P et al, EULAR 2011, Poster 6150

64 % Patients Not Achieving REM 64 Patient-derived Outcomes Measures That Contribute to The Most Near-Miss Remission* PGA SJC TJC CRP * Boolean Definition Studenic P et al, Ann Rheum Dis June 2012, doi: /annrheumdis

65 Take Home Message Patient-derived outcomes are significant determinants of: therapeutic response timing of response target achieved Patient-derived outcomes confound treat to target strategies

66 66 Keystone s Top 10: # 7 Tax Dollars CAN Be Saved With Biologic Dose Reduction

67 DOSERA STUDY

68 PRESERVE: Study Design 1

69 Proportion of Subjects PRESERVE Trial Period 2 Results: Proportion of Subjects Maintaining LDA at Week 88 * * *P-value < for comparison of E50+M vs M and E25 +M vs M Smolen J et al, Lancet March 2013, Vol 361,

70 Take Home Message Dose Reduction of Biologics is Possible in Patients Achieving a State of Remission or LDAS

71 71 Keystone s Top 10: # 8 Tax Dollars CANNOT Be Saved With Biologic-Free Remission in MTX-IRS With Exceptions

72 DOSERA STUDY

73 Smolen J et al, Lancet March 2013, Vol 361,

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75 Take Home Message Biologic-free remission is unlikely in MTX-IRs except possibly in patients achieving a deep remission.

76 76 Keystone s Top 10: # 9 Tax Dollars Can Be Saved By Using Combination MTX + Biologic In Early RA

77 OPTIMA Does achieving the target with MTX define a subpopulation with good prognosis to MTX? MTX Yes ADA 40 mg eow + MTX * DAS28<3.2 wk No ADA 40 mg eow + MTX Open label ADA 40 mg eow + MTX Primary Efficacy Outcome** Yes MTX MTX * DAS28<3.2 wk No Open label ADA 40 mg eow + MTX 26 weeks 52 weeks PERIOD 1 PERIOD ** Composite of DAS28 <3.2 and no radiographic progression * MTX titrated to 20 mg/wk by Wk 8 from baseline ( mtss <0.5)

78 OPTIMA % of Patinets High % of MTX+PBO achieved a LDA or clinical week 78 [arm 2: sustained ADA+MTX] (n=105) * [arm 4: sustained MTX] (n=112) ** *** DAS28(CRP)<3.2 DAS28(CRP) <2.6 SDAI<11 _ SDAI _ <3.3 *P=0.034; **P=0.002; ***P=0.019 ADA+MTX vs MTX+PBO LOCF ITT population

79 OPTIMA Can we remove ADA to patients who have reached the target with ADA+MTX? MTX ADA 40 mg eow + MTX * DAS28<3.2 wk Yes No ADA 40 mg eow + MTX Open label ADA 40 mg eow + MTX Yes MTX MTX * DAS28<3.2 wk No Open label ADA 40 mg eow + MTX 26 weeks 52 weeks PERIOD 1 PERIOD * MTX titrated to 20 mg/wk by Wk 8

80 OPTIMA Groups achieved very high disease control, differences suggest that some pts may have benefited from sustaining ADA+MTX % of Patinets [arm 1 ADA+MTX / MTX] (n=102) [arm 2: sustained ADA+MTX] (n=105) * ** DAS28(CRP)<3.2 DAS28(CRP) <2.6 SDAI _ <11 SDAI <3.3 _ *P=0.036; ** P=0.001 LOCF ITT population

81 Take Home Message Biologic-free remission is possible with early simultaneous initiation of MTX + TNFi. Early use of TNFi in MTX-IRs yields only slightly lower efficacy compared to initiation of combo Rx

82 82 Keystone s Top 10: # 10 Lessons Learned From Selling The Pharm

83 Career Limiting Statements 83

84 84 The most common side effect of biologics is.. POVERTY

85 85 Why would you evaluate tocilizumab monotherapy against adalimumab when we all already know that adalimumab monotherapy is not very efficacious?

86 86 All biologics have the same ACR responses in MTX-IRS 60/40/20 You can t tell a player without a program

87 87 Now, I want you all to say Adalimumab 3 times quickly!

88 You Can t Win! 88

89 89 Take Home Message At my age, career limiting statements can t be TOO limiting!

90 Thank You!

91 Questions? Speak Up!

92 Speak Up! Ed

93 And Finally. 93

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