James R. O Dell, M.D. University of Nebraska Medical Center

Transcription

1 Not everyone in the world needs a biologic: Lessons from TEAR and RACAT James R. O Dell, M.D. University of Nebraska Medical Center

2 Disclosure Declaration James O Dell, MD Advisory Board for Crescendo, BMS, GSK, Lilly, Coherus, Antares and Medac Editor of Kelley s/firestein s Textbook of Rheumatology Editor of RA Sections of UpToDate Published original description of Triple Therapy 1994

3 Value Based Care Should you care? How about the different Tiers of rheumatologists? In % of RA in US got a biological before MTX 2012 this was 36%! Those that got MTX first often got inadequately dosed.

4 Outline Lessons from two investigator initiated double blind randomized controlled North American trials The US TEAR trial Including MTX only group The RACAT trial Summary of above

5 Since the biologicals Biologicals are wonderful but They are in no way specific treatment for nor do they cure RA They are extremely expensive and have serious toxicity in a few patients Therefore they are not close to the whole answer

6 Non- Biological Changes in RA RX: Last Two Decades Earlier Diagnosis Criteria and CCP Importance of Early DMARD treatment More generalized and effective use of MTX Folic Acid Increase doses and switch to SC therapy Universal use of Combinations of DMARDs < 5% used in 1994 and currently vast majority of patients if not MTX controlled Treat to Target TICORA

7 Arthritis Rheum 2012; 64 :

8 TEAR Study Schema At Week 24, subjects in Arms 3 & 4 with DAS 3.2 will be stepped-up to additional active medications Toxicity Monitoring Every 6 Weeks; X-Ray at Screening, Weeks 48 and 102 DAS at Screening, Weeks 6, 12, 24, 30, 36, 48, 60, 72, 84, 96, 102 MTX 20mg/day; ETN 50mg/wk; SSZ 1000 mg BID; HCQ 200mg BID (or matching placebo) 8

9 Inclusion Criteria RA (ACR criteria) Disease duration < 3 years Active disease: 4 swollen, tender by 28 jt count RF + or CCP + or erosions = Poor Prognosis RA Limited Prior DMARD exposure Stable NSAIDs Oral prednisone allowed ( 10mg/day) No serious co-morbid conditions No significant renal, liver or hematologic lab abnormalities No active infections 9

10 Participant Demographics* Mean SD Range Disease Duration (months) mhaq HAQ Pain Age BMI DAS Painful Joints Swollen Joints * No difference by treatment groups 10

11 Observed DAS Week IE IT 5 SE ST DAS Week 0 (755) Week 12 (661) Step-up to Multiple DMARD at Week 24 if DAS Primary Analysis: Weeks 48 to 102 Week 24 (646) Week 36 (601) Week 48 (582) Comparison p-value Groups (IE, IT, SE, ST) 0.55 Time (I = S) 0.37 Trt (ETN > TT) wks 102 weeks Week 60 (522) Week 72 (518) Week 84 (508) Week 96 (485) Week 102 (476) 11

12 Efficacy DAS28 at 102 Weeks Mean (SD): By Therapy Group: Mtx Etanercept Groups: 3.04 (1.41) Triple Therapy Groups: 2.85 (1.39) By Time: Immediate Combination Groups: 2.94 (1.40) Step-up Groups : 3.03 (1.41) Factors associated with worse outcome: Female African-American Higher BMI Longer disease duration Higher DAS28 at screening 12

13 % Subjects in Study Meeting Criteria Outcome ACR Responses I vs S: p < Month 6 (646) Year 2 (476) I vs S: p = Month 6 (646) IE IT SE ST Year 2 (476) I vs S: p = Month 6 (646) ACR20 ACR50 ACR70 Year 2 (476) ACR Criteria at Month 6 shown only for subjects reaching Month 6 ACR Criteria at Year 2 shown only for subjects reaching Year 2 13

14 No difference among 4 groups Combined: Initial vs Step-up no difference Combined: Etanercept groups vs Triple (p = 0.047) If outlier removed p= NS TEAR Cumulative Probability Initial Etanercept Initial Triple Step-up Etanercept Step-up Triple

15 Summary of TEAR (US) Findings Initial Combination Therapy is not superior to Step-up clinically (DAS28) or radiographically (p = 0.92) Etanercept/MTX marginally better radiographically (0.57 TSS) and Triple is marginally better clinically (DAS less)

16 Arthritis Rheum 2013; 65 :

17 TEAR Trial DAS28 Over time 28% of MTX Group Had DAS28 < 3.2 Methotrexate Only Group MTX doses escalation: 10mg to 15 at 6 weeks; 15mg to 20mg at 24 weeks Escalation occurred if any tender or swollen joints

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20 Summary of MTX only group MTX responders continued to do very well clinically and radiographically Importantly those that need to Step-up also did well and therefore no advantage to combinations up front at 1 or 2 years At Baseline - MTX responders were: more likely to be male, Caucasian, trim, have lower disease activity and have less baseline radiographic disease.

21 RA: Comparison of Active Therapies (RACAT) CSP 551

22 80 MTX Failures: ACR Placebo Responders (%) Etanercept Infliximab Anakinra Adalimumab Weinblatt 24 Weeks 20 Lipsky 30 Weeks Cohen 24 Weeks 15 Weinblatt 24 Weeks 16 CSA Tugwell 24 Weeks SSZ HCQ SSZ & HCQ O'Dell 96 Weeks 20 Leflunomide Kremer 24 Weeks Gold Lehman 48 Weeks Abatacept Kremer 24 Weeks Rituximab Emery 24 Weeks Golimumab Kay 16 Weeks Tocilizumab Genevese 24 Weeks 14 Certizumab Keystone 24 Weeks Infliximab Abatacept Schiff 26 Weeks

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24 Rheumatoid Arthritis: Comparison of Active Therapies (RACAT CSP #551) 353 Patients with active disease despite 15 mg of methotrexate Randomized, Double-blind, 1 year equivalency trial testing two strategies Primary end point: DAS28 at 48 weeks Secondary end points: Sharp score progression at 1 year Robust economic analysis Includes DNA and Serum Bank

25 RACAT: Study Design Randomization DAS28 Improved 1.2? Primary Outcome: ** DAS28 *SSZ + HCQ Yes SSZ + HCQ No *Etanercept Yes Etanercept Yes Start 24 Weeks 48 Weeks *All patients continue to receive methotrexate Mean dose 19.6 mg/week Yes Open Continuation Open Continuation

26 Baseline Characteristics of Study Patients Strategy A (Triple) (n=178) Strategy B (Etanercept) (n=175) p-value Age, Mean + SD Female, % 77 (43.4%) 85 (48.9%) 0.29 Caucasian, % 161 (90.5%) 146 (84.4%) 0.09 BMI, Mean + SD Baseline Disease Characteristics RF+, % 117 (65.7%) 117 (67.2%) 0.76 Disease duration from diagnosis (years), Mean + SD DAS28 (CRP), Mean + SD Swollen joint count (of 28), Mean + SD Tender joint count (of 28), Mean + SD HAQII, Mean + SD ESR (mm/h), Mean + SD Modified SHARP, Mean + SD Methotrexate mg/week, Mean + SD Oral Steroids 84 (47.2%) 87 (49.7%) 0.64 Projected radiographic progression: Triple 3.70/yr and Etanercept 3.32/yr

27 1 Patient Flow Chart Completed per protocol from each strategy 88% of Triple and 89% of Etanercept

28 Primary Outcome: DAS 28 at 48 weeks DAS Triple Strategy Etanercept Strategy Non- Inferior P< In both Directions Week

29 DAS28 By Strategy - Divided by Switch DAS Triple-Triple Triple-Etanercept Etanercept-Triple Etanercept-Etanercept Switch rate = 27% for both P < For improvement After switch in both groups Week

30 5 Change from Baseline in Continuous Outcomes Measures, Mean (SD) Strategy A (Triple) Strategy B (Etanercept) p-value* DAS28 24 Weeks, (n=318) 48 Weeks Modified SHARP (TSS) 24 Weeks, (n=318) 48 Weeks CDAI 24 Weeks, (n=317) 48 Weeks *t-test comparing A vs. B on change from baseline.

31 DAS28 Response at 24 weeks and 48 weeks by treatment group DAS28 Response at 24 Weeks DAS28 Response at 48 Weeks Proportion with DAS28 Response (%) 40% 35% 30% 25% 20% 15% 10% 5% 0% 35% 25% P=0.04 DAS Triple 22% 13% P=0.03 DAS Etanercept Proportion with DAS28 Response (%) 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 42% 37% P=0.38 DAS Triple 25% 21% P=0.36 DAS Etanercept

32 Change from Baseline to 48 Weeks Triple Strategy Etanercept Strategy Change in Sharp Score Cumulative Probability

33 Toxicity Triple patients more likely to have GI complaints (30% vs 22%) Etanercept patients more likely to have infections (37% vs 25% or 50% more) - and importantly serious infections 12 vs 4

34 RACAT: Different Switch Points % Switch % Switch Triple Etanercept & 75% Switch 10 0 DAS ACR 20 DAS28 3.2

35 11 Summary: In MTX suboptimal responders the strategy of first adding SSA and HCQ is non-inferior to first adding etanercept ( DAS 28) (T) vs (E) (p<0.0001) Starting T first was not different radiographical (mtss) (T) vs +0.29(E); (p=0.43) The switch rate was 27% for both strategies Patients improved significantly after a switch from either therapy (p<0.0001).

36 So What about Swefot? Didn t it show that infliximab was superior to Triple when added to MTX in patients with active disease?

37 Swefot Trial 487 new onset RA Patients 258 (53%) did not achieve low disease activity with MTX 258 Patients randomized, Open labeled 2 Arms: Triple vs MTX + Infliximab No difference at 6 or 9 months At 12 months: 25% HCQ + SSZ achieved EULAR response 39% infliximab achieved EULAR response At 2 years: No difference van Vollenhoven et al. Lancet 2009; 374: Karlsson et al. Ann Rheum Dis 2013 epub

38 Swefot: Primary Outcome EULAR good response "Triple" "Infliximab" months 9 months 12 months 24 months

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41 What is all the fuss about lipid elevations with our therapies? Tocilizumab was the canary in the coal mine Appears all effective therapies increase LDL and HDL Chol/HDL ratios mostly stable However, all therapies are not created equal Evidence from the TEAR trial that elevations are less and Chol/HDL ratios are better with Triple v MTX etanercept (1) Further, functional HDL improved in both but significantly more so with Triple (2) 1. Charles-Schoeman C et. al. Arthritis Rheumatology 2016;68: Charles-Schoeman C et. al. Arthritis Rheumatology In Press

42 Optimal Economic Management of RA Start with MTX monotherapy push to at least 25 mg/wk ; state with or switch to Sub Q (controls 50% of patients) At 6 months add SSA and HCQ ( 25% of the rest) At 6 months switch to MTX + TNF Inhibitor (about 30% of patients will need biologicals). However, many of these will not reach targets and many others will need < full dose biological therapy. Remember in MTX TNF failure Triple therapy can be successful (RACAT trial data).

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44 Conclusions: The strategy of starting conventional combinations first before TNF inhib has been validated (RACAT and Swefot). The efficacy of triple therapy after failure of MTX etanercept and vice versa has been demonstrated for the first time (RACAT). The cost implications of these findings are substantial

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