A NEW LOOK AT RA Interactive Hot Topics Series Combining Conventional DMARDs to Achieve Treatment Goals I’m going to spend the next 15 minutes discussing different approaches to augmenting treatment for patients with rheumatoid arthritis (RA) who have had inadequate responses to oral methotrexate (MTX). MP-RA-0290

TEAR: Design SE* Step-up from IE Immediate IT Immediate triple tx Assess whether it is better to intensively treat all patients with early RA using combinations of drugs or to reserve this approach for MTX non-responders 2-year, double-blind, placebo-controlled RCT (n=755) IE Immediate oral MTX ≤20 mg/wk + ETN 50 mg/wk sc (n=244) SE* Step-up from oral MTX 20 mg/wk to oral MTX + ETN 50 mg/wk SC at wk 24 (n=255) IT Immediate triple tx oral MTX ≤20 mg/wk + SSZ 500 mg BID + HCQ 200 mg BID (n=132) ST* Step-up from oral MTX 20 mg/wk to triple tx oral MTX + SSZ + HCQ at wk 24 (n=124) The Treatment of Early Rheumatoid Arthritis (TEAR) trial had four different arms, two of which were relevant to the current topic. These two arms comparing “stepping up” to triple conventional oral therapy with conventional DMARDs vs combining oral MTX with etanercept (ETN) in patients who did not achieve low disease activity after 24 weeks of treatment with MTX alone. *Step up occurred if DAS28-ESR was ≥3.2 at week 24 IE, immediate active etanercept; IT, immediate triple therapy; RCT, randomized controlled trial; SE, step-up to etanercept; SSZ, sulfasalazine; ST, step-up to triple therapy; tx, therapy. Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2835.

TEAR: Low Disease Activity in Early RA Patients BL 72 2 3 6 7 DAS28 Visit Week 5 4 1 12 24 36 Year 1 60 84 Year 2 All groups Week 102 P=0.28 Step-up to multiple DMARDS at Week 24 if DAS28-ESR ≥ 3.2 for SE & ST groups IE SE ST IT All groups Week 48-102 P=NS No significant difference between adding a biologic and conventional agents The primary outcome of this study was the mean DAS-28-ESR from week 48 to week 102. At week 24, 28% of the subjects who were treated initially with MTX had DAS28 <3.2 and thus did not step up. Remaining patients stepped up to addition of ETN or to SSZ plus HCQ. There was no significant difference in outcomes for in patients in these two arms in the TEAR trial. At week 24, 28% of patients initially in the MTX-only arms (SE and ST) had DAS28 <3.2 and did not need to step up 41% and 43% of the immediate treatment (IE and IT) arms, respectively, had DAS28 <3.2 at week 24 IE, immediate active etanercept; IT, immediate triple therapy; RCT, randomized controlled trial; SE, step-up to etanercept; SSZ, sulfasalazine; ST, step-up to triple therapy; tx, therapy. Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2835. © 2012, American College of Rheumatology.

A Substantial Fraction of Patients Do Not Achieve Treatment Goals on Oral MTX So, let’s first consider what fraction of patients initiating treatment with oral MTX are likely to require a change in their treatment in order to gain control over their RA.

Percentage of Patients with Adequate Response to DMARD Monotherapy TEAR: Initial treatment with MTX with the option to step-up to treatment with either MTX plus etanercept or MTX plus SSZ plus HCQ if the DAS28 at week 24 is ≥3.21 SWEFOT: Initial treatment with MTX with the option to step-up to treatment with either MTX plus etanercept or MTX plus SSZ plus HCQ or infliximab if the DAS28 at 3-4 months is ≥3.22,3 A very large number of clinical trials have evaluated the efficacy of oral MTX monotherapy in patients with RA and results from two of them, TEAR and SWEFOT, are shown in this slide. Both of these studies assessed achievement of low disease activity with MTX monotherapy as one of several treatment arms and results indicated that someplace between 28 and 47% of patients reached this goal on oral MTX alone. These findings suggest that about one-half to three-fourths of patients who initiate treatment with oral MTX will require some augmentation of therapy. DAS, disease activity score; HCQ, hydrochloroquine; MTX, methotrexate; SSZ, sulfasalazine. Adapted from Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2835. Adapted from van Vollenhoven RF et al. Lancet. 2009; 374:459-466. Adapted from van Vollenhoven RF et al. Lancet. 2012; 379:1712-1720.

Before Adding Treatment, Consider MTX Route of Administration Before adding or switching agents, it is important to determine whether MTX treatment has been optimized.

SC Administration Improves MTX Bioavailability Single center, open- label, randomized, 2-period, 2-sequence, single-dose, crossover study in 4 dose groups (7.5 mg, 15 mg, 22.5 mg, and 30 mg) with 54 healthy adults Results from multiple studies have shown that systemic exposure to MTX does not rise linearly with oral dose and that bioavailability begins to decline with higher doses. This is not the case for subcutaneously administered MTX where the relationship between dose and area under the curve time versus plasma concentration curve is approximately linear. Thus, some patients may not achieve adequate exposure to MTX with oral delivery and may benefit from subcutaneous administration of the drug. SC, subcutaneous. Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:563-571.

Significant Improvement in Disease Control Following Switch From Oral to SC MTX Retrospective analysis of 103 RA patients switched from oral to SC MTX: 40 switched due to inadequate efficacy of oral MTX 63 patients switched due to gastrointestinal side effects of oral MTX P=0.006 This slide shows clinical results demonstrating significant improvement in DAS-28 scores for patients who were switched from oral to subcutaneous administration of MTX and followed for 3 months. Improvements in DAS-28 scores were observed for patients who switched treatment due to inadequate efficacy or intolerable side effects. P=0.0001 SC, subcutaneous; DAS, disease activity score. Hameed B, Jones H. Int J Rheum Dis. 2010;13:e83-e84. © 2010 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.

Intensifying Therapy: Biologics or Synthetic DMARDs? An alternative to adding a biologic to MTX is combination therapy with multiple conventional disease modifying drugs.

ACR20: Patients with Prior Suboptimal Response to MTX* Some of the patients enrolled in this trial had inadequate responses to prior MTX therapy with MTX monotherapy at a dose of 17.5 mg/week and this graph shows results for this subgroup. A substantial number of these patients achieved ACR20 and ACR50 with combination treatment, particularly with all three conventional disease modifying drugs. NS P<0.01 NS P=0.02 NS *Dosed at 17.5 mg/week; NS, not significant O’Dell J, et al. Arthritis Rheum. 2002;46:1164-1170.

Critical Comparisons: Adding Synthetic DMARDs vs a Biologic An important question that has been addressed in several studies is whether there is any significant difference between the benefits achieved from adding a biologic agent or other conventional DMARDs to treatment for patients who have had an inadequate response to oral MTX.

MTX Failures: ACR20 Responders (%) Adalimumab Leflunomide Golimumab Tocilizumab Certolizumab Placebo Etanercept Placebo Infliximab Anakinra SSZ + HCQ Abatacept Rituximab Inflimiab Abatacept Placebo Placebo Placebo CSA Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo SSZ HCQ Gold This slide shows 16 different therapies that have been shown to be effective in patients with inadequate response to MTX. In all cases on this slide the gray highlights the placebo response while the other bars indicate the efficacy of the therapy. Since the all therapies that we consider to be effective all of our biologics and many of the conventional drugs are shown on this slide. The point of this slide is that while all these therapies have been shown to be effective very few of them have been compared to each other until recently. Weinblatt ME, et al. N Engl J Med. 1999;340:253-259. Maini R, et al. Lancet. 1999;354:1932-1939. Cohen SC, et al Arthritis Rheum. 2002;46:614-24. Weinblatt ME, et al. Arthritis Rheum. 2003;48:35-45. Tugwell P, et al. N Engl J Med. 1995;333:137-141. O'Dell JR, et al. Arthritis Rheum. 2002;46:1164-1170. Kremer JM, et al. Ann Intern Med. 2002;137:726-733. Lehman AJ, et al. Arthritis Rheum. 2005;52:1360-1370. Kremer JM, et al. Ann Intern Med. 2006;144:856-876. Emery P, et al. Arthritis Rheum. 2006;54:1390-1400. Kay J, et al. Arthritis Rheum. 2008;58:964-965. Genovese M, et al Keystone EC, et al. Arthritis Rheum. 2008;58:3319-3329. Schiff M, et al. Ann Rheum Dis. 2008;67:1096-1103.

RACAT: Study Design Randomization Start 24 Weeks 48 Weeks DAS28 Improved ≥ 1.2? Yes No Primary Outcome: **∆ DAS28 *SSZ + HCQ SSZ + HCQ *Etanercept Etanercept Open Continuation RACAT (Rheumatoid Arthritis Comparison of Active Therapies) was a trial in patients with active disease despite methotrexate therapy. This was a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with RA who had active disease despite MTX to a triple therapy regimen of disease-modifying antirheumatic drugs (MTX, sulfasalazine, and hydroxychloroquine) or etanercept plus MTX. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the DAS28 score at week 48. *All patients continue to receive methotrexate ** Patients who switch at 24 weeks remained with their randomization group Mean dose 19.6 mg/week O'Dell JR, et al. N Engl J Med. 2013;369:307-318 (suppl).

Adding Conventional DMARDs vs a Biologic: RACAT Primary Endpoint 7 Triple therapy ETN-MTX 6 5 4 DAS28 Mean Score 3 2 1 Results from this study indicated no significant difference between these two treatments for the primary end point. 24 48 Week No. Evaluated Triple therapy ETN-MTX 178 175 157 161 154 155 O'Dell JR, et al. N Engl J Med. 2013;369:307-318. Copyright © 2013 Massachusetts Medical Society. Reproduced with permission Massachusetts Medical Society.

Change from Baseline to 48 Weeks in Sharp Score Triple Strategy Etanercept Strategy Change in Sharp Score Cumulative Probability 30 20 10 40 60 80 100 Study results also indicated no difference in radiologic results for the two treatment strategies. O'Dell JR, et al. N Engl J Med. 2013;369:307-318. Copyright © 2013 Massachusetts Medical Society. Reproduced with permission Massachusetts Medical Society.

DAS28 ≤ 3.2 Continued MTX monotherapy SWEFOT:1,2 MTX monotherapy (20 mg/wk for 3-4 months) (n=487) MTX responders DAS28 ≤ 3.2 (n = 229) MTX-IR DAS28 > 3.2 (n = 258) Intolerant (n=27) DAS28 ≤ 3.2 Continued MTX monotherapy (n = 145) DAS28 > 3.2 MTX + SSZ + HCQ (n = 130) DAS28 > 3.2 MTX + infliximab (n = 128) This slide shows the planned structure of SWEFOT. Patients whose DAS28 score was >3.2 after 3-4 months of MTX monotherapy were randomly allocated to continued MTX plus either SSZ (1000 mg twice daily, given orally) and HCQ (400 mg, given orally) or INF (3 mg/kg, given intravenously at weeks 0, 2, 6, and every 8 weeks thereafter). Withdrew for other reasons (n=57) 1. van Vollenhoven RF et al. Lancet. 2009; 374:459-466. 2. van Vollenhoven RF et al. Lancet. 2012; 379:1712-1720.

Time after Inclusion in Study SWEFOT: Achievement of Good EULAR Response (Triple Therapy vs MTX Plus Biologic) 80 MTX + SZZ + HCQ MTX + INF 70 60 50 P=0.0160 P=0.0988 Patients (%) 40 P=0.8884 30 20 10 This figure shows the proportion of patients achieving a good response according to EULAR criteria (compared with time to randomization) at 6, 9, and 12 months. The difference between the groups is not significant at 6 months or 9 months but becomes significant at 12 months. This is interesting and is attributed to some extent to the loss of patients from triple therapy to other conventional therapies and a loss of people from the Infliximab group who weren’t doing well to Etanercept. 6 months 9 months 12 months Time after Inclusion in Study EULAR, European League Against Rheumatism van Vollenhoven RF et al. Lancet. 2009; 374:459-466.

SWEFOT: Radiologic Progression (Triple Therapy vs MTX Plus Biologic) Delta Sharp- van der Heijde score MTX + SSZ + HCQ MTX + INF 20 40 60 80 100 120 -20 Proportion of patients (%) Because radiographic progression data are highly skewed across patient samples, results are best viewed with a cumulative probability plot. This plot shows that the majority of patients SWEFOT trial were not different in terms of clinically significant radiographic progression but perhaps a difference occurring in the extreme 10% of patients over on the right hand side of this curve. van Vollenhoven RF et al. Lancet. 2012; 379:1712-1720.

Time in Relation to Randomization, mo Biologic vs Conventional Combination Treatment and Work Loss in Early Rheumatoid Arthritis 22 20 18 16 14 12 10 8 6 4 2 Mean Work Loss, d/mo -12 -9 -7 -5 -3 -1 1 3 5 7 9 11 13 15 17 19 21 Time in Relation to Randomization, mo Pre-enrollment Run-in After randomization Randomization Biologic treatment (n=105) Conventional treatment (n=99) Controls (n=1020) This slide shows the results at 2 years from the work loss data from the SWEFOT trial What we can see here is that there are no difference between the group treated with conventional disease modifying drugs versus those treated with biologics. In fact the work loss was somewhat greater in those treated with biologics but this did not reach statistical significance for most of the studies. Therefore there is no advantage in work in choosing one of these approaches over the other. Eriksson, JK et al. JAMA Intern Med. 2013;173:1407-1414.

TEAR: Low Disease Activity in Early RA Patients BL 72 2 3 6 7 DAS28 Visit Week 5 4 1 12 24 36 Year 1 60 84 Year 2 All groups Week 102 P=0.28 Step-up to multiple DMARDS at Week 24 if DAS28-ESR ≥ 3.2 for SE & ST groups IE SE ST IT No significant difference between adding a biologic and conventional agents The primary outcome of this study was the mean DAS-28-ESR from weeks 48 to 102. At week 24, 28% of the subjects who had initially treated with MTX had DAS ESRs<3.2and thus did not step up. The remaining patients stepped up to the addition of ETN or to SSZ plus HCQ. There was no significant difference in the outcomes in patients in these two arms of the TEAR trial. At week 24, 28% of patients initially in the MTX-only arms (SE and ST) had DAS28 ≤3.2 and did not need to step up 41% and 43% of the immediate treatment (IE and IT) arms, respectively, had DAS28 ≤3.2 at week 24 IE, immediate active etanercept; IT, immediate triple therapy; RCT, randomized controlled trial; SE, step-up to etanercept; SSZ, sulfasalazine; ST, step-up to triple therapy; tx, therapy Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2835. © 2012, American College of Rheumatology.

TEAR Cumulative Probability 100 80 60 40 20 -20 Week 102 Change from Baseline Cumulative Probability IE SE ST IT Results from TEAR indicated no significant difference among radiographic outcomes for the four treatment arms. Most notably, results were the same for patients who stepped up to biologic plus MTX and those who received triple therapy with conventional disease modifying drugs. 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 IE, immediate active etanercept; IT, immediate triple therapy; RCT, randomized controlled trial; SE, step-up to etanercept; SSZ, sulfasalazine; ST, step-up to triple therapy; tx, therapy Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2835.

TEAR: Percent without Radiologic Progression No radiological progression was defined as a change in the Total Sharp Score ≤0.5 over 2 years. This outcome was achieved by 71% of the patients who had ETN added to MTX and 68.3% of those who were stepped up to triple combination therapy with conventional DMARDs. P=0.33 IE, immediate active etanercept; IT, immediate triple therapy; RCT, randomized controlled trial; SE, step-up to etanercept; SSZ, sulfasalazine; ST, step-up to triple therapy; tx, therapy Adapted from Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2835.

Summary So, what do we conclude?

Summary Many patients with RA have inadequate responses to MTX monotherapy and require additional treatment to control their disease Switching to SC MTX increases bioavailability and may improve clinical response Augmentation of therapy may be carried out by adding: Synthetic DMARDs A biologic agent Both of these approaches markedly improve clinical outcomes and limit radiologic progression: Synthetic DMARDs are less expensive: Many cost effective analyses have shown costs between $1 to $10 million dollars per QALY gained Many patients with RA have inadequate responses to MTX monotherapy and require additional treatment to control their disease. Switching to SC MTX increases bioavailability and may improve clinical responses in most of these patients. Treatment can also be advanced by either adding synthetic DMARDs to MTX or a biologic agent. Both of these approaches improve clinical outcomes and limit radiographic progression. Studies have shown that these approaches are similar to each other both clinically and radiographically. But the cost effectiveness of biologics over conventional disease modifying drugs in this group result in QALYs costing 1 to 10 million dollars.