Pros and Cons of Combination MTX+ Biologics vs Monotherapy with Biologics: the place of immunogenicity

Pros and Cons of Combination MTX+ Biologics vs Monotherapy with Biologics: the place of immunogenicity Daniel E Furst MD University of California in Los Angeles University of Washington University of Florence Arthritis Associates of Southern California Seattle Rheumatology Associates your company name. All rights reserved. Title of your presentation

Disclosures Abbvie Actelion Amgen BMS Corbus Cytori NIH Novartis Pfizer Roche/Genentech UCB

Prevalence Treatment Adherence Issues in RA Adherence Estimated 50-80% in RA patient population 1,10 Discrepancies in reported rates due to different approaches to measuring adherence 2, 4 Patients at- risk for low treatment adherence Presence of Complex Disease Socioeconomi c Factors Patient-Related Factors Health Education Gaps Multiple Low SES 7 Low self Low health literacy 1 comorbidities 1,3,4 efficacy 1,2,10 Frequent or complex medication dosing regimens 1 Low educational attainment 7 Lack of insurance coverage for treatment and/or high cost of medications5,6, 10 Am J Managed Care, 2003;9:5136-5144 Depression 10 Lack of social support and other life stressors 2,8,10 Poor patientprovider communication 2,8,9 1 Van den Bemt et al., Expert Rev. Clin. Immunol. 2012; 8(4):337 351; 2 Salt et al., Orthop Nurs. 2010 ; 29(4): 260 275; 3 Benner et al., Am J Health Syst Pharm. 2009;66(16):1471 7; 4 Shi et al., Expert Rev Pharmacoecon Outcomes Res. 2007 Apr;7(2):187-202; 5 Barlow et al., Am J Pharm Benefi ts. 2012;4(Special Issue):SP49-SP56) ; 6 Klippel JH, Am J of Pharm Benefits, 2012; 7 Zolnierek et al., Med Care. 2009 August ; 47(8): 826 834.; 8 Elliott et al., Dis Manage Health Outcomes 2008; 16 (1): 13-29; 9 Martin et al., J Rheumatol. 2008;35(4):618 24; 10 de Achaval et al., J Musculoskel Med, 2010; 27(10):399-94.

Direct Medical Costs for RA in 2001 Other Medications* (24.8%) Physician/ Health Professional Visits (7%) Testing (7.8%) Outpatient Surgery (1.2%) Hospitalization (16.5%) Biologic DMARDs (34.7%) Nonbiologic DMARDs (6.8%) * NSAIDs, GI medication, non-ra medications; radiographs, MRI, CT scans, endoscopies, laboratory tests, mammograms, bone density tests, and other examinations Michaud K et al. Arthritis Rheum. 2003;48:2750-2762.

Why does it matter if MTX is added? Why not to add MTX: Added toxicity Added complexity Decreases adherence Why add MTX: Added efficacy(?) Decrease cost of biologics(?)

Outline The clinical effect(s) or non-effects of MTX on Biologics Possible explanations for these effects.

MTX Effects( or non-effects) on Biologics TNFi Abatacept Rituximab Tocilizumab

DAS Score TEMPO Trial only examining 2 arms-etan vs Etan+MTX 6 5 4 Etanercept (n=223) MTX + Etanercept (n=231) 3 2 1 * Low disease activity DAS<=2.4 * 0 0 2 4 8 12 16 20 24 32 40 48 52 Weeks Analysis using LOCF. Data on file, Wyeth. *P<0.01 combination vs MTX or etanercept.

PREMIER Trial: ACR Responses at Week 52 MTX Adalimumab MTX + adalimumab 100 % of patients 80 60 40 20 * 63% 54% 73% 46% 42% 62% 28% 26% 46% 0 ACR20 ACR50 ACR70 *P=0.043 for MTX vs adalimumab, others NS. P<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone. Breedveld et al. ACR, 2004. Presentation L5.

PREMIER Study Change in Total Sharp Score 12 10 8 Adalimumab + MTX Adalimumab MTX 10.4 6 4 2 0 0 3.5 ** 2.1 * 0.8 5.7 ** 5.5 ** 3 * 0 26 52 78 104 1.3 * 1.9 * p<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone ** p<0.001 for adalimumab vs MTX alone

PREMIER Study Clinical Remission by DAS28<2.6(low disease activity) 60 50 * 43 * 49 Week 52 Week 104 % Patients 40 30 20 23 25 25 21 10 0 Adalimumab + MTX Adalimumab MTX *p<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone

With TNFi, MTX improves response in most ways, including radiographically remission data are less impressive (? Measurement effect)

MTX Effects( or non-effects) on Biologics TNFi Abatacept Rituximab Tocilizumab

DAS28 (CRP) DAS28 (CRP) Co-primary endpoints: Abatacept + MTX Co-primary: DAS-defined remission (DAS28 [CRP] <2.6) at Month 12 Co-primary: DAS-defined remission at Month 12 AND Month 18 Early RA if <3.2 Randomization* Abatacept + placebo withdraw ALL study meds Placebo + MTX if 3.2 then D/C RE-EXPOSURE period: If flare or worsening symptoms during Months 15 24 then 6 months open-label abatacept + MTX TREATMENT MRI was performed at Months 0, 6, 12, 18, and 24 0 12 18 24 *Randomization stratified by corticosteroid use at baseline Thanx to Vivien Bykerk Months Emery P. et al. ARD. 2014 15

Proportion of Patients (%) Proportion of Patients with DAS28-CRP Remission over Time (>3 Months 6 Months Disease Duration) Withdrawal period 14.7% 14.3% 13.8% 0 29 57 85 113 141 169 197 225 253 281 309 337 365 394 422 450 534 Visit Day Error bars represent 95% CI

Proportion of Patients (%) Proportion of Patients with Boolean Remission over Time (>6 Months Disease Duration) Withdrawal period 8.2% 4.4% 2.6% 0 29 57 85 113 141 169 197 225 253 281 309 337 365 394 422 450 534 Visit Day Error bars represent 95% CI

With abatacept, MTX response is probably still real measurement effect is also pronounced

WA16291: Design and Treatment Groups MTX (>10mg/wk) MTX inadequate responders R Rituximab, (1g x 2) Rituximab, (1g x 2) Cytoxan (750mg x 2) Rituximab (1g x 2) MTX (>10mg/wk) 17 day corticosteroid regimen in all arms R = randomisation N=40/arm Baseline 24 weeks

Phase 2a-Baseline Disease Characteristics Previous DMARDs (mean) Disease duration (yrs) Rituximab (n=40) Rituximab + MTX (n=40) 2.5 2.5 9 12 SJC (mean) 21 23 TJC (mean) 34 32 RF (median IU/mL) 159 149 CRP (mean mg/dl) 26 29 ESR (mean mm/h) 47 53 DAS28 6.8 6.8 Emery P et al. Arthritis Rheum. 2003;48:S439. Szczepanski L et al. Arthritis Rheum. 2003;48:S121..

Phase IIa ACR Responses 24 Wk 80 70 65* 73 Rituximab (n=40) 60 50 43 RTX+MTX (n=40) 40 30 20 33 15 23 10 0 ACR20 ACR50 ACR70 *P=0.025, P=0.001, P=0.003, P=0.059, P=0.005, P=0.048 P values using Fisher s Exact test, comparing MTX with each rituximab group Emery P et al. Arthritis Rheum. 2003;48:S439. Szczepanski L et al. Arthritis Rheum. 2003;48:S121.

With Rituximab, the pattern holds BUT here the response is less impressive

Patients (%) Patients (%) DBRCT CHARISMA: ACR response rates at Week 16 of TCZ monotherapy and in combination with MTXonly examine 2 of the 8 arms (small number of pts/gp)) Monotherapy Combination 80 70 60 50 40 30 20 10 0 41 29 MTX ACR20 ACR50 ACR70 16 31 6 2 TCZ 2 mg/ kg 61 63 28 6 TCZ 4 mg/ kg ** ** 41 16 TCZ 8 mg/ kg 80 70 60 50 40 30 20 10 0 41 29 **p<0.05 ***p=0.001 vs MTX ACR20 ACR50 ACR70 ** 64 63 32 37 16 14 12 MTX TCZ 2 mg/kg + MTX ** TCZ 4 mg/kg + MTX 74 53 *** ** 37 TCZ 8 mg/kg + MTX ** ACR20, ACR50 and ACR70 response rates at week 16 in the groups of patients receiving methotrexate (MTX) plus placebo, those receiving tocilizumab (TCZ) monotherapy, and those receiving combination therapy with TCZ plus MTX Conclusion: response in short term in small number of pts Maini RN, et al. Arthritis Rheum 2006;54:2817 2829

The FUNCTION trial: DAS28 remission and CDAI remission at 24 weeks Patients (%) 50 44.8 40 38.7 TCZ 8 mg/kg + MTX (n=290) TCZ 8 mg/kg (n=292) 30 20 24.5 20.5 10 0 DAS28-ESR <2.6 (primary endpoint) CDAI remission Conclusion: longer study and no differences Burmester G, et al. Oral presentation #OP0041. Thursday 13 June Hall 4

TCZ Mono.(N=115) vs TCZ+MTX(N=118) in MTX-IR: 24 wk, randomized, OL Trial- longer study, larger numbers Takeuchi T, Kaneky Y et al ARD 2013, 72(Suppl 3): 62(OPO040) P=0.04 But no differences in CDAI,SDAI Remission Also no differences in ACR70,HAQ-DI,EQ-5D Conclusion: Altho DAS28 Remission favors TCZ/MTX, But 7 other measures not different BUT OL

With Tocilizumab, the pattern is broken MTX adds only a little if at all

Why would this be? One reason could be immunogenicity. To examine this we can look at: SLR and meta-analysis of anti-drug antibodies against TNFi in RA and other rheumatic diseases Thomas SS Furst DE, Biodrugs.2015.27:241-258

Thomas SS Furst DE, Biodrugs.2015.27:241-258

ADAB Positivity by Medication

Thomas SS Furst DE, Biodrugs.2015.27:241-258

% Anti-Drug Anti-bodies by TNFi 0.35 0.3 0.3 % ADAB+ 0.25 0.23 0.2 0.15 0.1 0.05 0 0.06 0.04 0.02 IFX ADAB CZP GOL ETAN Thomas SS Furst DE, Biodrugs.2015.27:241-258

Anti-Drug Antibody positivity by Disease Disease RR 95%CI #Articles ELISA RIA Other RA 0.14 0.09-0.19 34 17 10 7 Inflamm.Bowel Disease 0.25 0.16-0.34 19 13 4 2 SpA 0.07 0.02-0.13 9 4 5 0 Thomas SS Furst DE, Biodrugs.2015.27:241-258

Effect of Immunosuppression on Anti- Drug Antibody positivity by Disease Disease RR 95%CI #Articles ELISA RIA Other RA 0.78 0.68-0.90 16 11 4 1 Inflamm.Bowel Disease 0.63 0.55-0.73 14 12 2 0 SpA 0.32 0.16-0.55 6 2 3 1 Thomas SS Furst DE, Biodrugs.2015.27:241-258

Effect of ADAB+ on Response

Thomas SS Furst DE, Biodrugs.2015.27:241-258

Effect of Anti-Drug Antibody positivity on Response by Disease Disease RR 95%CI #Articles RA 0.50 0.36-0.69 10 Inflamm.Bowel Disease 0.52 0.25-1.06 5 SpA 0.45 0.25-0.80 4

Effect of ADAB+ on Response by Medication Drug RR 95%CI # Articles Infliximab 0.46 0.30-0.69 8 Adalimumab 0.35 0.20-0.58 Golimumab 0.71 0.41-1.25 2 Certolizumab 1.14 -- 1 Etanercept 0.75 0.24-2.33 3 Thomas SS Furst DE, Biodrugs.2015.27:241-258

Random effect analysis on ADAB% by medication

Mixed effect model on ADAB% with individual variable as fixed effect Variable Name estimate p value age 0.00 0.35 gender 0.00 0.65 Disease Duration 0.02 0.002 Assay 0.14 0.003 MTX% 0.00 0.06 Other IS% 0.00 0.60 Prednisone% 0.00 0.58 Baseline_RA -0.06 0.26 Baseline_IBD 0.00 0.65 By Univariate analysis, ADAB% is significantly affected by Disease duration (p=0.002) and assay (0.003). For instance, every unit increase of disease duration (week or month?) will increase ADAB+ by 2 percent; RIA methods would measure 14% more ADAB+ than ELISA methods on average. The effect of MTX% to ADAB% is marginally significant (p=0.06), but the effect is very small (nearly zero). Thomas SS Furst DE, Biodrugs.2015.27:241-258

Immunogenicity of Rituximab in RA: an overview Mok CC. Drug Res Devel Ther 2014. 8:87-100 N=8 trials N=3361 No relationship to: RTX dose (500 vs 1000 mg) Efficacy Safety May be found at only 1 visit high Conclusion: may develop immunogenicity as much as TNFi No comment regarding method to detect ADA nor MTX etc

Immunogenicity of Abatacept in RA Kremer JM, et al. Ann Int Med, 2006. 144: 865-76; Genovese MC et al. NEJM, 2005. 353:1114-23 Kremer: N=657 RA Genovese: N=258 RA ADAB % Note: No comment with respect to efficacy or safety but numbers very small (N=9) Conclusion: very low immunogenicity; no details regarding bkgrnd med( eg MTX)

Immunogenicity of Tocilizumab in RA: in pts with AEs Stubenauch K, et al. ClinTher 2010:32:1577-1609 5 core trials N=2816 samples 10 of 11 tests positive by ELISA but only one + on repeat testing using more specific tests (surface plasmin resonance) Conclusion: very low immunogenicity. No idea of background meds

IFX Biosimilar Immunogenicity vs IFX reference compound: effect on safety Smolen JS, Choe J-Y et al. ARD EULAR 2016. abd FRI0162 DB RCT of IFX vs SB2(biosimilar) At wk 54, 94 IFX started SB2, 101 IFX continued IFX; 201 SB2 continued SB2 TEAE: IFX/SB2: 36.2%; IFX/IFX: 35.6%; SB2/SB2: 40.3% Efficacy remained: sustained and comparable % 16 12 8 4 New anti-drug anti-bodies 14.6 14.9 14.1 Conclusion: biosimilar IFX and SB2 were equally effective, safe and immunogenic 0 IFX/SB2 IFX/IFX SB2/SB2

Factors that might affect inconsistencies Immunogenicity Assays used to measure immunogenicity Outcome measures Patient Demographics Disease activity Previous Drug Usage and concomitant drug usage Placebo effects Pharmacokinetics( careful here)

Remission Rates Using Different Definitions Across 21 NA and European Countries Sokka T et al. A&R 2007 8.8 ACR Remission 20.2 DAS28 14.8 CDAI 13.2 CLIN28 5 10 15 20 25 30 Remission Rates(%)

Factors that mite affect inconsistencies Immunogenicity Assays used to measure immunogenicity Outcome measures Patient Demographics Disease activity Previous Drug Usage and concomitant drug usage Placebo effects Pharmacokinetics( careful here)

Predictors of sustained DMARD-free remission with routine DMARD use Sustained DMARD-free remission achieved 15 % of patients in Leiden EAC & 9.4% in ERAS Leiden Early Arthritis Clinic (EAC) n=454 British Early Rheumatoid Arthritis Study (ERAS) n=895 Thanx to Vivien Bykerk Van der Woude et al. Arth Rheum 2009

% Patients OPTIMA: Predictors of sustained Biologic-Free Disease Emery et al EULAR 2011 Better functional Status (lower HAQ) at Baseline Predicts Biologic-Free Disease Control, Weeks 52-78 DAS28<2.6 +HAQ<0.5 +ΔmTSS<0. 5 OR 95% CI P value Baseline HAQ 0.42 0.21, 0.83 0.01 SDAI 3.3 +HAQ<0.5 +ΔmTSS<0. 5 Weeks 52-78 Baseline HAQ 0.37 0.17, 0.18 0.009

Radiographic progression Etanercept + MTX Disease Activity and Radiographic Progression 8 6 MTX 8 6 ETN 8 6 MTX + ETN 4 4 4 2 2 2 0 0 0-2 -4 CRP normal CRP=5 15 CRP>15-2 -4 CRP normal CRP=5 15 CRP>15-2 -4 CRP normal CRP=5 15 CRP>15 The same pattern of response was noted with ta- DAS In some patients, treatment with anti-tnfs Halts radiographic progression even in the absence of clinical response (uncoupling) ETN + MTX uncouples the relationship that exists between disease activity and radiographic progression in RA patients Landewe R, et al. ACR, San Diego 2005, #867

Remission frequencies(das28 Remission for at least 3 months) in % of pts. Einarsson et al. THU0252, EULAR 2011

Concomitant Therapy at Study Entry Patients with Concomitant DMARD Information n=872 242 (28%) 0 DMARDs 32 (4%) 3 DMARDs 481 (55%) 1 DMARD 117 (13%) 2 DMARDs Genovese M, et al. N Engl J Med 2005;353:1114.

Effect in RA over 24 wks: a metaanalysis Azais J, Barnetche T et al. EULAR 2015. Abs SAT 0153 22 RCTs- 30 6 IFX;5 ETA;4 ADA; 25 3 CZP; 4 20 GOL 13 RCTs 15 used ACR 10 20; 14 RCTs used 5 ACR50 0 35 24.7 Percent 10.7 31.9 P<0.001 23.3 ACR 20 ACR 50 IV SQ

ATTRACT ACR20 Response Rate (%) 100 80 60 40 20 0 Trough Serum Levels of Infliximab and Clinical Improvement < 0.1 0.1-1 > 1-10 > 10 Serum Infliximab Concentration (mcg/ml) 3 mg/kg q 8 wks 3 mg/kg q 4 wks 10 mg/kg q 8 wks 4 mg/kg q 4 wks

Lack of response to Adalimumab correlates with anti-ada Ab and lower trough levels(higher clearance) Wang SL, Hauensteain S et al A&R, 2012, 64(Suppl): s819(abs1931 ) 100 ADA- treated pts Antibody and ADA concentrations used validated techniques Among 100 normals, cutoff: 0.55 U/ml( mean+3sd) Conclusion: anti-drug antibodies affect pharmacokinetics

Outline The clinical effect(s) of MTX on Biologics Possible explanations for these effects.