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

Transcription

1 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

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

3 Why does it matter whether we use MTX with biologics or use biologics as monotherapy? your company name. All rights reserved. Title of your presentation

4 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: 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): ; 2 Salt et al., Orthop Nurs ; 29(4): ; 3 Benner et al., Am J Health Syst Pharm. 2009;66(16):1471 7; 4 Shi et al., Expert Rev Pharmacoecon Outcomes Res Apr;7(2): ; 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 August ; 47(8): ; 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):

5 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:

6 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(?)

7 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

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

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

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

11 DAS Score TEMPO Trial only examining 2 arms-etan vs Etan+MTX Etanercept (n=223) MTX + Etanercept (n=231) * Low disease activity DAS<=2.4 * Weeks Analysis using LOCF. Data on file, Wyeth. *P<0.01 combination vs MTX or etanercept.

12 PREMIER Trial: ACR Responses at Week 52 MTX Adalimumab MTX + adalimumab 100 % of patients * 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, Presentation L5.

13 PREMIER Study Change in Total Sharp Score Adalimumab + MTX Adalimumab MTX ** 2.1 * ** 5.5 ** 3 * * 1.9 * p<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone ** p<0.001 for adalimumab vs MTX alone

14 PREMIER Study Clinical Remission by DAS28<2.6(low disease activity) * 43 * 49 Week 52 Week 104 % Patients Adalimumab + MTX Adalimumab MTX *p<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone

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

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

17 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 then 6 months open-label abatacept + MTX TREATMENT MRI was performed at Months 0, 6, 12, 18, and *Randomization stratified by corticosteroid use at baseline Thanx to Vivien Bykerk Months Emery P. et al. ARD

18 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% Visit Day Error bars represent 95% CI

19 Proportion of Patients (%) Proportion of Patients with Boolean Remission over Time (>6 Months Disease Duration) Withdrawal period 8.2% 4.4% 2.6% Visit Day Error bars represent 95% CI

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

21 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

22 Phase 2a-Baseline Disease Characteristics Previous DMARDs (mean) Disease duration (yrs) Rituximab (n=40) Rituximab + MTX (n=40) SJC (mean) TJC (mean) RF (median IU/mL) CRP (mean mg/dl) ESR (mean mm/h) DAS Emery P et al. Arthritis Rheum. 2003;48:S439. Szczepanski L et al. Arthritis Rheum. 2003;48:S121..

23 Phase IIa ACR Responses 24 Wk * 73 Rituximab (n=40) RTX+MTX (n=40) 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.

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

25 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 MTX ACR20 ACR50 ACR TCZ 2 mg/ kg TCZ 4 mg/ kg ** ** TCZ 8 mg/ kg **p<0.05 ***p=0.001 vs MTX ACR20 ACR50 ACR70 ** MTX TCZ 2 mg/kg + MTX ** TCZ 4 mg/kg + MTX *** ** 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:

26 The FUNCTION trial: DAS28 remission and CDAI remission at 24 weeks Patients (%) TCZ 8 mg/kg + MTX (n=290) TCZ 8 mg/kg (n=292) 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

27 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

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

29 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 :

30 Thomas SS Furst DE, Biodrugs :

31 ADAB Positivity by Medication

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35 Thomas SS Furst DE, Biodrugs :

36 % Anti-Drug Anti-bodies by TNFi % ADAB IFX ADAB CZP GOL ETAN Thomas SS Furst DE, Biodrugs :

37 Anti-Drug Antibody positivity by Disease Disease RR 95%CI #Articles ELISA RIA Other RA Inflamm.Bowel Disease SpA Thomas SS Furst DE, Biodrugs :

38 Effect of Immunosuppression on Anti- Drug Antibody positivity by Disease Disease RR 95%CI #Articles ELISA RIA Other RA Inflamm.Bowel Disease SpA Thomas SS Furst DE, Biodrugs :

39 Effect of ADAB+ on Response

40 Thomas SS Furst DE, Biodrugs :

41 Effect of Anti-Drug Antibody positivity on Response by Disease Disease RR 95%CI #Articles RA Inflamm.Bowel Disease SpA

42 Effect of ADAB+ on Response by Medication Drug RR 95%CI # Articles Infliximab Adalimumab Golimumab Certolizumab Etanercept Thomas SS Furst DE, Biodrugs :

43 Random effect analysis on ADAB% by medication

44 Mixed effect model on ADAB% with individual variable as fixed effect Variable Name estimate p value age gender Disease Duration Assay MTX% Other IS% Prednisone% Baseline_RA Baseline_IBD 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 :

45 Immunogenicity of Rituximab in RA: an overview Mok CC. Drug Res Devel Ther : 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

46 Immunogenicity of Abatacept in RA Kremer JM, et al. Ann Int Med, : ; Genovese MC et al. NEJM, : 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)

47 Immunogenicity of Tocilizumab in RA: in pts with AEs Stubenauch K, et al. ClinTher 2010:32: 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

48 IFX Biosimilar Immunogenicity vs IFX reference compound: effect on safety Smolen JS, Choe J-Y et al. ARD EULAR 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 % New anti-drug anti-bodies Conclusion: biosimilar IFX and SB2 were equally effective, safe and immunogenic 0 IFX/SB2 IFX/IFX SB2/SB2

49 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)

50 Remission Rates Using Different Definitions Across 21 NA and European Countries Sokka T et al. A&R ACR Remission 20.2 DAS CDAI 13.2 CLIN Remission Rates(%)

51 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)

52 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

53 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)

54 % 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 DAS28<2.6 +HAQ<0.5 +ΔmTSS<0. 5 OR 95% CI P value Baseline HAQ , SDAI 3.3 +HAQ<0.5 +ΔmTSS<0. 5 Weeks Baseline HAQ ,

55 Radiographic progression Etanercept + MTX Disease Activity and Radiographic Progression 8 6 MTX 8 6 ETN 8 6 MTX + ETN CRP normal CRP=5 15 CRP> CRP normal CRP=5 15 CRP> 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

56 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)

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

58 Concomitant Therapy at Study Entry Patients with Concomitant DMARD Information n= (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.

59 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)

60 Effect in RA over 24 wks: a metaanalysis Azais J, Barnetche T et al. EULAR Abs SAT RCTs IFX;5 ETA;4 ADA; 25 3 CZP; 4 20 GOL 13 RCTs 15 used ACR 10 20; 14 RCTs used 5 ACR Percent P< ACR 20 ACR 50 IV SQ

61 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

62 ATTRACT ACR20 Response Rate (%) Trough Serum Levels of Infliximab and Clinical Improvement < > 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

63 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

64 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)

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