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• Adherence Estimated 50-80% in RA patient population1,10
• Discrepancies in reported rates due to different approaches to measuring adherence2, 4
Patients at- risk for low treatment adherence
1Van den Bemt et al., Expert Rev. Clin. Immunol. 2012; 8(4):337–351; 2 Salt et al., Orthop Nurs. 2010 ; 29(4): 260–275; 3Benner et
al., Am J Health Syst Pharm. 2009;66(16):1471–7; 4Shi et al., Expert Rev Pharmacoecon Outcomes Res. 2007 Apr;7(2):187-202; 5Barlow et al., Am J Pharm Benefi ts. 2012;4(Special Issue):SP49-SP56) ; 6Klippel JH, Am J of Pharm Benefits, 2012; 7Zolnierek et
al., Med Care. 2009 August ; 47(8): 826–834.; 8Elliott et al., Dis Manage Health Outcomes 2008; 16 (1): 13-29; 9Martin et al., J
DBRCT CHARISMA: ACR response rates at Week 16 of TCZ monotherapy and in combination with MTX-only examine 2 of the 8 arms (small number of pts/gp))
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
Maini RN, et al. Arthritis Rheum 2006;54:2817‒2829
Pa
tien
ts (
%)
Monotherapy Combination
41
64 63
74
2932
37
53
16 14 12
37
0
10
20
30
40
50
60
70
80
MTX TCZ 2mg/kg +
MTX
TCZ 4mg/kg +
MTX
TCZ 8mg/kg +
MTX
ACR20 ACR50 ACR70
**
**
***
****** **
Pa
tien
ts (
%)
**p<0.05
***p=0.001 vs MTX
Conclusion: response in short term in small number of pts
The FUNCTION trial:DAS28 remission and CDAI remission at 24 weeks
44.8
24.5
38.7
20.5
0
10
20
30
40
50
DAS28-ESR <2.6 (primary endpoint) CDAI remission
Pa
tie
nts
(%
)
TCZ 8 mg/kg + MTX (n=290)
TCZ 8 mg/kg (n=292)
Burmester G, et al. Oral presentation #OP0041. Thursday 13 June Hall 4
Conclusion: longer study and no differences
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)
But no differences in CDAI,SDAI Remission
Also no differences in ACR70,HAQ-DI,EQ-5D
P=0.04
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
0.3
0.23
0.060.04
0.02
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
IFX ADAB CZP GOL ETAN
% ADAB+
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
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
Mixed effect model on ADAB% with individual variable as fixed
effect
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
overviewMok CC. Drug Res Devel Ther 2014. 8:87-100
high
N=8 trials
N=3361
No relationship to:
RTX dose (500 vs
1000 mg)
Efficacy
Safety
May be found at only
1 visit
Conclusion: may develop immunogenicity as much as TNFi
No comment regarding method to detect ADA nor MTX etc
Immunogenicity of Abatacept in RAKremer JM, et al. Ann Int Med, 2006. 144: 865-76; Genovese MC et al. NEJM, 2005.
353:1114-23
ADAB %
Note: No comment with respect to efficacy or
safety but numbers very small (N=9)
Kremer: N=657 RA
Genovese: N=258 RA
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 safetySmolen JS, Choe J-Y et al. ARD EULAR 2016. abd FRI0162
• DB RCT of IFX vsSB2(biosimilar)
• At wk 54, 94 IFX started SB2, 101 IFX continued IFX; 201 SB2 continued SB2