Poster - ispor

Comparative Efficacy of Novel Disease-Modifying Antirheumatic
Drugs as Monotherapy and in Combination With Methotrexate in
Rheumatoid Arthritis Patients With an Inadequate Response to Traditional
Disease-Modifying Antirheumatic Drugs: A Network Meta-Analysis
PMS5
Felicity Buckley,1 Jennie H. Best,2 Fred Dejonckheere,3 Axel Finckh,4 Tom W. J. Huizinga,5 Jeroen P. Jansen6
Mapi, Boston, MA, United States; 2Genentech, South San Francisco, CA, United States; 3F. Hoffmann-La Roche Ltd., Basel, Switzerland;
4
University of Geneva, Geneva, Switzerland; 5Leiden University, Leiden, Netherlands; 6Formerly of MAPI Consultancy, Boston, MA, United States
1
ACR20/50/70 Responses at 24 Weeks
ABSTRACT
•aTNF + MTX, TOFA + MTX, ABT intravenously (IV)/SC + MTX, and TCZ IV/SC + MTX demonstrated comparable ACR responses, whereas anakinra (ANA) +
OBJECTIVES: To compare ACR responses between novel DMARDs, either as monotherapy or in combination with methotrexate (MTX), including
subcutaneous (SC) abatacept and SC tocilizumab (TCZ), in RA patients with an inadequate response to conventional DMARDs (DMARD-IR).
METHODS: A systematic literature review identified 30 randomized clinical trials (RCTs) that evaluated abatacept (intravenous [IV] and SC), anakinra,
adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, tofacitinib, and TCZ (IV and SC). Reported treatment effects—ACR responses at
24 weeks—were synthesized by means of Bayesian network meta-analyses to compare the different treatments as monotherapy and combination
therapy. The effects of anti–tumor necrosis factor (aTNF) therapy were assumed to be interchangeable. aTNF data were pooled.
MTX was less efficacious (Figure 2)
Figure 2. Treatment effects (odds ratio + 95% CrI) for combination therapies relative to placebo (random effects network meta-analysis).
ACR20
RESULTS: The combination therapies aTNFs + MTX, tofacitinib + MTX, abatacept IV/SC + MTX, and TCZ IV/SC + MTX demonstrated comparable ACR
responses while anakinra + MTX was less efficacious. Among biologic monotherapies, greater ACR20/50/70 responses were observed with TCZ IV than
with aTNFs and tofacitinib. When comparing biologics + MTX with biologic monotherapies, ACR20, ACR50, and ACR70 responses with TCZ + MTX were
similar to TCZ as monotherapy (OR=1.04, 95% CI, 0.39-2.80; OR=1.28, 95% CI, 0.46-3.51; OR=0.97, 95% CI, 0.38-2.49, respectively). Greater
ACR20/50/70 responses were observed with aTNF + MTX than with aTNF monotherapy (OR=2.22; 95% CI, 0.46-10.83, probability better=84%;
OR=3.12, 95% CI, 0.60-16.32, probability better=92%; OR=1.39, 95% CI, 0.26-6.78, probability better=68%, respectively). Sensitivity analyses showed
conflicting results for the indirect comparison of tofacitinib + MTX versus tofacitinib.
ACR50
ACR70
ABT IV + MTX
ABT SC + MTX
CONCLUSIONS: Results suggest that most of the novel DMARDs, in combination with MTX, have similar levels of efficacy in DMARD-IR patients. As
monotherapy, TCZ is likely to have a greater response than aTNFs and tofacitinib. TCZ monotherapy also shows comparable efficacy compared with
TCZ + MTX, whereas aTNFs in combination with MTX showed greater ACR responses compared with aTNF monotherapy at 24 weeks.
ANA + MTX
INTRODUCTION
•The goals of therapy in rheumatoid arthritis (RA) are improvement in quality of life, control of symptoms, prevention of structural damage, and ultimately
aTNF + MTX
clinical remission. Abrogation of inflammation is the most important way to achieve these goals1
•Patients who are intolerant of or who show inadequate response (IR) to traditional disease-modifying antirheumatic drugs (DMARDs) are often treated with a
biologic agent in combination with traditional DMARDs
•However, one-third of RA patients receiving biologics receive them as monotherapy2-8
•A number of (network) meta-analyses indirectly compare the efficacy of biologics for RA. However, comparisons of the efficacy of biologics as monotherapy
TOFA + MTX
versus combination therapy with DMARDs are rare, and none include all currently approved biologics and tofacitinib (TOFA) (together referred to in this poster
as “novel DMARDs”)9-16
TCZ IV + MTX
OBJECTIVE
•To compare American College of Rheumatology (ACR) responses to novel DMARDs, as monotherapy or in combination with methotrexate (MTX) including
subcutaneous (SC) abatacept (ABT) and tocilizumab (TCZ), in RA patients with IR to traditional DMARDs (DMARD-IR)
TCZ SC + MTX
METHODS
0
Identification and Selection of Studies
5
10
15
20
OR vs Placebo + MTX
•MEDLINE® and EMBASE® databases were searched simultaneously for articles published in English, from January 1990 to April 2013, according to a
predefined search strategy
•Among biologic monotherapies, greater ACR20/50/70 responses were observed with TCZ than with aTNF or TOFA (Table 2)
Table 2. Treatment Effects for Monotherapies (random effects network meta-analysis)
Odds Ratio (95% CrI)
Analysis
•Bayesian network meta-analysis models were used17-19 to synthesize the results of the included studies and simultaneously obtain the effect estimates of
ACR20
ACR50
ACR70
aTNF vs placebo
6.52
(3.39, 12.80)
6.78
(3.18, 15.35)
12.00
(3.91, 50.98)
TOFA vs placebo
4.75
(2.15, 10.18)
4.94
(1.21, 21.25)
3.78
(0.87, 19.25)
TCZ vs placebo
12.28
(3.73, 40.76)
16.26
(4.53, 62.01)
28.48
(5.92, 151.10)
TCZ vs aTNF
1.87
(0.67, 5.06)
2.41
(0.84, 6.89)
2.31
(0.85, 5.88)
TCZ vs TOFA
2.58
(0.64, 10.82)
3.34
(0.47, 23.35)
7.34
(0.83, 72.11)
TOFA vs aTNF
0.72
(0.26, 1.98)
0.73
(0.14, 3.82)
0.32
(0.04, 2.20)
the novel DMARDs in their usual dose, alone and combined with MTX, in terms of ACR20/50/70 response at 24 weeks compared with placebo
•Treatment effects were presented as relative response along with a 95% credible interval (95% CrI; reflecting the range of true estimates with 95% probability)
•Fixed and random effects models were compared regarding goodness-of-fit to the data. The random effects model was considered appropriate for synthesis
of the available evidence
•We assumed that the different anti–tumor necrosis factor (aTNF) agents have similar efficacy, as demonstrated previously.9,14,15 Given this and the limited data
identified for aTNF monotherapy in DMARD-IR patients, aTNF data were pooled and considered a treatment class
RESULTS
Studies
•30 studies that met the inclusion criteria for review, that were conducted in comparable patient populations, and that provided sufficient ACR information at
24 weeks were included in the analysis
•The evidence network of randomized controlled trials is provided in Figure 1
Figure 1. Evidence network.a
TOFA
+
MTX
1
aTNF
1
TCZ IV
1
TCZ IV
+
MTX
4
2
3
1
aTNF
+
MTX
1
12
3
PBO
1
ABT SC
+
MTX
•ACR20/50/70 responses observed with TCZ monotherapy were similar to those observed with TCZ + MTX (Table 3)
• Greater ACR20/50/70 responses were observed with aTNF + MTX than with aTNF monotherapy (Table 3)
•Sensitivity analyses showed conflicting results for TOFA monotherapy versus TOFA + MTX
1
ABT IV
+
MTX
Table 3. Monotherapies Relative to Combination Therapies (random effects network meta-analysis)
Odds Ratio (95% CrI)
PBO
+
MTX
2
ACR20
ACR50
ACR70
aTNF vs aTNF + MTX
0.45
(0.09, 2.17)
0.32
(0.06, 1.67)
0.72
(0.15, 3.86)
TOFA vs TOFA + MTX
0.45
(0.06, 2.99)
0.27
(0.03, 3.18)
0.13
(0.01, 1.90)
TCZ vs TCZ + MTX
0.96
(0.36, 2.60)
0.78
(0.29, 2.16)
1.03
(0.40, 2.64)
1
TOFA
30
OR, odds ratio.
•The relevance of each citation and subsequent full-text report was assessed according to predefined selection criteria
−− Population: Adult RA patients who responded inadequately or for whom treatment with traditional DMARDs failed, as defined in each trial
−− Intervention: Novel DMARDs, at their recommended dose, as monotherapy or in combination
−− Comparator: Any placebo or active intervention
−− Outcome: ACR20/50/70 response at 24 weeks
−− Study design: Randomized controlled trials
TCZ SC
+
MTX
25
ANA
+
MTX
ANA, anakinra; IV, intravenously; PBO, placebo.
a
Numbers refer to available direct comparisons of the 30 included studies.
Patient Population
•Despite some variation in patient characteristics across studies (eg, duration of disease), no systematic differences were observed across the different types of
comparisons (Table 1),20-49 indicating the feasibility of the indirect comparison
Interventions
Study
ABT IV 10 mg/kg Q4W+ MTX
Kremer 200320
Placebo + MTX
ABT IV 10 mg/kg Q4W + MTX
Kremer 2006
21
Placebo + MTX
ABT IV 10 mg/kg Q4W + MTX
Schiff 2008
(ATTEST)
22
IFX 3 mg/kg Q8W + MTX
Placebo + MTX
ABT SC 125 mg QW + MTX
Genovese 2011
(AQUIRE)
23
ABT IV 10 mg/kg Q4W + MTX
ABT SC 125 mg QW + MTX
Weinblatt 201324
(AMPLE)
ADA 40 mg Q2W+ MTX
ANA 100 mg QD + MTX
Cohen 2004
25
Placebo + MTX
van de Putte 2004
26
ADA 40 mg Q2W
Placebo
van Vollenhoven
201127
(AUGUST-2)
ADA 40 mg Q2W
Weinblatt 200328
(ARMADA)
ADA 40 mg Q2W + MTX
Keystone 200429
Placebo
Placebo + MTX
ADA 40 mg Q2W + MTX
Placebo + MTX
Fleischmann 200930
(FAST4WARD)
CTZ 400 mg Q4W
Keystone 2008
(RAPID 1)
CTZ 200 mg Q2W + MTX
Smolen 200932
(RAPID 2)
CTZ 200 mg Q2W + MTX
31
Placebo
Placebo + MTX
Placebo + MTX
CTZ 400 mg Q4W + MTX
Choy 2012
33
Placebo + MTX
Moreland 1999
34
Weinblatt 199935
ETN 25 mg BW
Placebo
ETN 25 mg BW + MTX
Placebo + MTX
GLB 50 mg Q4W + MTX
Kay 200836
Placebo + MTX
Keystone 200937
(GO-FORWARD)
GLB 50 mg Q4W + MTX
Maini 199938
(ATTRACT)
IFX 3 mg/kg Q8W + MTX
Westhovens 200639
(START)
IFX 3 mg/kg Q8W + MTX
Smolen 200840
(OPTION)
TCZ IV 8 mg/kg Q4W + MTX
Dougados 201341
(ACT-RAY)
TCZ IV 8 mg/kg Q4W + MTX
Kremer 201142
(LITHE)
TCZ IV 8 mg/kg Q4W + MTX
Burmester 201243
(SUMMACTA)
TCZ SC 162 mg QW
Gabay 201344
(ADACTA)
TCZ IV 8 mg/kg Q4W
Fleischmann
201245
(ORAL-Solo)
TOFA 5 mg BID
Fleischmann
201246
TOFA 5 mg BID
Placebo + MTX
Placebo + MTX
Placebo + MTX
Placebo + MTX
TCZ IV 8 mg/kg Q4W
Placebo + MTX
TCZ IV 8 mg/kg Q4W
ADA 40 mg
Placebo
Placebo
TOFA 5 mg or 10 mg BID + MTX
van Vollenhoven
201247
ADA 40 mg Q2W+ MTX
Placebo + MTX (followed by TOFA 5 mg)
Placebo + MTX (followed by TOFA 10 mg)
Kremer 2012
48
TOFA 5 mg + MTX
Placebo + MTX
TOFA 5 mg + MTX
van der Heijde
201349
Placebo + MTX (followed by TOFA 5 mg)
Placebo + MTX (followed by TOFA 10 mg)
Patients,
n
Age,
y
Female,
%
Disease
Duration, y
115
119
433
219
156
165
110
736
721
318
328
250
251
113
110
79
76
67
62
207
200
111
109
393
199
246
127
126
121
78
80
59
30
35
35
89
133
86
88
360
363
205
204
277
276
398
393
558
537
163
162
243
122
49
59
204
204
56
52
71
69
321
81
79
56
55
52
50
49
49
49
50
50
51
51
56
57
53
54
53
54
57
56
56
56
53
55
51
52
52
52
53
56
53
51
48
53
57a
52a
52a
52a
54
51
53
42
51
51
53
54
53
51
52
53
54
53
52
50
54
53
53
53
56
52
52
53
54
53
52
75
66
78
82
83
87
82
84
80
81
82
79
75
80
77
64
64
75
82
76
73
78
89
82
84
84
84
72
66
74
76
90
73
86
74
81
82
81
80
80
83
NR
NR
82
79
82
83
83
83
79
82
85
86
88
88
85
79
77
75
80
81
84
80
91
10
9
9
9
8
8
7
8
8
2
2
11
10
11
12
9
8
12
11
11
11
9
10
6
6
6
6
9
10
11
12
13
13
8
6
5a
7a
10
11
8
8
8
8
8
8
9
9
9
9
7
6
8
8
8
11
8
8
7
9
9
9
9
9
10
SJC
TJC
21.3 30.8
21.8 29.2
21.4 31.0
22.1 32.3
21.3 31.6
20.1 30.3
20.3 31.7
20.4 30.1
19.4 29.1
15.8 25.4
15.9 26.3
20.1 26.8
20.0 24.5
20.5 33.7
19.8 35.5
16.2 27.8
16.4 24.3
17.3 28.0
16.9 28.7
19.3 27.3
19.0 28.1
21.2 29.6
19.9 28.3
9.9a 12.4a
9.7a 13.0a
20.5 30.1
21.9 30.4
22.8 29.0
22.2 31.0
25.0 33.0
25.0 35.0
20.0 28.0
17.0 28.0
NR NR
NR NR
13.0a 26.0a
12.0a 21.0a
22.0 32.0
21.0 31.0
15.0 22.0
15.0 22.0
19.5 31.9
20.7 32.8
14.4 25.8
15.3 26.6
17.3 29.3
16.6 27.9
15.1 27.5
16.8 28.8
11.3 15.9
12.4 16.5
16.3 29.4
17.3 28.9
17.4 27.1
16.9 25.9
16.7 28.5
16.4 26.7
16.9 26.6
16.4 28.1
14.1 21.5
15.7 21.6
14.1 24.1
14 23.3
14.5 22.6
ESR,
mm/h
CRP,
mg/L
RF Positive,
%
NR
NR
NR
NR
49.4
47.0
47.8
NR
NR
NR
NR
41.5
42.9
55.8
56.1
41.7
39.3
NR
NR
NR
NR
30.9
35.6
43.5a
45.0a
43.7
40.8
24.4
25.9
35.0
39.0
25.0
36.0
NR
NR
NR
NR
49.0
49.0
NR
NR
51.2
49.7
39.9
39.6
46.4
46.5
NR
NR
50.5
45.5
53.1
50.9
47.4
46.2
48.6
48.5
52.7
42.9
NR
NR
50.1
47.8
54.4
29
32
33
28
31
27
33
26
27
16
15
27
26
52.6
57
16.6
16.5
21
31
18
18
11.6
11.3
16a
16a
14.2
13.5
11.9
13.1
47.0
41.0
22.0
26.0
21.0a
20.0a
10.0a
8.0a
39.0
40.0
16.0
12.0
26.0
24.0
NR
NR
23.0
22.0
NR
NR
26.0
25.0
22.9
17.8
24.5
23.5
14.9
17.5
20.3
11.6
18.0
18.9
15.5
12.2
15.3
90
90
82
79
87
77
85
84.8
85.9
76
77.4
76
78
80
82
NR
NR
NR
NR
82
90
100
100
80
83
78
78
74
79
79
79
84
90
NR
NR
81
81
84
77
83
81
83
71
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
77.5
74.5
66.8
68.2
71.4
60.8
83
83
75.2
79.7
75.3
ADA, adalimumab; ANA, anakinra; BID, twice a day; BW, body weight; CRP, C-reactive protein; CTZ, certolizumab; ESR, erythrocyte sedimentation rate; ETN, etanercept; GLB, golimumab; IFX, infliximab; IV, intravenously;
NR, not reported; QD, every day; QW, every week; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; RF, rheumatoid factor; SJC, swollen joint count; TJC, tender joint count.
a
Median value. All other values are means.
Presented at the ISPOR (International Society for Pharmacoeconomics and Outcomes Research) 19th Annual International Meeting;
May 31–June 4, 2014; Montreal, QC, Canada
•Probabilities of ACR20/50/70 response by treatment at 24 weeks (obtained with the network meta-analysis) are provided in Figure 3
Figure 3. ACR20/50/70 response (±95% CrI) at 24 weeks (random effects network meta-analysis).
ACR20
ACR50
100
Probability of Response, %
Table 1. Study and Patient Baseline Characteristics
ACR70
73.9
71.7
90
71.9
80
51.3
68.8
72.7
54.6
57.7
68.7
56.3
30.8
57.8
50.0
60
24.4
50
58.4
39.2
41.8
51.6
70
56.5
75.3
61.1
29.7
21.1
20.0
17.6
29.0
13.2
26.2
20.1
30.8
40
30
20
10
0
15.4
5.4
17.4
4.6
6.2
1.5
PBO
aTNF
TOFA
TCZ
PBO
+
MTX
ABT IV ABT SC
+
+
MTX
MTX
ANA
+
MTX
aTNF
+
MTX
TOFA TCZ IV TCZ SC
+
+
+
MTX
MTX
MTX
PBO, placebo.
DISCUSSION
•3 rituximab trials50-52 were not included in the analysis because, contrary to all other considered biologics, its label is restricted to aTNF-IR patients
•5 randomized controlled trials evaluating the efficacy of biologics were excluded from this analysis because they were not considered comparable with the
other studies
−− TEMPO: DMARD-IR, but the majority of this patient population was MTX naive (unlike all other included studies) and, as such, was excluded53
−− Combe 2006: Only sulfasalazine background therapy was used54
−− Genovese 2008, Weinblatt 2012, Yazici 2012: Background DMARD therapy was not limited to MTX. Any DMARD or, in some circumstances, multiple
DMARDs were permitted55-57
•The evidence base of this network meta-analysis consists of randomized controlled trials. However, randomization holds within trials and not across trials.
Although we did not observe systematic differences in patient characteristics across different types of direct comparisons, the risk for unmeasured
differences and, therefore, possible bias was always present in the indirect comparisons
•Adjustment for differences in placebo response across the aTNF trials resulted in similar treatment effects for the aTNFs (analysis not shown). This supports
our approach to consider the different aTNFs as a single class
•Because we pooled the aTNF results (with a random effects model), we believed that adjustment for differences in placebo response was not necessary to
obtain a valid indirect comparison with other classes of biologics
CONCLUSIONS
•Based on a network meta-analysis involving indirect comparison of trial findings, the following observations can be made for DMARD-IR RA patients
−− The efficacy of the SC formulations of abatacept and tocilizumab is comparable to that of their IV formulations
−− Tocilizumab + methotrexate has efficacy comparable with that of other novel DMARDs + methotrexate
−− Tocilizumab monotherapy is associated with a larger ACR response than is seen with aTNF or tofacitinib
−− aTNF monotherapy is likely to show a lower ACR response than aTNF + methotrexate
−− The response to tocilizumab monotherapy is similar to the response to tocilizumab + methotrexate
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This study was funded by Roche.
Support for third-party editorial assistance for this poster was provided by F. Hoffmann-La Roche Ltd.

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