Targeted therapies: rationale for earlier use in RA.

Report
ELAR congress, Alexandria 2013
Treat to Target, Role of Orencia
in Achieving the target.
Prof. Hassan El-Shahaly
Professor of Rheumatology and Rehabilitation
Suez Canal University
Rheumatoid Arthritis Challenges
• Complex, multifactorial pathogenesis
• Fluctuating clinical course; unpredictable
prognosis
• Characterized by:
– Progressive joint destruction
– Loss of physical function
– Poor quality of life
CLASSIFICATION CRITERIA FOR RA
ACR /EULAR classification criteria for RA
Rationale
1987 ACR
criteria
Current
trends in RA
Elaborated in
established RA
Recognize the
patients as soon
as possible
Considered as
classification
criteria
Treat the patients
as soon as the
diagnosis is made
Lack of sensitivity
in early disease
investigate new
drugs/strategies
at an early stage
of the disease
Early treatment reduces disability
5 years later
Degree of Disability*
after 5 Years
3.0
2.4
2.5
2.3
2.0
1.5
1.0
0.9
0.5
0.0
<6 months
(n = 60)
6-12 months
(n = 47)
* Odds ratio of HAQ ≥1
according to: Wiles NJ, et al. Arthritis Rheum 2001; 44: 1033 - 42
>12 months
(n = 76)
5
ACR /EULAR classification criteria for RA
Objectives
To recognise the
disease at an early
stage.
To develop a set of • Identify the subset at
high risk of chronicity &
rules to be applied in
erosion
newly patients with • Be used as a basis for
undifferentiated
initiating disease
synovitis
modifying therapy
Aletaha D, et al. Ann Rheum Dis 2010 ; 69:1580-8 ; Arthritis Rheum 2010;62:2569-81
2009 ACR / EULAR for the classification
& diagnosis of rheumatoïd arthritis
≥1 1 swollen joint
Typical RA
erosion
on X-ray*
Not best explained by
another disease
Yes
New criteria
for RA
Fulfilled?
RA
yes
No
Joint involvement(0-5)
1 large joint
0
2-10 large joints
1
1-3 small joints
(large joints not counted)
2
4-10 small joints
(large joints not counted)
> 10 joints
(at Least one small joint)
3
5
Sérology (0-3)
RF négative ET ACPA négative
0
RF low level (1 à 3 x ULN ) OR
ACPA low level (1 à 3 x ULN)
2
RF high level(> 3 x ULN) OR
ACPA high level (> 3 x ULN)
3
Symptoms duration (0-1)
< 6 weeks
0
≥ 6 weeks
1
Acute Phase reactants (0-1)
No RA
Aletaha D, et al. Ann Rheum Dis 2010 ; 69:1580-8 ; Arthritis Rheum 2010;62:2569-81
* van der Heidje D et al Ann Rheum Dis 2013 Feb 7
CRP normal AND ESR normal
0
CRP abnormal OR ESR abnormal
1
RA: score ≥ 6
MANAGEMENT
Management of patients with RA
Therapeutic objectives
Sustained
Remission
Prevention /
arrest of
joint damage
Remission
Prevention /
reversal of
disability
Prevention
of systemic
co-morbidities:
CV diseases,
osteoporosis….
EULAR RECOMMENDATIONS FOR THE MANAGEMENT OF RA WITH
SYNTHETIC AND BIOLOGICAL DMARDs
RECOMMENDATION 1: Therapy with synthetic DMARDS
should be started as soon as the diagnosis of RA is made
RECOMMENDATION 2: Treatment should be aimed at reaching a
target of remission or low disease activity as soon as possible in
every patient; as long as the target has not been reached,
adjustment of the treatment should be done by frequent and strict
monitoring.
RECOMMENDATION 3: Methotrexate should be part of the
first treatment strategy in patients with active RA.
Combe et al. Ann. Rheum. Dis. 2007; 66: 34-45
Smolen J. et al.Ann Rheum Dis 2010;-69:964-75
Turning recommendations into optimal
treatment strategies
Tight control
using
composite
measures
Consider
poor
prognostic
factors
Early
institution
of DMARDs
Early
referral
Predetermined
treatment
targets
Starting
biologic
agents
Short & long -term
goals
Remission or
LDAS
as soon
as possible
Treat to
target
Rheumatologists
are primary
carers
Shared decision
between
doctor
and
patient
Maximising
HRQOL
for the
long-term
12
Newer RA Treatment Strategies
• Intensive
management
• Treat to Target
• Combination
DMARD strategies
• Remission
induction
Aggressive Strategies
• Monotherapy with frequent switches
– Sawtooth (Fries)
• Classical step-up (pyramid)
– MTX+SSZ+HO-Chl (O’Dell)
– MTX+Leflunomide
– Others
• Step-down
– COBRA
Combination Step-Down Therapy:
COBRA Trial
1.6
Step-down
(MTX + SSZ + Pred)
Pooled Index
1.2
SSZ alone
0.8
Prednisolone
60 mg/day
0.4
Step-down
therapy
Prednisolone 7.5 mg/day
MTX 7.5 mg/week
SSZ 2000 mg/day
SSZ
0.0
0
Boers M et al. Lancet. 1997;350:309-318.
16
Weeks
28
Tight control and predefined strategy


Systematic literature review: from 1995 to 2008
Meta-analysis of 6 studies
Tight control
without predefined protocol
Van Tuyl, 2008
Fransen, 2003
Tight control
with predefined protocol
Fransen, 2005
Tight control
without predefined protocol
0,25 (IC95 : 0,03-0,46)
Grigor, 2002
Goekoop, 2009
Verstappen, 2007
Tight control
with predefined protocol
0,97 (IC95 : 0,64-1,3)
-0,4
-0,2
0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
1,8
2,0
Mean difference in DAS28 change
Randomised effect model
Schipper LG et al Rheumatology 2010;49:2154-64
Traditional DMARDs Are Effective
but Do Not Maintain Long-term Response
Cumulative Retention Rates
Retention Rates of DMARDs
100
Legend:
Methotrexate
Sulfasalazine
Chloroquine
Parenteral Gold
Oral Gold
Penicillamine
Azathioprine
Cyclosporine
Combination
90
80
70
60
50
40
30
20
10
0
0
12
24
36
48
60
72
Time (Months)
84
96
108
120
EULAR RECOMMENDATIONS
Taking steps to improve clinical outcome
Main
target
Adapt therapy
according to
disease activity
Active RA
Main longterm target
Adapt therapy if
state is lost
Sustained
remission
Remission
Use a composite
measure of disease
activity every
1–3 months
Assess disease
activity about every
3–4 months
Sustained low
disease
activity
Low disease
activity
Adapt therapy
according to disease
activity
Smolen J, et al. Ann Rheum Dis 2010;69:631–637.
Adapt therapy if
state is lost
Alternative
target
Alternative
long-term
target
18
Phase I of EULAR RA Management
Algorithm
*The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low
disease activity
19
Smolen JS, et al. Ann Rheum Dis 2010;69:964–75
Phase II of EULAR RA Management
Algorithm
*The treatment target is clinical remission or, if remission is unlikely to be achieved, at
least low disease activity
20
Smolen JS, et al. Ann Rheum Dis 2010;69:964–75
Phase III of EULAR RA Management
Algorithm
*The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low
disease activity
21
Smolen JS, et al. Ann Rheum Dis 2010;69:964–75
Different Biologics for RA
Tracey D, et al. Pharmacology & Therapeutics 117 (2008) 244–279.
23
Down-regulation of T cell
Upstream T-cell Modulation
with ORENCIA® (abatacept)
APC
APC
MHC
CTLA-4
T-cell receptor
CD28
CD28
ORENCIA
T cell
T cell
CTLA-4 binding: down-regulation
of T cell
ORENCIA inhibits T-cell activation by binding to CD80 and
CD86. The relationship of these biologic response
markers to the mechanisms by which ORENCIA exerts its
effects in rheumatoid arthritis (RA) is unknown.
Adapted from Kremer JM. J Clin Rheumatol. 2005;11:S55–S62.
Efficacy of initial MTX vs MTX + biological agent
in Early RA
Forest plot of risk ratios for clinical remission
•RR 1.74; 95% CI (1.54, 1.98)
•no heterogeneity I2 0%; p = 0.496
Kuriya B et al. Ann Rheum Dis online first april 26, 2010
Efficacy of initial MTX vs MTX + biological agent
in Early RA
Forest plot of risk ratios for radiographic remission
•RR 1.30; 95% CI (1.01, 1.68)
•Significant heterogeneity I2 0%; p = 0.001
Kuriya B et al. Ann Rheum Dis online first april 26, 2010
CLINICAL TRIALS FOR ABATACEPT
AGREE (MTX-naïve)
AGREE study design: patients
with early RA and poor
prognostic factors*
Double-blind period1
Inclusion criteria
•
•
•
•
Early RA (≤2 years)
MTX-naïve
RF+ and/or anti-CCP2+
≥1 erosion
Screening
Abatacept + MTX**
Open-label period2
232
(n=256)
Abatacept + MTX
Placebo + MTX**
433
227
(n=253)
Day 1
1:1 Randomisation
Year 1
Co-primary endpoints
• DAS28 (CRP) <2.6
• Total Genant-modified Sharp score
Year 2
• DAS28 (CRP)
• X-Ray progression
• HAQ-DI
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.
**MTX initiated at 7.5 mg/week at study entry, then increased to 15 mg at Week 4 and up to 20 mg at Week 8 until study completion;
Dose reduction to 15 mg/week was permitted due to toxicity or intolerability; AGREE=Abatacept study to Gauge Remission and joint damage
progression in MTX naïve patients with Early Erosive RA; CCP2+=cyclic citrullinated peptide positive.
1. Westhovens R, et al. Ann Rheum Dis 2009;68:1870–1877; 2. Bathon J et al. Ann Rheum Dis. 2011;70:1949–1956.
27
AGREE (MTX-naïve)
Significantly greater proportion of
abatacept-treated patients achieved
DAS28 remission at Year 1*
Proportion of patients achieving
DAS28 remission (%)
100
90
80
Abatacept + MTX (n=256)
Placebo + MTX (n=253)
70
60
p<0.001
50
40
30
20
41.4%
23.3%
10
0
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.
Data are based on an ITT population, with patients who discontinued considered non-responders.
Westhovens R, et al. Ann Rheum Dis 2009;68:1870–1877.
28
AGREE (MTX-naïve)
Abatacept provides sustained efficacy
through 2 years in patients with early RA
(≤2 years)*
Early
referral
Proportion of patients achieving
DAS28-CRP remission (%, 95% CI)
Year 1
100
Abatacept added to MTX alone group
90
80
70
60
55.2%
46.1%
50
44.5%
40
30
26.9%
20
10
0
0 29
85
Abatacept plus MTX (n=232)
141
197
253 309 365
Visit day
MTX alone (n=227)
449
553
617
729
MTX alone switched to abatacept plus MTX (n=227)
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.
Data are based on a modified ITT population, including patients who entered the open-label period and patients who discontinued considered nonresponders.
Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956.
29
AGREE (MTX-naïve)
Adding abatacept to MTX slows the
rate of radiographic progression*
2.0
Mean change from
baseline in Sharp total score
Abatacept added to MTX alone group
1.48
1.75
∆=0.25 Yr 1–2
1.0
0.84
0.65
p<0.001 for ∆Yr 1–2 vs ∆ BL–Yr 1
Patients with X-rays at all timepoints (n=207)
∆=0.66 BL-Yr 1
0.0
Baseline
∆=0.18 Yr 1–2
Year 1
Year 2
Visit day
Abatacept plus MTX
MTX alone
MTX alone switched to abatacept plus MTX
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.
Data are as-observed for patients treated in the open-label period.
Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956.
30
AGREE (MTX-naïve)
Abatacept leads to sustained HAQ normalisation
(≤0.5) over 2 years in half of treated patients*
Proportion of patients achieving
HAQ normalisation (%)
100
Abatacept + MTX (n=232)
90
MTX alone (n=227)
80
MTX alone switched to abatacept + MTX (n=227)
70
60
50
40
30
20
10
0
Year 1
Year 2
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.
Data are as-observed for all patients who entered the open-label extension.
Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956.
31
Efficacy and Safety of Abatacept or
Infliximab Versus Placebo
ATTEST Trial
•
A Phase III, Multicenter, Randomized, Double-blind, Placebocontrolled Trial on the efficacy and safety of abatacept or Infliximab
versus placebo in Patients with Rheumatoid Arthritis and an
Inadequate Response to Methotrexate
32
Primary Objective
ATTEST
–To study the efficacy of Abatacept in reduction of
disease activity in comparison to placebo as measured
by disease activity score (DAS) 28 (ESR) at 6 months
(day 197)
–Determine ACR 20, 50, and ACR 70 response rates for
subjects treated with placebo, abatacept, or infliximab
at 6 months and 12 months
the primary endpoint was not designed to be a head-to-head
comparison between Abatacept and infliximab.
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
Abatacept + MTX and infliximab + MTX ACR20
response rates are similar at Month 3
ATTEST
ACR response rate (%)
80
70
ACR 20
Abatacept
60
ACR 20
Infliximab
50
40
ACR 50
Abatacept
30
ACR 50
Infliximab
20
ACR 70
Abatacept
10
ACR 70
Infliximab
0
1

29 57 85 113 141 169 197 225 253 281 309 337 365
Visit day
The onset of action of infliximab was generally more rapid than abatacept however, by
day 85, ACR 20 responses are similar
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
34
ATTEST
Further improvement from Month 6 to 12 was
observed with abatacept + MTX in ACR 20 response
ATTEST
ACR response rate (%)
80
70
ACR 20
Abatacept
60
ACR 20
Infliximab
50
40
ACR 50
Abatacept
30
ACR 50
Infliximab
20
ACR 70
Abatacept
10
ACR 70
Infliximab
0
1


29 57 85 113 141 169 197 225 253 281 309 337 365
Visit day
The onset of action of infliximab was generally more rapid than abatacept up to Day 85
By Day 365, ACR 20 responses were higher with abatacept than with infliximab (ACR 20:
72.4 vs 55.8%, difference of 16.7 [95% CI: 5.5, 27.8])
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
35
ACR Responses at 6 Months
ATTEST
80.0
80
66.7
*
70.0
60
50
41.8
Patients (%)
Patients (%)
70
*
40.4
40
60.0
‡
59.4
50.0
‡
41.8
37.0
40.0
‡
†
30
20
30.0
20
20.0
20
9.1
10
24.2
20.5
0
9.1
10.0
0.0
ACR20
ACR50
Abatacept + MTX (n=156)
ACR70
Placebo + MTX (n=110)
ACR20
Infliximab + MTX (n=165)
ACR50
ACR70
Placebo + MTX (n=110)
ITT population; D/C =Non responders *p<0.001; †p<0.05 and ‡p<0.01; Χ square test; p-values represent active drug versus placebo
The study was conducted in RA patients with inadequate response to MTX and was not designed to demonstrate non-inferiority
or superiority of ORENCIA vs infliximab
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
36
ACR responses at 12 months
Percentage of patients
ATTEST
80
70
60
50
40
30
20
10
0
72.4
55.8
45.5
36.4
26.3
ACR20
ACR50
Abatacept + MTX (n=156)
20.6
ACR70
Infliximab + MTX (n=165)
ITT population; D/c =Non responders
The study was conducted in RA patients with inadequate response to MTX and was not designed to demonstrate
non-inferiority or superiority of ORENCIA vs infliximab
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
37
Abatacept+MTX Delivered Sustained Improvements
in ACR Responses Over 2 Years
ATTEST-LTE
Infliximab patients switched to abatacept
Open label LTE period
DB period
ACR Responders (%)
89% (83,94)*
87% (80,93)*
84% (78,91)*
71% (63,79)*
69% (61,77)*
61 (52,70)*
55% (46,64)*
45% (36,54)*
43 (35,52)*
41% (32,50)*
31% (23,39)*
24% (16,31)*
Visit (month)
0
3
6
9
12
15
18
21
24
Data are for patients who entered the open-label period, and had data available at the
considered time point (as-observed analysis)
Abatacept+MTX
Treatment groups represent treatment received during the double-blind period
Infliximab 3mg/kg + MTX
to abatacept
*95% confidence intervals
Schiff M and Bessette L Clin Rheum 2010 ; 29: 583-519 9
38
ABATACEPT
SHORT & LONG -TERM EFFICACY
COCHRANE META-ANALYSIS
Abatacept provides similar short-term efficacy
at 6 months compared with other biologic agents
Abatacept
•
Placebo-adjusted analysis, based on
ACR50 responses
•
Mixed populations included:
Adalimumab
Anakinra
– MTX-IR
– DMARD-IR
– Anti-TNF-IR
Etanercept
Infliximab
•
Rituximab
0.1
1.0
Favours Placebo
All biologic agents showed significantly
greater efficacy compared with placebo,
except anakinra
10
Favours Biologic
GLIMMIX: Odds Ratio (95% CI)
Studies included only approved dosages.
Singh JA, et al. Cochrane Database Syst Rev 2009;4:CD007848.
40
Cumulative incidence of time to RAPID≥3.6
response* (%)
Abatacept short-term efficacy is
similar to other biologic agents in real
life
80
Abatacept
Adalimumab
60
Etanercept
Infliximab
40
20
0
0
16
2 12
3
18
4
24 5
30
6
Month
*Adjusted for age and duration of disease.
Prospective patient data from the Arthritis Registry Monitoring Database in patients receiving abatacept (n=114), etanercept (n=148), infliximab (n=38) and
adalimumab (n=85).
3,574 encounters were reviewed for this analysis. A total of 385 treatment courses were determined. 272 of the 385 courses represent the only biologic
medication used by an individual; 40 individuals used two biologic medications at different times, while 11 had used three biologics.
Yazici Y, et al. Arthritis Rheum 2011; 63(Suppl 10):S873. Abstract 2233.
Abatacept leads to reductions in synovitis and
structural damage by Month 4 – MRI data
Synovitis
Osteitis
Erosion
3.0
Adjusted mean change
(95% confidence interval)
2.0
1.5
1.0
1.0
0.5
0.4
0.0
-0.3
-1.0
-2.0
-3.0
-1.9
Abatacept + MTX (n=25)
Placebo + MTX (n=23)
MRI (OMERACT RAMRIS) scores from baseline to Month 4 in MTX-IR patients treated with abatacept + MTX or placebo: synovitis of the wrist; osteitis
and erosion scores of wrist and hand.
Conaghan P, et al. Ann Rheum Dis 2011;70(Suppl 3):151
Improvements with abatacept seen via
sonographic monitoring
•
•
•
•
•
•
M.E. 51 year old man with RA
Disease duration: 3 years
Rheumatoid factor: positive
Anti-CCP Ab: positive
DAS28: 6.9
Finger pain: VAS 6
16 months later:
• DAS28: 2.4
• Finger pain: VAS 0
16 Months
Conclusion: Excellent responder
Personal communication, Walter Grassi.
43
LONG TERM GOAL ACHIEVEMENT
BY ABATACEPT
An increasing proportion of abatacept patients show
sustained LDAS or DAS28 remission over 7 years
Double-blind
phase
100
Open-label LTE phase
90
Response (95% CI)
Responders (%)
80
LDAS
70
69.7% (54.0, 85.4)
n/N=23/33
48.2% (37.4, 58.9)
n/N=40/83
60
Remission
50
51.5% (34.5, 68.6)
n/N=17/33
40
30
20
25.3% (15.9, 34.7)
n/N=21/83
10
0
0
0.5
1
2
3
4
5
6
7
Year
DAS28 CRP-defined remission = DAS28 <2.6; LDAS=DAS28 (CRP) ≤3.2.
Data are based on all patients originally randomised to 10 mg/kg abatacept who entered the LTE, with data available at the visit of interest
(as-observed analysis). Mean disease duration was 9.9 (10.1) years.
Westhovens R, et al. Ann Rheum Dis 2009;68(Suppl3):577. Poster SAT0108.
45
AIM (MTX-IR)
Abatacept has demonstrated increasing reductions in
rate of structural damage progression through Year 5
Mean change from baseline in
Genant-modified sharp scores (TS)
4
*0.29
3.5
*0.43
Year 1
3
*0.68
2.5
2
*0.26
*0.34
*0.74
*0.37
1.5
1
*0.41
*1.48
0.5
*0.80
0
0
1
Abatacept + MTX
2
Placebo + MTX
3
Year
4
5
Placebo + MTX switched to abatacept + MTX
*Mean change in TS from year to year.
Data are for those patients who entered the open-label period, and had evaluable radiographs available at the appropriate time points.
Treatment groups represent treatment received in the double-blind period.
TS=Total Score
Schiff M, et al. Rheumatology 2011;50:437–449; Orencia SmPC November 2011; Data on file;
Genant HK, et al. Ann Rheum Dis 2008;67(Suppl 2):193.
46
AIM (MTX-IR)
Sustained improvement in physical function with
abatacept over 5 years (HAQ-DI response)
Double-blind
phase
Open-label LTE phase
Responders (%)
100
90
80
74.2%
(69.0, 79.4)
70
71.8%
(67.2, 76.4)
60
50
40
30
20
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Year
Data are based on all patients originally randomised to abatacept who entered the long-term extension, with data available at the visit of interest (asobserved analysis).
HAQ-DI response ≥ 0.3.
Schiff M and Bessette L. Clin Rheum 2010;29:583–591.
Abatacept has a retention rate that is
comparable with or higher than the
anti-TNF agents
LT- RCT
Subjects remaining at the end of 4 years of LTE
n/N
%
Infliximab1
295/511
62%
Etanercept2
429/581
74%
Adalimumab3
147/262
56%
394/539
73%
Abatacept4*
(IM101102)
•
Retention may be considered as a surrogate marker of long-term efficacy for
biologic agents5
*Summation of the original abatacept plus placebo treatment groups who entered LTE.
Data from literature search on the long-term efficacy results from open-label extension studies of anti-TNFs (in MTX-naïve and MTX-IR patients).
1. Vander Cruyssen B, et al. Arthritis Res Ther 2006;8:R112; 2. Moreland LW, et al. J Rheum 2006;33:854–861;
3. Weinblatt M, et al. Ann Rheum Dis 2006;65:753–759; 4. Data on file; 5. Hetland ML, et al. Arthitis Rheum 2010;62:22–32.
48
Abatacept: Safety Issues
Acute infusion reactions
• 9.8% vs 6.7% placebo, mild-moderate
Malignancy & Infection outcomes
• 4134 Abatacept-treated patients compared with
41,529 DMARD treated patients in 5 cohorts
• No increased rates of malignancy, infection over
6 years.
aSibilia
J, Westhovens R. Safety of T-cell costimulation modulation with abatacept in patients with
rheumatoid arthritis. Clin Exp Rheumatol 2007;25 (5Suppl46):S46-56. bSimon TA et al. Malignancies In RA
Abatacept clinical development program. ARD 2008.
RA Safety Population
Abatacept
Placebo
N = 1,955
N = 989
(204)
(134)
Double-Blind, Controlled
(Biologic Background)
N = 2,339
Open-Label, Uncontrolled
N = 2,688
Cumulative
(Double-Blind and Open-Label)
BLA/4M
Overview of Patients with Adverse Events
Double-Blind, Controlled Study Periods
Number (%) of Patients
Abatacept
N = 1955
Placebo
N = 989
AEs
1736 (88.8)
840 (84.9)
SAEs
266 (13.6)
122 (12.3)
Discontinuation due to AEs
107 (5.5)
39 (3.9)
10 (0.5)
6 (0.6)
Deaths
Most Common Infections (≥ 5%)
Double-Blind, Controlled Study Periods
Number (%) of Patients
Preferred Term
Abatacept
N = 1955
Placebo
N = 989
Total Patients with Infections
1051 (53.8)
478 (48.3)
Upper Respiratory Tract Infection
248 (12.7)
119 (12.0)
Nasopharyngitis
225 (11.5)
90 (9.1)
Sinusitis
125 (6.4)
68 (6.9)
Urinary Tract Infection
113 (5.8)
45 (4.6)
Influenza
111 (5.7)
52 (5.3)
Bronchitis
101 (5.2)
45 (4.6)
Serious Infections (≥ 0.2%)
Double-Blind, Controlled Study Periods
Number (%) of Patients
Abatacept
N = 1955
Placebo
N = 989
58 (3.0)
19 (1.9)
Pneumonia
9 (0.5)
5 (0.5)
Cellulitis
5 (0.3)
2 (0.2)
Urinary Tract Infection
4 (0.2)
1 (0.1)
Bronchitis
4 (0.2)
0
Diverticulitis
3 (0.2)
0
Pyelonephritis Acute
3 (0.2)
0
1 (<0.1)
3 (0.3)
Preferred Term
Total Patients with Serious Infections
Sepsis
Predictors and Risk of Infection in
Rheumatoid Arthritis
 Relative Risk to general population: 1.9 [1.7 – 2.1]
 Best predictors:






RA severity / disease activity
Age
Corticosteroid therapy
Comorbid diseases: CVD, CHF, CRF, DM, lung disease
Previous infection
Joint surgery
 Contributory role of DMARDs not clearly defined
Moreland et al. J Rheum 2001;28:1238-44.
Tuberculosis
Cumulative Study Periods
• 2 cases of presumed tuberculosis with
abatacept
– Tuberculous Infection (Double-Blind):
• Presented with cervical lymphadenitis; diagnosis based on
histology
– Pulmonary Tuberculosis Suspected (Open-Label)
• Presented with dry cough, fever, diaphoresis and crepitus;
diagnosis based on clinical presentation and chest radiograph
• 1 case of presumed tuberculosis with placebo
– Tuberculosis - Suspect (Double-Blind):
• Unknown presentation; no definitive diagnosis
Malignancy
Integrated safety summary
Continued use of abatacept does not increase the risk
of malignancy over time
Clinical trial
experience
Short term
Short term
(2,331 p–y)
Long term
(9,752 p–y)
Cumulative
(12,132 p–y)
Placebo
Abatacept
Abatacept
Abatacept
0.59
(0.19–1.37)
0.69
(0.39–1.11)
0.74
(0.58–0.93)
0.73
(0.58–0.89)
–
0.04
(0.00–0.24)
0.08
(0.04–0.16)
0.07
(0.03–0.14)
0.59
(0.19–1.37)
0.60
(0.33–1.01)
0.60
(0.45–0.77)
0.59
(0.46–0.75)
–
0.21
(0.07–0.50)
0.13
(0.07–0.23)
0.15
(0.09–0.23)
0.82
(0.33–1.70)
0.82
(0.49–1.28)
0.74
(0.58–0.93)
0.73
(0.58–0.90)
Malignancies, incidence rate (95% CI)
Malignancies
(excluding NMSC)
Lymphoma
Total solid organ
(combined)
Lung cancer
NMSC
NMSC=non-melanoma skin cancer; Data over a 7-year period; Data lock December 2009. 12,132 p–y of exposure (N=4,149).
Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–5. Abstract 390.
57
Malignancies: Double-Blind studies
Malignant
Abatacept: 29 (1.5%)
Placebo: 11 (1.1%%)
Non-Melanoma Skin
CA
Abatacept: 15 (0.8%)
Placebo: 6 (0.5%)
Solid Organ CA
Abatacept: 13 (0.7%)
Placebo: 5 (0.5%)
58
Hematologic
Abatacept: 2 (0.1%)
Placebo: 0
Immunogenicity was low in the
abatacept clinical trial program
• Overall incidence of anti-abatacept antibody
responses was 4.8% (187/3,985) in patients
treated for up to 8 years with abatacept
• In patients assessed for antibodies at least 42 days
after discontinuation of abatacept, incidence of
immunogenicity was 5.5% (103/1,888)1
– There was no apparent correlation of antibody
development to clinical response or adverse event
based on this limited dataset of patients with
antibodies1
59
BIOLOGICS AND PREGNANCY
Drug
#
cases
Developmental
toxicity - animals
Fetal problems – Humans
Drug Discontinuation?
ETA
51
-
Preterm , VACTERL
Vert,anal, CVS, tracheobr
fistula, renal, & Limb
At missed period, (+)
pregnancy test
INF
81
-
TOF, intestinal malrotation
At missed period, (+)
pregnancy test
ADA
13
-
Preterm, limb reduction,
Tracheobronchomalacia
At missed period, (+)
pregnancy test
RIT
10
B cell depletion
(2nd/3rd tri)
Lymphopenia (1st tri)
12 mos pre-pregnancy
ABAT
0
+/None (?)
unknown
10 wks pre-pregnancy
*1 case each - CZP, ANA, 0 - GOL and ABA; no animal and human/fetal toxicity
reported; drug discontinuation recommended for GOL, CZP, ANA
Ostensen M, Forger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol 2009;5:382-90.
UptoDate 2009
60
Conclusions
Abatacept in RA:
• Is efficacious in achieving remission in early RA
• Is efficacious in short and long term treatment
• Has a high retention rate
• Is a safe and reliable drug
THANK YOU
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