Eular 2011

1. EULAR 2011-RA updates
By A.Arputha Selvaraj APMP IIM Calcutta
BMS
India

2. Agenda
We will discuss updates from EULAR 2011 about:
1. Diagnosis of RA
2. RA remission
3. Early RA
4. Safety of medications in RA
5. Imaging in RA
6. Other updates in RA

3. Diagnosis
BMS
India

4. 2010 ACR/EULAR RA criteria in clinical practice: Prediction
of clinical RA & distribution of patients with early UA
• New ACR/EULAR criteria → predicts risk of RA (early)
- Tree format or scoring system → ≥ 6 points = RA
• NOR-VEAC: (SJC ≥1 with ≤16 weeks duration, 18-75 ys)
•
128/343 definite RA by both versions new criteria
•
82/83 (98.8%) >10 joints = RA vs 3/111 (2.7%) 2-10 joints
•
57/60 (95%) ↑ ACPA and/or RF = RA
• Sensitivity 85.9%; specificity 80.5%; LR+ 4.4, LR- 0.18;
area under the ROC curve (95% CI) was 0.92 (0.89-0.95)
Criteria performed well in predicting clinical RA, particularly in
seropositive patients
Mjaavatten MD, et al. EULAR 2011, London, #SAT0373
BMS
India

5. Comparison of 1987 & 2010 classification
criteria for RA in patients with early arthritis
•
•
•
•
•
253 pts with ≥1 swollen joint for
≥4 wks; symptoms < 1 y
RF+ 34.4% pts
CCP+ 28.6% pts
Gold std: pts Dx after 2 ys f/u
Estimate sensitivity, specificity,
PPV, NPV, LR+ &
LR-
• RA diagnosis
108 pts (42.7%) with 2010 criteria
• 114 pts (45.1%) with 1987 criteria
2010
1987
Sens. (%)
80
86
Spec. (%)
81.7
81.7
PPV (%)
74.1
75.4
NPV (%)
86.2
89.9
LR+
4.37
4.7
LR-
0.245
0.171
LR = likelihood ratio
No relevant differences in RA diagnosis using 1987 or 2010 criteria
Fernandez-Ortiz AM, et al. EULAR 2011, London, #SAT0396
BMS
India

6. Remission
BMS
India

7. CATCH: Remission prevalence in early RA new criteria vs other criteria
RF+/
CCP+ (n)
Bio
%
Mean CRP
(mg/dL)
100
80
DAS28<2.8
56/62
7
0.33
60
DAS28<2.0
55/61
7
0.26
40
SDAI<3.3
59/64
9
0.32
CDAI<2.8
58/64
10
0.38
ACR/EULAR
54/65
8
0.27
% remission at 12 months
53
36
27
20
25
22
0
• ACR/EULAR criteria agrees with SDAI (k=0.75) & CDAI (k=0.73)
• Fair agreement with DAS28<2.6 (k=0.32) & DAS28<2.0 (k=0.35)
All remission is not the same1,2
1. Kuriya B, et al. EULAR 2011, London, #SAT0405;
2. Bernard M, et al. Ibid, #OP0027
BMS
India

8. Utility of 2011 ACR/EULAR 2011
remission criteria
• US VA and community practice cohort study1
- 1,341 VA patients / 9,700 visits (91% men)
– 1,168 community practice patients / 6,362 visits (28% men)
– Remission (US VA / community practice):
• Cross-sectional: 8.9% / 8.3%
• Cumulative: 24.4% / 19.0% over mean of 2.2 ys
• 1.9 - 4.6% patients met remission at ≥2 visits
• Among all patients, <3% had remission lasting 2 ys
• Non-inclusion of feet may overestimate remission3
• Patients in ACR/EULAR remission have function capacity = to normal 4
Remission is uncommon in the clinic, especially long term
1. Michaud K, et al. EULAR 2011, London, #FRI0333;
2. Vermeer M, et al. Ibid, #OP0311;
3. Bakker MF, et al. Ibid, #SAT0376;
4. Listing J, et al. Ibid, #THU0351
BMS
India

9. BRASS: Radiological progression in remission by new
ACR/EULAR criteria vs other criteria
DAS BL rem.
TSS mean ann. change
% w/ prog.
LR+ good outcome
DAS28(CRP)<2.6
106
0.93 (median 0)
30%
1.5
SDAI<3.3
37
0.65 (median 0)
24%
2.1
CDAI<2.8
26
0.37 (median 0)
19%
2.8
ACR/EULAR≤1
30
1.08 (median 0)
20%
2.6
ΔTSS in pts assessed to be in remission by DAS28, CDAI, ACR/EULAR
15
DAS28 2.6
10
CDAI
5
ACR/EULAR
0
0
10
20
30
40
50
% patients
60
70
80
New ACR/EULAR criteria performed similarly to established criteria
Lillegraven S, et al. EULAR 2011, London, #SAT0398
90
100
BMS
India

10. Power Doppler ultrasound is useful in
determining true remission
•
109 RA pts on TNFi in DAS28
remission for 6 months
•
49.5% PDUS- / 50.4% PDUS+
• No PD signal, no radiological
progression
•
29.1% with PD signal had
radiological progression
Image courtesy of AF Wells, MD, PhD
• Absence of PD signal guarantees arrest of radiologic progression, whereas
pts with PD signal are at risk for progression despite treatment with TNFi
• This risk increases with higher PD grades
PDUS may be useful in evaluating pts considered to be in remission
Raffeiner B, et al. EULAR 2011, London, #OP0029
BMS
India

11. Early RA
BMS
India

12. T2T strategies in early RA:
OPTIMA Study design
• MTX-naive pts ≥18 ys with RA <1 y & active disease (DAS28>3.2,
ESR ≥28 mm/h or CRP ≥1.5 mg/dL), and either >1 erosions, RF+ or anti-CCP+
n=207
n=466**
ADA 40 mg
EOW+MTX *
n=460**
MTX*
0w
PERIOD 1
Yes
DAS28
<3.2
No
n=259
n=112
Yes
DAS28
<3.2
No
n=348
26 w
MTX
n=102
ADA 40 mg
EOW+MTX n=105
OL ADA 40 mg
EOW+MTX
MTX
OL ADA 40 mg
EOW+MTX
PERIOD 2
* MTX titrated to 20 mg/wk by Wk 8; ** Completed study period
Smolen J, et al. EULAR 2011, London, #THU0243
ARM 1
ADA+MTX / MTX
ARM 2
Sustained ADA+MTX
ARM 3
ADA+MTX IR/ADA+MTX
Primary
efficacy
outcome†
ARM 4
Sustained MTX
† DAS28 <3.2
ARM 5
MTX IR/ADA+MTX
at Week 78
and mTSS <0.5
78 w
BMS
India

13. OPTIMA: ADA+MTX / MTX vs
sustained ADA+MTX
ADA+MTX / MTX (n=88)
100
Sustained ADA+MTX (n=94)
ACR
ACR20
Radiographic prog: % pts
100
ACR50
ACR70
80
80
89.0
88.0
89.0
85.0
89.0
60
81.0
40
60
20
40
26 30 34 38 42 46 50 54 58 62 66 70 74 78
Weeks
0
26
52
78
Weeks
For many early RA patients in LDA on TNFi/MTX, TNFi can be
withdrawn for a year; some patients may need continued treatment
Smolen J, et al. EULAR 2011, London, #THU0243
BMS
India

14. OPTIMA: Sustained ADA+MTX
vs sustained MTX at Week 78
Sustained ADA+MTX (n=94)
100
80
Sustained MTX (n=98)
*
*
X-ray progression
100
*
60
89
88
89
75
82
82
78
52
78
40
50
20
25
0
LDAS +
mTSS
0.5 from
BL
ACR20
ACR50
ACR70
*P<0.05: ADA+MTX vs
sustained MTX
0
26
•
44% Arm 2 v 24% Arm 1
achieved LDA during phase 1
Although both groups did well in LDA; patients on TNFi/ MTX did slightly
better than those on MTX alone
N Smolen J, et al. EULAR 2011, Lon don, #THU0243
BMS
India

15. Is there a window of opportunity in early RA?
• 8 year f/u of PREMIER: DBPCRCT of ADA, MTX, ADA + MTX early RA (<3 ys) 1
• After 2 ys all pts were on ADA; MTX could be added (30-35% did)
100
MTX (n=89)
80
60
ADA (n=92)
MTX/ADA (n=89)
71.3
58.4
49.5
40
50.6
43.8
28.3
28.7
16.9
20
11.8
0
DAS28 <2.6
SDAI ≤ 3.3
DAS28<2.6 + HAQ ≤ 0.5 +
ΔTSS ≤ 0.5
• Group 5 from OPTIMA (MTX/IR  MTX/ADA at 6 months): comparable
response to MTX/ADA from the start2
Early aggressive therapy may achieve long-term benefit in early RA
Breedveld F, et al. EULAR 2011, London, #THU0230
BMS
India

16. Early addition of low-dose prednisone to
tight control: CAMERA II
• DB study, 236 early RA pts (<1 y)
80
• MTX + PBO vs MTX + Pred 10 mg QD
70
MTX+Pred
M
TX
60
- Pred continued for 2 ys
- Evaluated once a month
P=0.09
50
• ADA added for failure to reach target
40
• At 2 years:
- Lower disease activity and disability
in Pred group
30
- No ↑ DM, infections or fractures
- Lower LFTs and ADA in Pred group
P<0.001
20
10
0
% REM
% on TNFi
Low-dose prednisone at start of Tx leads to better control and no
increase in toxicity
Bakker MF, et al. EULAR 2011, London, #OP0138
% AE
BMS
India

17. Smokers have no “window of opportunity”
Change in DAS28 over time
• Data from BARFOT
- 12 mo f/u in 1,587
early RA patients
• Pts with early disease
(<3 mos) show significant
improvement, each month,
when treated
-0.05
Non smoker
Current smoker
-1.50
-2.50
• Smokers did not show this
trend
-3.50
2 - 12 months
Smokers are less likely to respond to early treatment of RA
Söderlin M, et al. EULAR 2011, London, #SAT0372
2 - 12 months
BMS
India

18. Stopping TNFi in RA
•
Japanese study: stop ADA if DAS28≤2.6 x 6 mos1
- Mean RA duration 8 ys
- Stable MTX (mean dose 12.5 mg)
- ADA for ≥1 y
•
40/163 pts stopped ADA: data on 27 pts at 24 weeks
- 16/27 in DAS remission; mean DAS28 = 1.8 at entry
- 3/27 LDAS
- 8/27 flared; mean DAS28 = 2.2 at entry
•
90% of DAS28≤1.9 did not flare at 6 months
TNFi may be stopped in patients who attain DAS remission for
6 months; especially with very low DAS28
Tanaka Y, et al. EULAR 2011, London, #OP0154
BMS
India

19. Treat-to-Target in routine clinical care
•
2 studies using DAS28 remission as
target in “standard therapy”
• No preset order of med use
• DAS28 remission in 26.5%1 & 32%2
• ACR/EULAR remission in only 8.6%1
- Is ACR/EULAR remission too strict?
• Use of most recent ESR/CRP (up to
3 mos from visit) does not effect
validity of DAS283
Baseline Year 3
DAS28
median
4.0
3.1*
Remission %
22.8
32*
LDAS only %
12.5
19.6*
35.3
51.6*
1.35
1.25
LDAS +
remission %
HAQ
median
*P<0.001
Treating to a target feasible in routine clinical care using currently
available therapies; results in high rates of remission and LDAS
1. Favarato MH, et al. EULAR 2011, London, #SAT0374;
2. Gullick NJ, et al. Ibid, #SAT0209;
3. Brode S, et al. Ibid, #SAT0202
BMS
India

20. REALISTIC study: CZP in
DMARD-IR and TNFi-IR RA pts
•
1,063 pts, 37.6% with TNFi exposure; 20.3% received CZP as monotherapy
100
80
60
40
CZP (n=320)
Control (n=80)
P<0.001
P<0.01
53.5
47.2
27.5
51.9
47.6
25
20.8
20
27.8
52.3
25
53.5
25
46.7
48.3
30.6
12.5
0
Prior TNFi No prior
TNFi
ACR20
0
1
≥2
No. of concomitant
DMARDS
0
1
2
No. of prior TNFi
CZP shows efficacy after TNFi exposure and as monotherapy in RA
Weinblatt ME, et al. EULAR 2011, London, #FRI0214
BMS
BMS
India
India

21. No mortality differences between TNF inhibitors
•
ARTIS database (Sweden);
N=6,322
2
1.5
•
•
Compared mortality
between ADA, ETN and IFX
211 deaths (3.3%)
1
Ref
0.5
0
ETN
(n=2,686)
ADA
(n=1,609) (n=2,027)
No difference in mortality regardless of adjustments for co-factors
or other modeling techniques
Simard J, et al. EULAR 2011, London, #OP0158
IFX
BMS
India

22. Safety
BMS
India

23. Effect of treatment on mortality in RA
ETN pts
• BSRBR RA pts, DAS28>4.2
DMARD
controls
>5 y f/u; ETN vs DMARDs
N (pt-ys)
3,470
(14,382)
1,365
(5,583)
• ETN: higher disease activity /
Mean f/u
4.1 ys
4.1 ys
Age
55.4 ys
59.5 ys*
RA duration
13.6 ys
9.6 ys*
HAQ
2.1
1.7
Deaths
188
127
Deaths/1000
pt-ys
13.1
22.2
•
severity, less comorbidity
• Mortality: adj. HR 0.59 (0.44-0.78)
0.786 (0.57-1.08): depends on
time censure modeling
• Caveats: patients excluded if
switched to other biologics
*P<0.001
Mortality not elevated; may be lower with TNFi therapy in RA
Emery P, et al. EULAR 2011, London, #LB0007
BMS
India

24. CV risk in RA is independent of disease
duration but varies with disease activity
• EULAR identifies RA disease
duration >10 ys as CV risk factor
However:
•
855 pts (6,388 pt-ys) → 90 1st CV
events: MI, CVA, heart failure
• CV risk ↓↓ only with DAS28 <2.9
over time vs other groups (P=0.04)
• No difference in survival
distribution between disease
duration < or > 10 ys
Cumulative survival for different DAS28
levels (< 10 ys disease duration)
1.0
0.9
0.8
Low (<2.9)
Low-medium (<2.9-3.6)
Medium-high 3.6-4.3)
High (>4.3)
0.7
0.0
5.0
10.0
15.0 20.0
Time to event (years)
RA duration does not aggravate CV risk over time; CV risk not ↑ after
10 ys of disease duration vs 1st 10 ys; CV risk ↓↓ lower only with DAS28 <2.9
Arts EEA, et al. EULAR 2011, London, #OP0161
25.0
BMS
India

25. Cancer risk and RA treatments: Two studies
8
BSRBR - DMARD1
(n=3,727; 148 w/cancer)
Lym
7
Lung
4
1
0
13,699 pts; 5,598 on TNFi
• Cancer in 313
NHL
•
RR: 1.05 (CI 95% 0.82-1.34)
vs DMARD
•
Melan
5
2
•
ph
6
3
DANBIO - TNFi2
No increase in any CA
Myelo
- Including NMSC &
non-Hodgkins
All excl.
NMSC
- No effect of duration of Tx
Solid
reast
Colorect
B
- Also true for PsA & “other”
arthritis
DMARD use is associated with 50% increase in all cancers
1. Mercer LK, et al. EULAR 2011, London, #FRI0338;
2. Dreyer L, et al. Ibid, #FRI0203
BMS
India

26. SIE with TNFi in RA: DREAM and GISEA registries
10
9
8
7
DREAM registry1
(N=2,157, since 2003)
10
GISEA registry2
(N=2,769)
8
6
5
6
4
3
4
2
1
2
0
0
ETN
ADA
IFX
• Adj HR: 1.02 ADA vs IFX; 0.59 vs mAb
• IFX pts tended to have worse prognosis
ETN
IFX
• Sig diff in SI risk in ADA, ETN & IFX
pts (P<0.0001)
TNFi is associated with small but significant risk of SI
1. van Dartel S, et al. EULAR 2011, London, #FRI0222;
2. Atzeni F, et al. Ibid, #THU0229
ADA
BMS
India

27. Risk factors associated with GI perforation
in RA patients
Diverticulitis
Diverticulosis w/o diverticulitis
Other DMARDs w/ glucocorticoids
Glucocorticoids w/o any DMARD
MTX w/ glucocorticoids
Biologics w/ glucocorticoids
Biologics w/o glucocorticoids
Other DMARDs w/o glucocorticoids
No DMARDs or glucocorticoid
NSAID
Baseline CCI
Age 65+
Age 40-64
Female
Urban
CCI = Charlson Comorbidity index
0
RR of GI perforation during f/u (adjusted results)
HR (95% CI)
1
2
3
4
11
13
15
GI perforation is rare and increases with age, steroids, and
especially history of diverticulitis; NSAIDs impose a minor risk
Curtis J, et al. EULAR 2011, London, #OP0159
17
19
BMS
India

28. Quantiferon (QTF) vs TST performance in
TNFi-treated patients
• 150 AS/RA pts screened by Hx, CXR, IGRA, TST
• TST more frequently positive than QFT
• Clinical suspicion of LTBI in 21 patients (based on
LTBI risk factors)
TST+
45%
56%
QFT+
9.3%
• 14 (9.3%) QTF+ & 67 (45%) TST+
-
56% agreement: TST + QTF (k=0.1; P=0.01)
• 17% had indeterminate results
- Assoc. w/ elderly, DMARD, pred. use
- Results turn negative after TNFi
• 6 QFT+ pts Tx for LTBI (INH/RIF x3 mo)
- F/u QFT was negative in 4 pts
Assoc. w/
LTBI risk
factors
21%
(RR=2.5)
QFT+ more strongly associated with LTBI risk factors
Indeterminates may convert to negative with 6 mos of TNFi
Cabantous L, et al. EULAR 2011, London, #THU0249
50%
(RR=4.8)
BMS
India

29. Imaging
BMS
India

30. Which comes first: JSN vs JE?
PREMIER, MTX-naive, early RA
3
•
2
226/17,644 (1.3%) evaluable
joints lacked JSN at Wk 26 but
had JSN progression by Wk 52
- 49 (21.7%) JE-/SJ– 44 (19.5%) JE-/SJ+
1
– 66 (29.2%) JE+/SJ– 67 (29.6%) JE+/SJ+
0
JE
@Wk26
All
Swelling
Wks 26-52
MTX vs
ADA
MTX vs
ADA+MTX
• Both JE & swelling assoc. with
the onset of JSN at Week 52
Erosions contribute to JSN: JSN is the main driver of functional disability
Landewe R, et al. EULAR 2011, London, #FRI0209;
Aletaha D, et al. Ann Rheum Dis. 2011;70:733-9;
Landewe R, et al. Ann Rheum Dis. 2011;70:717-8
BMS
India

31. Do NSAIDs affect US activity in RA patients?
N=58
Stopped
NSAID
Continued
NSAID
P-value
SJC
+1.5
-1.0
<0.001
TJC
+2.5
0
<0.001
GSUS
+9.5
+1.0
<0.001
PDUS
+4
0
<0.001
GSUS score >0
4 joints
1 joint
<0.001
PDUS score >0
2 joints
0 joints
0.005
NSAIDs may decrease both GSUS and PDUS signal resulting in
lower scores despite ongoing disease activity; consideration
should be given to NSAID effect in designing US clinical studies
Zayat AS, et al. EULAR 2011, London, #OP0242
BMS
India

32. Early reductions in synovitis & osteitis with TCZ are
maintained through Week 52: ACT-RAY MRI substudy
• RA pts (n=63) on stable MTX
randomized to MTX or PBO +
TCZ 8 mg/kg IV every 4 weeks
• Decreases in synovitis &
Synovitis
Osteitis
20
15
osteitis at Week 12 sustained
at Week 52
erosions over 52 weeks
5
• No patients developed new
*P<0.05 vs BL
10
• No significant change in mean
Erosions
0
regions of synovitis
*
*
BL
Week 12
Early reduction of synovitis & osteitis by MRI with TCZ
maintained through 1 year
Troum O, et al. EULAR 2011, London, #SAT0282
*
*
Week 52
BMS
India

33. Xiralite vs ultrasound and MRI
• Fluorescence optical imaging
(IV indocyanine green) to assess
inflammation of the hand
• Information collected at various phases
post-injection
• Early-phase imaging showed good
agreement with clinical exam, PDUS,
MRI, and less with GSUS
•
92% (53/57) swollen joints and
94% (63/67) joints with MRI synovitis
showed positive findings
• Limitations: thick skin, palmar
tenosynovitis
Comparison
Method
Sensitivity Specificity
Clinical exam
58%
90%
Xiralite P1
34%
95%
Xiralite P2
83%
69%
Xiralite P3
60%
92%
Fluorescence optical imaging with Xiralite system sensitive in
detecting early inflammation
Werner, et al. EULAR 2011, London, #FRI0048;
Werner, et al. Ibid, #SAT0101
BMS
India

34. JIA
BMS
India

35. Switching in JIA
•
•
In SoJIA (German JIA Registry,
N=1,345), switching to 2nd
TNFi or ABA was
unsuccessful1
In PolyJIA switching to a 2nd
TNFi gave favorable results1
20
Systemic JIA: Last response
0 response
PedACR30
PedACR50
PedACR70
15
10
5
0
ETN
n=26
•
In some PolyJIA pts, switching
to CZP may also be effective2
Switching from one biologic to
another may be effective, but SoJIA
patients respond differently than
PolyJIA patients
1. Horneff G, et al. EULAR 2011, London, #FRI0176;
2. Tzaribachev N, et al. Ibid, #FRI0194
40
IFX ADA ANA TCZ ABA
n=1
n=4 n=21 n=2
n=2
Poly JIA: Last response
30
20
10
0
ETN IFX ADA ANA TCZ ABA
n=57 n=10 n=43
n=4
n=4
n=5
BMS
India

36. TENDER: TCZ effective in persistent SoJIA
• 12 wk DBPCRT followed by OL Tx
• TCZ 8 (>30 kg) or 12 (<30 kg) mg/kg
ACR30+no fever
100
• All patients received OL TCZ 8 or
12 mg/kg in part 2
Week 52
60
• Week 12 response maintained at Week
52; 52% pts able to D/C steroids
Week 12
ACR90
80
• Primary outcome: ACR JIA 30 + no fever
ACR70
40
• Safety: 15 SIEs; 1 infusion reaction; 2
grade IV neutropenias; 3 deaths
(1 MVA; 1 pneumothorax; 1 unknown)
20
0
Control
(n=37)
One year of TCZ is highly effective and generally well
tolerated in patients with SoJIA
De Benedetti F, et al. EULAR 2011, London, #OP0006
TCZ
(n=75)
TCZ
(n=88)
BMS
India

37. Miscellaneous
BMS
India

38. Work outcomes
• GLM+MTX vs MTX ↑ employability
% patients unemployable at
BL and
40
employable at Week 241
33*
by 0.96 ys (female)/0.87 ys (males)1
• RA imposes a burden similar to DM
justifying cost of treatment2
30
*P<0.05
- Incremental cost (RA vs DM )
• $5,212 vs $3,698 vs
$4,014
– Incremental days absent
• 3.58 vs 2.73 vs 6.42
• Young patients more likely to
consider themselves a burden3
20
15
10
0
Placebo + MTX Combined GLM +
MTX
RA imposes a significant burden to both employers and caregivers
Treatment with TNFi + MTX can improve employability
1. Han C, et al. EULAR 2011, London, #THU0045;
2. Brook RA, et al. Ibid, #THU0031;
3. Bergman M, et al. Ibid, #FRI0241
BMS
India

39. Alcohol intake and inflammatory polyarthritis
(IP) in Norfolk Arthritis Register (NOAR)
•
184 incident IP patients among
25,639 population
1.0
•
138 fulfilled 1987 RA criteria
0.8
• Smoking ↑ risk RA & IP
0.7
• EtOH 16% ↓ risk/unit consumed
1.3
↓risk for every 1 unit/day consumed
(hazard ratio)
0.6
0.5
IP
RA
Sero+ IP
Fully adj. age, gender , smoking, BMI, diabetes,
social class
Fully adj. age, gender , smoking, BMI, diabetes,
social class, parity & breastfeeding
HR (95% CI)
↑ risk IP in
smokers
↓ risk RA in
smokers
Alcohol intake ↓
risk of IP
1.70 (1.12-2.57)
1.68 (1.03-2.73)
0.84 (0.72-0.97)
Alcohol consistently shown to decrease risk of IP and RA and
negates effect of smoking
Lahiri M, et al. EULAR 2011, London, #OP0025
BMS
India

40. Sexual dysfunction in RA
•
231 RA patients1
- 91 male/140 female
•
Among men
- 49/91 (53.8%) reported ED
•
•
•
•
•
18/49 mild
16/49 mild to moderate
13/49 moderate
2/49 severe
Among women
- 67/150 (44.6%) reported
sexual dysfunction
- Dyspareunia due to
decrease lubrication most
common complaint
1. El Miedany Y, et al. EULAR 2011, London, #SAT0232;
2. Sharma P et al. Ibid, #SAT0213
RA has a significant impact on my
sex life2
100%
80%
60%
67%
65%
72%
40%
20%
All
Men
Women
0%
Sexual dysfunction is
common in RA; strong
association between sexual
dysfunction and
cardiovascular disease
BMS
India

41. Patient-reported outcome measures
•
•
Japan1 & Finland2 - pts evaluated
with RAPID3, CDAI and DAS28
Correlation:1
3
- RAPID3 vs DAS28 r=0.66
- RAPID 3 vs CDAI r=0.78
•
•
Standard change
RAPID3 vs CDAI2
5
Remission agreement good
between RAPID3, CDAI
ACR/EULAR and DAS281
Any measure using 3 or 4 of ACR
core data set will measure
disease activity well3
4
2
1
0
-1
-2
-3
-4
-5
-5
-4 -3 -2 -1 0 1 2 3 4
Standard change of RAPID3
5
RAPID3 requires minimal input from physicians and can serve as a
useful alternative to other measures in clinical practice
1. Seto Y, et al. EULAR 2011, London, #SAT0409;
2. Sokka T, et al. Ibid, #FRI0280;
3. Bergman M, et al. Ibid, #THU0300
BMS
India

42. Utility of a biomarker test in RA
• Multi-biomarker disease activity
0.9
(MBDA; sold as VECTRA™) test
for RA
•
0.8
126 pts from BeSt
Predictors of X-ray
progression Year 1 to 2
0.5
0.4
• Serum at BL and 1 y; correlated
with ΔSHS (BL1, 2 ys)
0.7
0.6
0.3
0.2
0.1
0
Biomarker test results correlate with
outcomes, including X-ray, as do other
measures and markers
Allaart C, et al. EULAR 2011, London, #THU0319
Weinblatt ME, et al. Ibid, #THU0339
BMS
India

43. Anakinra as first-line biologic: Results from
real-world Italian GISEA retrospective registry
• RA patients starting biologics from 14 centers in Italy
•
129 starting anakinra matched 1:4 with 515 starting ADA or ETN
- Matched age, sex, disease activity, year of treatment (anakinra patients
had increased disease duration, higher HAQ, higher PtG)
• Results: remission at 12 months
- Anakinra = 18.6%; TNFi = 26%
- TNFi patients had significantly lower baseline disease duration, pain,
global health and HAQ scores
- Univariate analysis suggests that longer disease duration and higher
HAQ score may account for difference in remission rates
Anakinra remission rates somewhat lower than TNFi, but still
remains proven biologic option in patients with active RA
Sfriso P, et al. EULAR 2011, London, #SAT0283
BMS
India

44. Periodontal disease (PD) and RA
Severe PD occurs 10-15% RA pts
• Dutch study:1 98 RA pts assessed
with PD Screening and RA activity
- 50% had PD (18% severe)
– More RA smokers had PD (P=0.01);
- PD assoc. w/ higher DAS28 & CRP
P=0.047
6
•
TJC
15
SJC
CRP
DAS28
10
5
4
0
w/ PD
w/o PD
BL
2
0
Brazilian study:2 18 pts had dental
exams pre/post TNFi x 6 mo
- Mostly IFX: 15 (83%)
- Significant response to TNFi w/o
change in PD status
6 mo
BL
6 mo
– PD+ (8/18): no improvement after
1-2
PD score
3-6
6 mos of TNFi treatment
- PD- (10/18): respond best to TNFi
PD prevalent in RA; TNFi treatment does not affect PD, but patients with
PD may have blunted response to TNFi
1. De Smit M, et al. EULAR2011, London, #THU0289;
2. Savioli C, et al. Ibid, #SAT0138
BMS
India

45. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in
combination with traditional DMARDs (ORAL Sync)
•
792 active RA: DMARD-IR (4:4:1:1)
• PBO for 6 months (rescue at Mo 3) vs Tofa 5 or 10 mg BID
• Multinational study:
- 22% North America
– 8.3% South America
– 28.3% Europe (85% Eastern Europe)
– 41.4% Rest of world (28% China)
• Co-1° EP
- ACR20 (NRI), Mo 6
- HAQ-DI ∆ from BL, Mo 3
- DAS28-4(ESR) <2.6, Mo 6
Kremer J, et al. EULAR 2011, London, #LB0005
BMS
India

46. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in
combination with traditional DMARDs (ORAL Sync)
Tender joints (68), mean
Swollen joints (66), mean
HAQ-DI, mean
DAS28-4(ESR), mean
Prior DMARD use
MTX, %
Other traditional DMARDs, %
TNFi, %
Other Biologic DMARD use, %
Disposition
Patients completing, %
D/C due to AE, %
D/C due LOE, %
5 mg BID 10 mg BID PBO5 mg
n=315
n=318
BID n=79
25.0
26.6
27.2
14.5
14.4
14.6
1.44
1.43
1.45
6.29
6.36
6.44
Kremer J, et al. EULAR 2011, London, #LB0005
PBO10 mg
BID n=80
21.9
13.9
1.24
6.16
86.7
73.7
7.3
2.2
82.7
76.1
6.0
3.1
83.5
69.6
6.3
7.6
82.5
77.5
6.3
0.0
82.1
6.4
5.1
79.2
9.1
3.8
89.9
2.5
3.8
83.8
3.8
3.8
BMS
India
78

47. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in
combination with traditional DMARDs (ORAL Sync)
ACR20 at Mo 6
70
PBO
Tofa 5 mg
Tofa 10 mg
*
52.7
60
*
58.3
50
40
30
31.2
20
10
0
*P<0.0001 vs PBO
Kremer J, et al. EULAR 2011, London, #LB0005
BMS
India

48. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in
combination with traditional DMARDs (ORAL Sync)
HAQ-DI to Month 3
PBO
Tofa 5 mg
*
12
11.0
10
-0.21
8
-0.3
6
-0.4
-0.6
*
14.8
14
-0.1
-0.5
Tofa 10 mg
16
0
-0.2
DAS28<2.6 to Month 6
4
-0.46
2.7
2
*
-0.56
*
0
*P<0.0001 vs PBO
Kremer J, et al. EULAR 2011, London, #LB0005
BMS
India

49. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in
combination with traditional DMARDs (ORAL Sync)
%
Months 0-3
Months 3-6
Post Month 6
5 mg 10 mg
5 mg 10 mg PBO PBO 5 mg 10 mg PBO PBO
BID BID PBO PBO BID BID 5 10 BID BID 5 10
n=315n=318n=159 n=81 n=315n=318 n=38 n=40 n=315n=318 n=79 n=80
SAE
2.9
2.5
3.8
0
1.6
2.2
0
0
2.2
2.8
2.5
0
SIE
0.6
1.2
0
0
0
0
0.3
0.3
1.0
2.5
0
0
D/C
AE
4.1
4.1
1.3
1.2
1.9
2.5
0
2.5
0.3
2.8
0
1.3
Kremer J, et al. EULAR 2011, London, #LB0005
BMS
India

50. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in
combination with traditional DMARDs (ORAL Sync)
PBO
Month 3
Post Month 6
5 mg 10 mg PBO5 PBO10 5 mg 10 mg
Change from baseline (LS Mean)
ANC (103/mm3)
-0.02
-0.75*
-0.99*
-0.72
-0.66
-0.79
-0.90
Hb (g/dL)
-0.04
0.28
0.11
0.41
0.23
0.44
0.19
LDL (%)
-0.61
15.65*
18.26*
7.72
12.85
16.24 19.93
Serum Cr (mg/dL)
0.02
0.03
0.06*
0.05
0.08
0.06
0.08
AST>1x ULN (%)
13.8
23.5
29.4
19.1
26.7
19.4
24.6
AST>3x ULN (%)
<1.0
<1.0
<1.0
1.1
<1.0
0
1.4
ALT>1x ULN (%)
17.6
27.9
34.2
18.8
27.4
22.2
23.2
ALT>3x ULN (%)
<1.0
1.9
<1.0
2.6
1.9
0
1.4
P<0.0001 vs PBO
*
Kremer J, et al. EULAR 2011, London, #LB0005
BMS
India
82

51. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in
combination with traditional DMARDs (ORAL Sync)
4 deaths
•
•
81-year old man (US): Traumatic brain injury and intracranial hemorrhage
following a fall 22 days after discontinuing 5 mg
37-year old man (China): Found dead on Day 174 of 10 mg
- Cause of death: Acute heart failure due to valvular heart disease
•
48-year old man (Russia): Hospitalized for worsening RA; discontinued
5 mg at Day 292; died 42 days later
- Cause of death: Infection by DSMB
•
58-year old man (US): Presented with DOE, CHF, anemia, renal
insufficiency at Day 357 on 10 mg; developed progressive pulmonary
infiltrates, respiratory failure and pulmonary hypertension resulting in death
- Cause of death: Infection by DSMB
4 OIs: 1 disseminated H zoster; 1 cryptococcal pneumonia; 2 TB
Tofacitinib effective in combination with DMARDs
Overall safety still being evaluated
Kremer J, et al. EULAR 2011, London, #LB0005
BMS
India

52. Can you correct the lipid elevations caused by Tofa?
OL Tofa with or without blinded atorvastatin (A)
• Tofa 10 mg BID for 6 weeks, then randomized to A 10 mg QD vs PBO for
6 more weeks; 1° EP: % change in LDL-C Weeks 6-121
• Previous data suggests Tofa ↑LDL-C ≈ 25%2; A ↓LDL-C ≈ 26-37%3
Week 0
Week 6
Week 12
n=111
n=97
n=92
Total chol: A (n=50)
185.6
229.5 (24%↑)
170.0 (26.0%↓)**
PBO (n=47)
202.0
244.4 (21%↑)
250.0 (2.3%↑)
LDL-C:
A (n=50)
109.1
126.0 (16%↑)
81.9 (35.3%↓)**
PBO (n=47)
118.0
140.0 (19 %↑)
148.1 (5.8%↑)
TGs:
A (n=50)
99.5
109.0 (10%↑)
95.0 (14.7%↓)*
PBO (n=47)
102.0
109.0 (7%↑)
115.0 (5.5%↑)
HDL-C
50.5
66.6 (32%↑)
↑ no difference
Apo A1
135.5
164.5 ( 21%↑)
↑ no difference
Median LDL-C achieved in the ATP-III optimal target range
(<100 mg/dL). Efficacy not diminished; similar safety
1. McInnes I, et al. EULAR 2011, London, #LB0003;
2. Kremer J, et al. Arth Rheum 2009;60(Supplement 10):1925;
3. Atorvastatin US approved package labeling, June 2009
*P<0.01; **P<0.0001
BMS
BMS India
India

53. Tofacitinib (Tofa): Phase III monotherapy
(ORAL Solo)¹
ACR20
100
PBO (n=122)
Tofa 5 mg (n=243)
Tofa 10 mg (n=245)
All P<0.05 or P<0.0001 versus placebo except Tofa 5 mg with prior biologic
80
60
40
20
0
• Pfizer press release on X-ray progression: 10 mg but not 5 mg Tofa effective2
• 21 patients in Korea (Phase IIb mono): Significantly less progression than on DMARD controls 3
Tofacitinib effective in multiple subgroups; DB X-ray data coming
1. Fleischmann R, et al. EULAR 2011, London, #SAT0243;
2. Pfizer Press Release April 15, 2011;
3. Choi IH, et al. EULAR 2011, London, #SAT0240
BMS
India

54. ORAL Solo: SF-36 domain scores at Month 3
PF
Age/Gender Norms
Tofa 10 mg BID (n=224)
Tofa 5 mg BID (n=223)
PBO (n=108)
Composite
(Weighted balance)
* MHI
**
*
RE
90
80
70
60
50
40
30
20
10
0
*
RP
*
*
BP
*P<0.05
**P<0.01
***P<0.001
*P<0.0001 vs BL
GHP **
* SF
*
VIT
Clinically meaningful improvements in ALL PROs
Strand V, et al. EULAR 2011, London, #OP0063
*
*
*
*
*
BMS
India

55. Fostamatinib (Syk kinase inhibitor) and
HRQOL: Phase II RCT
• Pro-drug; currently in Phase III RCTs (OSKIRA trials) in RA1
• Phase II RCT: Syk vs PBO in MTX-IR RA at 6 mos2
- Pain (VAS); Patient global (VAS); HAQ-DI; SF-36, FACIT
Patient Reported Outcomes
PBO
n=153
Mean ∆ from BL at Mo 6
SF-36 PCS
SF-36 MCS
FACIT-Fatigue
4.9
3.7
4.5
Fostamatinib
n=304
150 mg QD
100 mg BID3
n=152
n=152
5.9
2.0
5.7
8.5**
4.0
7.4*
*P<0.05; **P≤0.001
- Improvements at Week 1 in Pain and HAQ statistically significant in both Rx
groups vs PBO; Patient global only in 100 mg BID; but not sustained
Improvement in PROs at 6 months only in PCS and FACIT with 100 mg BID
1. Baluom M,et al. EULAR 2011, London, #SAT0247;
2. Weinblatt ME, et al. NEJM 2010;363:1303-12;
3. Weinblatt, ME et al. EULAR 2011, London, #OP0057
BMS
India

56. Tocilizumab in the US (ACT-STAR)
•
•
•
•
•
24-week OL study
DMARD or DMARD + Bio IR at BL
• TCZ 4 mg/kg + DMARD
• TCZ 8 mg/kg + DMARD
- Biologic-IR alone at BL
• TCZ 8 mg/kg monotherapy
3 GI perforations:
- 1 Crohn's, 2 diverticulitis
(subsequently diagnosed)
21% on statins at BL, 11% added
statins during the study
42% TCZ 4 mg/kg + DMARD
maintained to Month 6
% Patients
SAE
SAE → D/C
Deaths (n)
SIE
PMNs (Gr 3)
ALT: 1.5-3x ULN
>3x ULN
LDL-C ≥130
(<130 at BL)
TCZ 4/8 TCZ 8 TCZ 8
+DMARD +DMARD
n=364
n=381 n=138
8.0
3.0
2
3.6
0.8
7.9
8.4
1.0
0
3.9
2.4
13.2
5.8
2.2
0
2.9
5.1
6.1
2.1
1.4
1.5
16.8
17.7
11.7
No difference in SAE, SIE or efficacy between COMBO & MONO TCZ
Is 4 mg/kg really safer than 8 mg/kg?
Weinblatt ME, et al. EULAR 2011, London, #LB0006
BMS
India

57. ACT-STAR: Patient Disposition
Patients enrolled (N=886)
Randomized to
TCZ 4 mg/kg* + DMARD
n=363**
Randomized to
TCZ 8 mg/kg + DMARD
n=360
Assigned to
TCZ 8 mg/kg monotherapy
n=163
Switched to TCZ 8
at Week 8
n=142 (39.2%)
Completed study
n=302
Completed study
n=126
Switched to TCZ 8
after Week 8
n=68 (18.8%)
Withdrew
n=58
Withdrew
n=37
Only exposed to
TCZ 4
n=152 (42.0%)
Safety
n=17
Safety
n=11
Completed study, n=303
Withdrew, n=60
(35 safety / 25 non-safety)
Non-safety
n=41
Non-safety
n=26
*Patients randomized to TCZ 4 + DMARD may have withdrawn prior to Week 8 while still receiving TCZ 4, or after
Week 8 while receiving TCZ 4 or TCZ 8; **1 patient randomized did not receive drug
Weinblatt ME, et al. EULAR 2011, London, #LB0006
BMS
India

58. Tocilizumab: Long-term safety in RCT
• LTE; 4,009 pts (median treatment duration 3.6 ys); 12,293 pt-ys (to 02/2010)
• Most patients on 8 mg/kg q month
Event rate/100 pt-ys (95% CI) over 12-month periods
SAE
SIE
CVA
MI
0-12
15.7 (14.4, 17.1)
4.6 (3.9, 5.4)
0.3 (0.1, 0.5)
0.3 (0.1, 0.5)
13-24
13.9 (12.6, 15.2)
3.9 (3.2, 4.7)
0.1 (0.0, 0.3)
0.2 (0.1, 0.4)
25-36
15.2 (13.7, 16.7)
5.2 (4.3, 6.1)
0.2 (0.1, 0.4)
0.3 (0.1, 0.6)
37-48
14.4 (12.8, 16.0)
4.9 (4.0, 5.9)
0.1 (0.0, 0.3)
0.5 (0.3, 0.9)
Overall
14.7 (14.0,15.4)
4.6 (4.3, 5.0)
0.2 (0.1,0.3)
0.3 (0.2, 0.4)
• Most common AEs leading to discontinuation: Laboratory abnormalities
- 1.1/100 pt-ys, transaminase elevations
• GI perforations 0.24/100 pt-ys; RA background rate 0.17/100 pt-ys
Stable rates of SAE, SIE and CV events over 4 years
Genovese M, et al. EULAR 2011, London, #SAT0270
BMS
India

59. In MTX-IR patients is it better to add TCZ or
switch to TCZ? (ACT-RAY)
2-year RCT
TCZ 8
Endpoint (%)
+MTX
- 24-week data
n=277
- Biologic-naive
DAS28<2.6
40.4
- 8.2 ys disease
61.7
- DAS28(ESR)=6.35 (median) LDAS
- TCZ 8 mg/kg q 4 weeks
ACR20
71.8
• 1º EP: DAS≤2.6
ACR70
24.9
LFT abnormalities (%)
• Other than LFTs, safety
1.5-3x ULN
8.5
data no difference
>3-5x ULN
1.7
•
Efficacy equal whether switch or add.
Do you want to switch rather than add?
Dougados M, et al. EULAR 2011, London, #OP0020
TCZ 8
+PBO
n=276
34.8
51.4*
70.7
25.7
4.4
0.4
*P=0.028
BMS
India

60. aIL-6 mAb in MTX-IR
• Asialated mAb to IL-6 NOT IL-6R
• 80, 160, 320 mg vs PBO,
IV+MTX q 8 wks1
• T½ = 30 days
Responders (%) 1°EP: Week 12 ACR and LDAS
ACR20
100
ACR50
*P<0.05
LDAS
*
*
82
81
*
80
ACR70
71
• SC vs IV dosing:2
- Bioavailability of ALD518
≈ 60% for SC vs IV dosing
- Rapid, sustained reductions in
serum CRP all doses, IV or SC
60
*
50
*
40
34
27
27
9
• Phase III with SC dosing
3
7
12
*
25
21
20
33
46
13
0
PBO (n=33)
Positive proof of concept at Week 12
1. Mease P, et al. ACR 2010, Atlanta, #2168;
2. Shakib S, et al. EULAR 2011, London, #SAT0296
80 mg (n=32) 160 mg (n=34) 320 mg (n=28)
BMS
BMS India
India

61. aIL-6 mAb and HRQOL: SC in Phase III RCTs
Combined BL
Age/Gender Norms
PBO+MTX n=30
80 mg+MTX n=29
160 mg+MTX n=33
320 mg+MTX n=26
*P< 0.05
†P<0.05
‡P<0.05
-PF90
80
‡* H
70
60
R
‡
50
40
30
20
‡*
10
E
B *‡
0
• SC dosing planned in
Phase III RCTs
Mean changes in SF-36
domains support dose selection ‡ * F
and benefit of 320 mg
Strand V, et al. EULAR 2011, London, #SAT0304;
Shakib et al, Ibid, #SAT0296
G *‡
V *† ‡
BMS
India

62. Other aIL-6 mAbs in development
• CNTO 136: POC in Phase II RCT in DMARD-IR:1
- Part 1: 100 mg SC q 2 weeks x5 well tolerated; interim analysis at Week 12
- ACR20: 21% vs 75% (P=0.002); DAS28(CRP) -0.65 vs -1.66 (P=0.001);
good/moderate EULAR: 11%/21% vs 38%/44% (P=0.015) in active group
ACR components (P<0.05 for all, except patient pain)
- 1 SAE: staphylococcal cellulitis in active
- ↓PMNs; ↑ALT; ↑cholesterol in 2/14 PBO vs 3/5 active
- Part 2: Dose-ranging
• CDP6038: Single dose IV and SC administration in 67 healthy volunteers:2
- Selectively blocks final assembly step of IL-6 signaling complex
- PK, PD after IV [0.001-10.0 mg/kg] and SC [0.3, 1.0 or 3.0 mg/kg] dosing
- TEAE higher with PBO vs active: 52.9% vs 33.3%: ‟flu, diarrhea, URI
- ↓PMN; WBC counts and ↑ALT without dose dependency; no ∆ in lipids
- Median T½ = 31.1 days IV and SC; independent of dose
1. Hsu B, et al. EULAR 2011, London, #FRI0345;
2. Hickling M, et al. Ibid, #FRI0378
BMS
India

63. Rituximab long-term safety in RCTs
Incidence per 100 pt-ys
PBO
n=818
• RTX vs PBO:
• Up to 9.5 years follow-up
• Up to 17 courses of RTX
• RTX 500/1000 mg x 2
• AE, SAE/100 pt-ys:
Similar, courses 1-6
• Malignancy SIR: 0.99 vs
SEER
Pt-ys
AE
SAE
Infection
SIE
SOI
All RTX >5 ys RTX
n=3,194
n=627
1,107
11,962
4,418
315
14
90
3.8
0.09
263
14
82
3.9
0.06
254
14
75
3.3
NR
NR, not reported
RTX safety appears to be stable from course to course and over
time in patients who remain in LTE studies
van Vollenhoven RF, et al. EULAR 2011, London, #SAT0267
BMS
India

64. Rituximab potpourri
• B-cell count at Week 26 may predict subsequent response to RTX1
- Absence of B-cells at Week 26: 100% stable/improving DAS28 at Week 40
- Presence of B-cells at Week 26: 45% worse DAS28 at Week 40
• Impaired response to pneumococcal vaccination with RTX2
- RTX and MTX (not TNF-IR) associated with impaired antibody response
following vaccination with heptavalent pneumococcal conjugate vaccine
• JCPyV infections in RTX-treated patients3
-
38% of RTX-treated patients with multiple tests for JCPyV DNA had virus in urine
(generally reported at approximately >75% in the normal population4)
- Isolates belonged to different genotypes not associated with PML
• Patients treated with the addition of RTX to a biologic over 26 weeks 5
- SIE 1.7% vs 1.9% in REFLEX; only 42.6% EULAR moderate/good response
1. Vital E, et al. EULAR 2011, London #OP0012;
2. Kapetanovic MC, et al. Ibid, #OP00163;
3. Verheyen J, et al. Ibid, #SAT0268;
4. Walker DL, Padgett BL Prog Clin Biol Res 1983;105:99-106;
5. Rigby W, et al. EULAR 2011, London, #SAT0308
BMS
India

65. Ofatumumab (OFA), a fully human
aCD20 mAb, in biologic-naive RA
• Phase III double-blind vs PBO1
• MTX-IR; mean 8.5 ys disease
•
•
•
700 mg OFA at Weeks 0 and 2,
+ 100 mg IV MP
1º EP: ACR20 at Week 24
Safety
- No immunogenicity
- Rash (21%); urticaria (12%) vs
<1% PBO
•
SC in development without
steroid pre-treatment2
ACR20
ACR50
60
ACR70
**
50
50
40
30
**
27
27
*
13
20
11
10
2
0
PBO
Small delta in ACR responses; SC in development
1. Taylor PC, et al. EULAR 2011, London, #OP0019;
2. Kurrasch R, et al. Ibid, #SAT0288
OFA
n=131
n=129
*P<0.01; **P<0.001
BMS
India

66. Anti-BAFF mAb in RA1
80
ACR20
70
• 156 MTX-IR; active RA
61
54
44
45
• LY 1, 3, 10, 30, 60,120 mg SC q 4 wks x6
47
40
40
30
7*
ACR50
60
50
• Human mAb; neutralizes membrane-bound
and soluble BAFF
38
33
22
20
10
10
10
11
0
PBO
1
3
10
30
LY mg
*P<0.05 vs PBO
(one-sided Fisher‟s exact test)
8
•
1° EP: Dose response of ACR50
• Safety:
- SAE: 10% LY vs 11.1% PBO
- SIE: 2.5% LY vs 0% PBO
• Decreases in mean IgM and IgA at higher
LY doses: Not associated with infections
60 120
• Study with LY IV Q 3 weeks X3 at 30 or 80
mg vs PBO in TNF-IR; ACR50 at Wk 16 as
1° EP, not statistically different2
Anti-BAFF mAb, at these doses and frequency, not effective in RA
1. Genovese M, et al. EULAR 2011, London, #OP0017;
2. Genovese M, et al. Ibid, #SAT0275
BMS
India

67. Safety of SC abatacept in patients with RA:
Analysis of five RCTs ≤4.5 years
•
Exposure (SC)1
- 1,879 patients
- 3,086 pt-ys
- 1,191 (63%) treated >18 mos
- Mean duration of treatment
20 mos (range: 2-56)
•
Exposure (IV)2
- 4,149 patients
- 12,132 pt-ys
- 1,165 (28%) treated ≥5 ys
- Mean duration of treatment
36 mos (range: 2-104)
Safety SC ≈ IV abatacept
1. Alten R, et al. EULAR 2011, London, #SAT0292;
2. Hochberg MC, et al. ACR 2010, Atlanta, #390
SAEs
IV ABA
10 mg/kg
0.55
0.60
(0.47-0.76)
9.53
14.61
(8.46-10.72)
Deaths
SC ABA
125 mg/wk
(0.34-0.89)
Incidence rates:
Events/100 pt-ys
(13.85-15.41)
Serious infections
SIEs
Pneumonia
Lobar
pneumonia
Herpes zoster
TB
1.94
2.87
(1.50-2.50)
(2.57-3.19)
0.36
0.46
(0.20-0.65)
(0.34-0.59)
0.10
0.11
(0.03-0.30)
(0.06-0.18)
0.10
0.03
(0.03-0.30)
(0.01-0.08)
0.03
0.03
(0.00-0.23)
(0.00-0.23)
BMS
BMS
India
India

68. Does SC abatacept require IV loading?
•
1.6
1.4
1.2
Comparison of two Phase III trials, with or without IV loading1
HAQ-DI
6.0
Baseline Month 3
1.0
1.1
4.0
3.0
0.8
0.6
0.7
0.4
5.4
4.7
3.8
3.2
2.0
1.0
0.2
0.0
0.0
IV loading (n=167) No IV loading (n=100)
•
Baseline Month 3
5.0
1.4
1.3
DAS(CRP)
IV loading (n=167) No IV loading (n=100)
Similar Cmin in both studies2
Not head-to-head; IV probably not needed
1. Nash P, et al. EULAR 2011, London, #SAT0287;
2. Murphy, B et al. Ibid, #FRI0346
BMS
India

69. Abatacept potpourri
One can effectively and safely switch from IV to
SC1
• IV vs SC in a head-to-head is equal in efficacy 2
• Subset analysis of fixed dose of ABA SC vs IV
for weight and disease duration have equal
benefits and similar safety3
• It appears that we can effectively and safely start
and stop SC ABA3
•
1. Keystone E, et al. EULAR 2011, London, #FRI0351;
2. Genovese M, et al. Ibid, #OP0023;
3. Kaine JL, et al. Ibid, #FRI0366
BMS
India

70. Abatacept & tocilizumab in routine care
(DANBIO)
•
ABA (n=150), TCZ (n=178)
- almost all after first biologic
•
48-week results
•
Drug survival:
- ABA 50%
- TCZ 60%
DAS28 variables: Time since treatment initiation (weeks)
6
14
Abatacept
Tocilizumab
5
4
•
DAS28(CRP) remission:
- ABA 26% (n=38)
- TCZ 58% (n=19)
EULAR good/moderate:
- ABA 77%
- TCZ 84%
6
2
4
1
2
0
0
6
36
12
48
24
70
Abatacept
80
Tocilizumab
60
50
40
30
20
10
0
0
6
12
24
36
In TNF-IR, 2/3 of ABA, TCZ survive to 48 weeks
Leffers HC, et al. EULAR 2011, London, #FRI0358
Tocilizumab
10
8
3
0
•
Abatacept
12
48
0
6
12
24
20
18
16
14
12
10
8
6
4
2
0
36
48
Abatacept
Tocilizumab
0
6
12
24
36
48
BMS
India

71. Abatacept & rituximab use after malignancy:
AIR & ORA registries
•
Prospective 5-yr registries
ABA
- AIR = RTX; n=2,000
- ORA = ABA; n=1,000
•
History of cancer
268 RTX (13.6%)
– 54 ABA (5.4%)
Death
RTX
1 (infection)
5 (cancer)
1
3
-
•
•
Most common cancer: Breast
Median duration after cancer to
first infusion
- RTX 4 ys
- ABA 7 ys
•
191/268 RTX, 41/54 ABA had
follow-up
New cancer
New
metastasis
Severe
infection
6
1
(18 mos after
1st infusion)
7.4%
7.1%
Is it really preferable to use rituximab vs other biologics in patients
with previous cancer?
Gottenberg JE, et al. EULAR 2011, London, #FRI0363
BMS
India

72. Drug retention in TNF-IR:
2nd TNFi or ABA/RTX/TCZ
•
Swiss RA cohort SCQM-RA;
1,497 biologic courses in TNF-IR
-
–
•
Time to discontinuation of biologic agents
858 2nd TNF
629 non-TNF biologic
Total of 2,142 pt-ys on biologics
- Higher GC and MTX in TNF group
- Prior TNFs: 2.7 TNF group vs
2.0 non-TNF group
•
Drug retention:
-
•
2nd TNF vs non-TNF:
Adjusted HR 2.12 (1.74-2.6)
Other BIO
Anti-TNF
80
60
40
20
P<0.001
Median survival time
- 2nd TNF = 21 mos (IQR 8-53)
– Non-TNF = 32 mos (IQR 14-64)
•
100
Reasons for discontinuation unknown
0
0
1
2
3
4
Time (year)
Swiss conclude: After first TNF, non-TNF biologics are better;
do you agree?
Martin-du-Pan Prujim S, et al. EULAR 2011, London, #SAT0298
5
BMS
India

73. Not ready for prime time
• Oral S1P lyase inhibitor LX3305: Failed in Phase II to show efficacy in MTX
IR in RA with a good safety profile
- Higher doses will be explored in a further IB study for efficacy and safety¹
• IL-10 producing T-reg 1 cells: In human serum in patients with severe RA,
migration to synovium and suppressive capacity demonstrated2
• Anti-lymphotoxin mAb: Phase I RCT in DMARD-IR RA: SAD, MAD:
3 mg/kg q 2 wks x 3: at Week 6 preliminary efficacy; linear PK, biologic
effect: ↓↓ CXCL-13 demonstrated with acceptable safety; not POC3
• Rheumavax: Autologous tolerizing dendritic cells exposed to citrullinated
peptides: Phase I in 18 DR+ACPA+DMARD-IR RA vs 11 controls [OL]4:
-
7 maintained DAS<2.6 over 6 mos; 6 attained DAS<2.6 for 3-6 mos; 5: NR
– 9 controls: NR; 2: DAS ↓
1.
2.
3.
4.
Fleischmann R, et al. EULAR 2011, London, #OP0059;
Asnagli H, et al. Ibid, #OP0119;
Emu B, et al. Ibid, #OP0018;
Thomas R, et al. Ibid, #LB0004
BMS
India

74. BMS
India