Download - EULAR 2011 updates

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EULAR 2011-RA updates

By A.Arputha Selvaraj APMP IIM Calcutta

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

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Diagnosis

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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

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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

Sens. (%)

Spec. (%)

PPV (%)

NPV (%)

LR+

LR-

2010 1987

80 86

81.7 81.7

74.1 75.4

86.2 89.9

4.37 4.7

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

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Remission

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CATCH: Remission prevalence in early RA -new criteria vs other criteria

RF+/ Bio CCP+ (n) %

100 Mean CRP (mg/dL) 80

% remission at 12 months

DAS28<2.8 56/62 7 0.33 60 53 DAS28<2.0 55/61 7 0.26

SDAI<3.3 59/64 9 0.32

CDAI<2.8 58/64 10 0.38

ACR/EULAR 54/65 8 0.27

40

20

0

36 27 25 22

• 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

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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 normal4

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

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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/EULAR15

10 DAS28 2.6

CDAI 5 ACR/EULAR

0

0 10 20 30 40 50 60 70 80 90 100% patients

New ACR/EULAR criteria performed similarly to established criteria

Lillegraven S, et al. EULAR 2011, London, #SAT0398

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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

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Early RA

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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=466**

ADA 40 mg EOW+MTX *

n=460**

MTX*

n=207

Yes DAS28

<3.2 No

n=259

n=112 Yes

DAS28 <3.2

No

MTX n=102

ADA 40 mg EOW+MTX n=105

OL ADA 40 mg EOW+MTX

MTX

OL ADA 40 mg EOW+MTX

ARM 1 ADA+MTX / MTX

ARM 2 Sustained ADA+MTX

ARM 3 Primary ADA+MTX IR/ADA+MTX efficacy

outcome†

ARM 4 Sustained MTX

† DAS28 <3.2

and mTSS <0.5 ARM 5

n=348 MTX IR/ADA+MTX at Week 78

0 w PERIOD 1 26 w

PERIOD 2 78 w

* MTX titrated to 20 mg/wk by Wk 8; ** Completed study period

Smolen J, et al. EULAR 2011, London, #THU0243

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OPTIMA: ADA+MTX / MTX vs sustained ADA+MTX

ADA+MTX / MTX (n=88)

ACR

Sustained ADA+MTX (n=94)

Radiographic prog: % pts 100 ACR20

100 89.0 88.0 89.0

ACR50 80

ACR70

60

40 26 30 34 38 42 46 50 54 58 62 66 70 74 78

Weeks

80 89.0

60

40

20

0 26

85.0 81.0

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

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OPTIMA: Sustained ADA+MTX vs sustained MTX at Week 78

Sustained ADA+MTX (n=94) Sustained MTX (n=98)

100

80

60

40

20

0

*

LDAS + mTSS 0.5 from

BL

* 100 *

75

50

25

0 ACR20 ACR50 ACR70

*P<0.05: ADA+MTX vs • sustained MTX

X-ray progression 89 88 89

82 82 78

26 52 78

44% Arm 2 v 24% Arm 1 achieved LDA during phase 1

Although both groups did well in LDA; patients on TNFi/ MTX did slightlybetter than those on MTX alone

N Smolen J, et al. EULAR 2011, Lon don, #THU0243

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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

80

60

40

71.3 58.4

49.5

MTX (n=89)

43.8

28.3

ADA (n=92) MTX/ADA (n=89)

50.6

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

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Early addition of low-dose prednisone to tight control: CAMERA II

• DB study, 236 early RA pts (<1 y)

• MTX + PBO vs MTX + Pred 10 mg QD

- Pred continued for 2 ys

- Evaluated once a month

• ADA added for failure to reach target

• At 2 years:

- Lower disease activity and disability in Pred group

- No ↑ DM, infections or fractures

- Lower LFTs and ADA in Pred group

80 P=0.09 MTX+Pred

70 MTX 60

50

40 P<0.001

30

20

10

0 % REM % on TNFi % AE

Low-dose prednisone at start of Tx leads to better control and noincrease in toxicity

Bakker MF, et al. EULAR 2011, London, #OP0138

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Smokers have no “window of opportunity”

• 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

• Smokers did not show this trend

Change in DAS28 over time

-0.05 Non smoker Current smoker

-1.50

-2.50

-3.50

2 - 12 months 2 - 12 months

Smokers are less likely to respond to early treatment of RA

Söderlin M, et al. EULAR 2011, London, #SAT0372

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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 for6 months; especially with very low DAS28

Tanaka Y, et al. EULAR 2011, London, #OP0154

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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

DAS28 median

Remission %

LDAS only %

LDAS + remission % HAQ median

*P<0.001

Baseline Year 3

4.0 3.1*

22.8 32*

12.5 19.6*

35.3 51.6*

1.35 1.25

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

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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 CZP (n=320) P<0.001 Control (n=80)

80

60

40

20

0

P<0.01

47.2

27.5

53.5

25

47.6

20.8

51.9 52.3

27.8 25

53.5 46.7 48.3

30.6 25

12.5

Prior TNFi No prior 0 1 ≥2 0 1 2TNFi

ACR20 No. of concomitant No. of prior TNFiDMARDS

CZP shows efficacy after TNFi exposure and as monotherapy in RA

Weinblatt ME, et al. EULAR 2011, London, #FRI0214

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No mortality differences between TNF inhibitors

2 • ARTIS database (Sweden); N=6,322

1.5

• Compared mortality Ref1

between ADA, ETN and IFX

0.5

• 211 deaths (3.3%)

0 ETN ADA IFX

(n=2,686) (n=1,609) (n=2,027)

No difference in mortality regardless of adjustments for co-factorsor other modeling techniques

Simard J, et al. EULAR 2011, London, #OP0158

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Safety

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Effect of treatment on mortality in RA

• BSRBR RA pts, DAS28>4.2

• >5 y f/u; ETN vs DMARDs

• ETN: higher disease activity / 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

N (pt-ys)

Mean f/u

Age

RA duration

HAQ

Deaths

Deaths/1000 pt-ys

*P<0.001

ETN pts DMARD controls

3,470 1,365 (14,382) (5,583)

4.1 ys 4.1 ys

55.4 ys 59.5 ys*

13.6 ys 9.6 ys*

2.1 1.7

188 127

13.1 22.2

Mortality not elevated; may be lower with TNFi therapy in RA

Emery P, et al. EULAR 2011, London, #LB0007

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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

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

distribution between disease 0.0

duration < or > 10 ys 5.0 10.0 15.0 20.0 25.0

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

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Cancer risk and RA treatments: Two studies

8

7

6

5

4

3

2

1

0

BSRBR - DMARD1

(n=3,727; 148 w/cancer)

Lym

ph

NHL Melan

Myelo Lung

All excl. NMSC

Solid B

reast Colorect

DANBIO - TNFi2

• 13,699 pts; 5,598 on TNFi

• Cancer in 313

• RR: 1.05 (CI 95% 0.82-1.34) vs DMARD

• No increase in any CA

- Including NMSC & non-Hodgkins

- No effect of duration of Tx

- 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

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SIE with TNFi in RA: DREAM and GISEA registries

10 DREAM registry1 10 GISEA registry2

9 (N=2,157, since 2003) (N=2,769)

8 87

6 65

4 43

2 2

1

0 0ETN ADA IFX ETN ADA IFX

• Adj HR: 1.02 ADA vs IFX; 0.59 vs mAb • Sig diff in SI risk in ADA, ETN & IFX• IFX pts tended to have worse prognosis 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

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Risk factors associated with GI perforation in RA patients

RR of GI perforation during f/u (adjusted results) HR (95% CI)

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 1 2 3 4 11 13 15 17 19

GI perforation is rare and increases with age, steroids, andespecially history of diverticulitis; NSAIDs impose a minor risk

Curtis J, et al. EULAR 2011, London, #OP0159

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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)

• 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

56% TST+ QFT+ 45% 9.3%

- 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% 50% (RR=2.5) (RR=4.8)

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

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Imaging

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Which comes first: JSN vs JE? PREMIER, MTX-naive, early RA

3

2

1

0 JE All

@Wk26 Swelling Wks 26-52

MTX vs MTX vs ADA ADA+MTX

• 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+

– 66 (29.2%) JE+/SJ-

– 67 (29.6%) JE+/SJ+

• 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

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Do NSAIDs affect US activity in RA patients?

N=58 Stopped Continued P-valueNSAID NSAID

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 inlower scores despite ongoing disease activity; considerationshould be given to NSAID effect in designing US clinical studies

Zayat AS, et al. EULAR 2011, London, #OP0242

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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 & osteitis at Week 12 sustained at Week 52

Synovitis

20 15

10

Osteitis Erosions

*P<0.05 vs BL

* • No significant change in mean erosions over 52 weeks

• No patients developed new regions of synovitis

5

0

*

BL Week 12

* *

Week 52

Early reduction of synovitis & osteitis by MRI with TCZmaintained through 1 year

Troum O, et al. EULAR 2011, London, #SAT0282

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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

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JIA

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Switching in JIA

• In SoJIA (German JIA Registry, 20

N=1,345), switching to 2nd 15

TNFi or ABA was 10 unsuccessful1

5

• In PolyJIA switching to a 2nd 0

TNFi gave favorable results1

• In some PolyJIA pts, switching 40

to CZP may also be effective2 30

20

Switching from one biologic to 10

another may be effective, but SoJIA patients respond differently than 0

PolyJIA patients

1. Horneff G, et al. EULAR 2011, London, #FRI0176;

Systemic JIA: Last response

0 response PedACR30 PedACR50 PedACR70

ETN IFX ADA ANA TCZ ABA n=26 n=1 n=4 n=21 n=2 n=2

Poly JIA: Last response

ETN IFX ADA ANA TCZ ABA n=57 n=10 n=43 n=4 n=4 n=5

2. Tzaribachev N, et al. Ibid, #FRI0194

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TENDER: TCZ effective in persistent SoJIA

• 12 wk DBPCRT followed by OL Tx

• TCZ 8 (>30 kg) or 12 (<30 kg) mg/kg

• All patients received OL TCZ 8 or 12 mg/kg in part 2

• Primary outcome: ACR JIA 30 + no fever

• Week 12 response maintained at Week 52; 52% pts able to D/C steroids

• Safety: 15 SIEs; 1 infusion reaction; 2 grade IV neutropenias; 3 deaths (1 MVA; 1 pneumothorax; 1 unknown)

ACR30+no fever ACR70 ACR90

100 Week 12 Week 52

80

60

40

20

0 Control TCZ TCZ (n=37) (n=75) (n=88)

One year of TCZ is highly effective and generally welltolerated in patients with SoJIA

De Benedetti F, et al. EULAR 2011, London, #OP0006

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Miscellaneous

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Work outcomes

• GLM+MTX vs MTX ↑ employability by 0.96 ys (female)/0.87 ys (males)1

• RA imposes a burden similar to DM justifying cost of treatment2

- 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

% patients unemployable at

BL and

40 employable at Week 241 33*

30 *P<0.05

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

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Alcohol intake and inflammatory polyarthritis (IP) in Norfolk Arthritis Register (NOAR)

1.3 ↓risk for every 1 unit/day consumed

(hazard ratio)

1.0

0.8

0.7

0.6

0.5 IP RA Sero+ IP

• 184 incident IP patients among 25,639 population

• 138 fulfilled 1987 RA criteria

• Smoking ↑ risk RA & IP

• EtOH 16% ↓ risk/unit consumed

HR (95% CI) ↑ risk IP in

Fully adj. age, gender , smoking, BMI, diabetes, social class

Fully adj. age, gender , smoking, BMI, diabetes, social class, parity & breastfeeding

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 andnegates effect of smoking

Lahiri M, et al. EULAR 2011, London, #OP0025

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Sexual dysfunction in RA

• 231 RA patients1

- 91 male/140 female

• Among men

RA has a significant impact on my sex life2

100% 72% All

- 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

80% 67% 65% 60%

40%

20%

0%

Sexual dysfunction is common in RA; strong association between sexual dysfunction and cardiovascular disease

Men

Women

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Patient-reported outcome measures

• Japan1 & Finland2 - pts evaluated with RAPID3, CDAI and DAS28

• Correlation:1

- RAPID3 vs DAS28 r=0.66

- RAPID 3 vs CDAI r=0.78

• 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

5

4

3

2

1

0

-1

-2

-3

-4

-5 -5

Standard change RAPID3 vs CDAI2

-4 -3 -2 -1 0 1 2 3 4 5 Standard change of RAPID3

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

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Utility of a biomarker test in RA

• Multi-biomarker disease activity (MBDA; sold as VECTRA™) test for RA

• 126 pts from BeSt

• Serum at BL and 1 y; correlated with ΔSHS (BL1, 2 ys)

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

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Predictors of X-ray progression Year 1 to 2

BMS

India

BMS

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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

BMS

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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

• 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

TJC SJC DAS28 CRP

15

10 6

54 w/o PD w/ PD

0 2 BL 6 mo BL 6 mo

– PD+ (8/18): no improvement after0 6 mos of TNFi treatment

1-2 3-6PD score - PD- (10/18): respond best to TNFi

PD prevalent in RA; TNFi treatment does not affect PD, but patients withPD may have blunted response to TNFi

1. De Smit M, et al. EULAR2011, London, #THU0289;2. Savioli C, et al. Ibid, #SAT0138

BMS

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BMS

India

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

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BMS

India

Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) incombination with traditional DMARDs (ORAL Sync)

5 mg BID 10 mg BID PBO5 mg PBO10 mgn=315 n=318 BID n=79 BID n=80

Tender joints (68), mean 25.0 26.6 27.2 21.9Swollen joints (66), mean 14.5 14.4 14.6 13.9HAQ-DI, mean 1.44 1.43 1.45 1.24DAS28-4(ESR), mean 6.29 6.36 6.44 6.16Prior DMARD useMTX, % 86.7 82.7 83.5 82.5

Other traditional DMARDs, % 73.7 76.1 69.6 77.5

TNFi, % 7.3 6.0 6.3 6.3Other Biologic DMARD use, % 2.2 3.1 7.6 0.0DispositionPatients completing, % 82.1 79.2 89.9 83.8D/C due to AE, % 6.4 9.1 2.5 3.8D/C due LOE, % 5.1 3.8 3.8 3.8

Kremer J, et al. EULAR 2011, London, #LB0005 78

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BMS

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ACR20 at Mo 6

PBO Tofa 5 mg Tofa 10 mg 70

60

50

40

30

20

10

0

* 52.7

31.2

* 58.3

*P<0.0001 vs PBO


BMS

India

BMS

India


0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

HAQ-DI to Month 3

PBO

-0.21

-0.46 *

-0.56 *

Tofa 5 mg

16

14

12

10

8

6

4

2

0

DAS28<2.6 to Month 6

Tofa 10 mg * 14.8

* 11.0

2.7

*P<0.0001 vs PBO


BMS

India

BMS

India

Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) incombination 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 PBOBID 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


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Month 3 Post Month 6

PBO 5 mg 10 mg PBO5 PBO10 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 82

BMS

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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


BMS

India

BMS

India

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 12n=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;

*P<0.01; **P<0.0001

3. Atorvastatin US approved package labeling, June 2009BMS India

BMS

India

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 controls3

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

BMS

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ORAL Solo: SF-36 domain scores at Month 3

Age/Gender Norms Tofa 10 mg BID (n=224) Tofa 5 mg BID (n=223) PBO (n=108) Composite (Weighted balance)

*P<0.05 **P<0.01 ***P<0.001

*P<0.0001 vs BL

* MHI **

* RE

* SF *

PF 90 80 70 60 50 40 30 20 10 0

VIT

*

RP * *

BP

GHP ** *

*

*

* *

Clinically meaningful improvements in ALL PROs Strand V, et al. EULAR 2011, London, #OP0063

BMS

India

BMS

India

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 Fostamatinibn=153 n=304

Mean ∆ from BL at Mo 6 150 mg QD 100 mg BID3

n=152 n=152SF-36 PCS 4.9 5.9 8.5**

SF-36 MCS 3.7 2.0 4.0FACIT-Fatigue 4.5 5.7 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

BMS

India

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 +DMARD +DMARD

n=364 n=381

8.0 8.4 3.0 1.0 2 0

3.6 3.9 0.8 2.4 7.9 13.2

2.1 1.4

16.8 17.7

TCZ 8

n=138

5.8 2.2 0

2.9 5.1 6.1

1.5

11.7

No difference in SAE, SIE or efficacy between COMBO & MONO TCZIs 4 mg/kg really safer than 8 mg/kg?

Weinblatt ME, et al. EULAR 2011, London, #LB0006

BMS

India

BMS

India

ACT-STAR: Patient Disposition

Patients enrolled (N=886)

Randomized to TCZ 4 mg/kg* + DMARD

n=363**

Switched to TCZ 8 at Week 8

n=142 (39.2%)

Switched to TCZ 8 after Week 8 n=68 (18.8%)

Only exposed to TCZ 4

n=152 (42.0%)

Completed study, n=303 Withdrew, n=60

(35 safety / 25 non-safety)

Randomized to TCZ 8 mg/kg + DMARD

n=360

Completed study n=302

Withdrew n=58

Safety n=17

Non-safety n=41

Assigned to TCZ 8 mg/kg monotherapy

n=163

Completed study n=126

Withdrew n=37

Safety n=11

Non-safety n=26

*Patients randomized to TCZ 4 + DMARD may have withdrawn prior to Week 8 while still receiving TCZ 4, or afterWeek 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

BMS

India

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

0-12 13-24 25-36 37-48 Overall

SAE 15.7 (14.4, 17.1) 13.9 (12.6, 15.2) 15.2 (13.7, 16.7) 14.4 (12.8, 16.0) 14.7 (14.0,15.4)

SIE 4.6 (3.9, 5.4) 3.9 (3.2, 4.7) 5.2 (4.3, 6.1) 4.9 (4.0, 5.9) 4.6 (4.3, 5.0)

CVA 0.3 (0.1, 0.5) 0.1 (0.0, 0.3) 0.2 (0.1, 0.4) 0.1 (0.0, 0.3) 0.2 (0.1,0.3)

MI 0.3 (0.1, 0.5) 0.2 (0.1, 0.4) 0.3 (0.1, 0.6) 0.5 (0.3, 0.9) 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

BMS

India

In MTX-IR patients is it better to add TCZ or switch to TCZ? (ACT-RAY)

• 2-year RCT - 24-week data - Biologic-naive

Endpoint (%) TCZ 8 TCZ 8 +MTX +PBO n=277 n=276

- 8.2 ys disease DAS28<2.6 40.4 34.8

- DAS28(ESR)=6.35 (median) LDAS 61.7 51.4*

- TCZ 8 mg/kg q 4 weeks ACR20 71.8 70.7• 1º EP: DAS≤2.6 ACR70 24.9 25.7

• Other than LFTs, safety data no difference

LFT abnormalities (%)

1.5-3x ULN 8.5 4.4

>3-5x ULN 1.7 0.4

*P=0.028Efficacy equal whether switch or add.Do you want to switch rather than add?

Dougados M, et al. EULAR 2011, London, #OP0020

BMS

India

BMS

India

aIL-6 mAb in MTX-IR

• Asialated mAb to IL-6 NOT IL-6R

• 80, 160, 320 mg vs PBO, 100

IV+MTX q 8 wks1

Responders (%) 1°EP: Week 12 ACR and LDAS

ACR20 ACR50 ACR70 LDAS

*P<0.05

• T½ = 30 days 80

• SC vs IV dosing:2 60

- Bioavailability of ALD518 ≈ 60% for SC vs IV dosing

40

- Rapid, sustained reductions in serum CRP all doses, IV or SC 20

• Phase III with SC dosing

0

27

9 3

* 81

* 71

27 21

12 7

* 82

* 50

* 34 33

* 25

13

46

PBO (n=33) 80 mg (n=32) 160 mg (n=34) 320 mg (n=28)

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

BMS India

BMS

India

aIL-6 mAb and HRQOL: SC in Phase III RCTs

- -PF Combined BL 90

80 Age/Gender Norms ‡ * 70 ‡ 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 ‡ *

• SC dosing planned in Phase III RCTs

H

E

60

50

40

30

20

10

0

R

* ‡ B

Mean changes in SF-36 domains support dose selection ‡ * F G * ‡and benefit of 320 mg

V *† ‡Strand V, et al. EULAR 2011, London, #SAT0304;Shakib et al, Ibid, #SAT0296

BMS

India

BMS

India

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

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BMS

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Rituximab long-term safety in RCTs

Incidence per 100 pt-ys

• 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

PBO All RTX n=818 n=3,194

1,107 11,962

315 263 14 14

90 82 3.8 3.9

>5 ys RTX n=627

4,418

254 14

75 3.3

SOI 0.09 0.06 NR

NR, not reported

RTX safety appears to be stable from course to course and overtime in patients who remain in LTE studies

van Vollenhoven RF, et al. EULAR 2011, London, #SAT0267

BMS

India

BMS

India

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 weeks5

- 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

BMS

India

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 ** 50

50

40

30 27

20

11 10

2 0

PBO n=131

ACR70

** 27

* 13

OFA n=129

Small delta in ACR responses; SC in development*P<0.01; **P<0.001

1. Taylor PC, et al. EULAR 2011, London, #OP0019;2. Kurrasch R, et al. Ibid, #SAT0288

BMS

India

BMS

India

Anti-BAFF mAb in RA1

80

70

60

50

40

30

20

10

0

ACR20 ACR50

61

47 44 45

40

33

22

10 10 11

PBO 1 3 10 30

LY mg

• 7*

• 54

•

38 •

•

8

•

60 120 •

Human mAb; neutralizes membrane-bound and soluble BAFF

156 MTX-IR; active RA

LY 1, 3, 10, 30, 60,120 mg SC q 4 wks x6

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

Study with LY IV Q 3 weeks X3 at 30 or 80 *P<0.05 vs PBO (one-sided Fisher‟s exact test) 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

BMS

India

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;

Incidence rates: Events/100 pt-ys

Deaths

SAEs

Serious infections

SIEs

Pneumonia

Lobar pneumonia

Herpes zoster

TB

SC ABA IV ABA 125 mg/wk 10 mg/kg

0.55 0.60 (0.34-0.89) (0.47-0.76)

9.53 14.61 (8.46-10.72) (13.85-15.41)

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)

2. Hochberg MC, et al. ACR 2010, Atlanta, #390

BMS India

BMS

India

Does SC abatacept require IV loading?

• Comparison of two Phase III trials, with or without IV loading1

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

•

HAQ-DI

Baseline Month 3

1.4 1.3

1.1

0.7

IV loading (n=167) No IV loading (n=100)

Similar Cmin in both studies2

6.0

5.0

4.0

3.0

2.0

1.0

0.0

DAS(CRP)

Baseline Month 3

5.4

4.7

3.8

3.2

IV loading (n=167) No IV loading (n=100)

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

BMS

India

Abatacept potpourri

• One can effectively and safely switch from IV to SC1

• IV vs SC in a head-to-head is equal in efficacy2

• 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

BMS

India

Abatacept & tocilizumab in routine care (DANBIO)

• ABA (n=150), TCZ (n=178) - almost all after first biologic

DAS28 variables: Time since treatment initiation (weeks) 6 14

Abatacept

• 48-week results

• Drug survival: - ABA 50% - TCZ 60%

• DAS28(CRP) remission: - ABA 26% (n=38) - TCZ 58% (n=19)

• EULAR good/moderate: - ABA 77% - TCZ 84%

5

4

3

2

1

0 0 6 12

24

80 70

60

50

40

30

20

10

0 0 6 12 24

Abatacept

Tocilizumab

36 48

Abatacept

Tocilizumab

36 48

12

10

8

6

4

2

0 0 6 12 24

20

18 16

14 12

10 8 6 4

2 0

0 6 12 24

Tocilizumab

36 48

Abatacept

Tocilizumab

36 48

In TNF-IR, 2/3 of ABA, TCZ survive to 48 weeks

Leffers HC, et al. EULAR 2011, London, #FRI0358

BMS

India

BMS

India

Abatacept & rituximab use after malignancy: AIR & ORA registries

• Prospective 5-yr registries - AIR = RTX; n=2,000 - ORA = ABA; n=1,000

• History of cancer - 268 RTX (13.6%) – 54 ABA (5.4%)

• 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

Death

New cancer

New metastasis

Severe infection

ABA

1 (infection)

1

1

7.4%

RTX

5 (cancer)

3

6 (18 mos after 1st infusion)

7.1%

Is it really preferable to use rituximab vs other biologics in patientswith previous cancer?

Gottenberg JE, et al. EULAR 2011, London, #FRI0363

BMS

India

BMS

India

Drug retention in TNF-IR: 2nd TNFi or ABA/RTX/TCZ • Swiss RA cohort SCQM-RA;

1,497 biologic courses in TNF-IR - 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)

• Median survival time - 2nd TNF = 21 mos (IQR 8-53)

– Non-TNF = 32 mos (IQR 14-64)

• Reasons for discontinuation unknown

Time to discontinuation of biologic agents

100

Other BIO 80 Anti-TNF

60

40

20 P<0.001

0

0 1 2 3 4 5 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

BMS

India

BMS

India

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. Fleischmann R, et al. EULAR 2011, London, #OP0059;2. Asnagli H, et al. Ibid, #OP0119;3. Emu B, et al. Ibid, #OP0018;4. Thomas R, et al. Ibid, #LB0004

BMS

India

BMS

India

Download - EULAR 2011 updates

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