Treat to Target, Role of Orencia in Achieving the target.

Prof. Hassan El-ShahalyProfessor of Rheumatology and Rehabilitation

Suez Canal University

ELAR congress, Alexandria 2013

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

Rationale 1987 ACR

criteria

Elaborated in established RA

Considered as classification

criteria

Lack of sensitivity in early disease

Current trends in RA

Recognize the patients as soon

as possible

Treat the patients as soon as the

diagnosis is made

investigate new drugs/strategies at an early stage of the disease

ACR /EULAR classification criteria for RA

5

Early treatment reduces disability 5 years later

according to: Wiles NJ, et al. Arthritis Rheum 2001; 44: 1033 - 42* Odds ratio of HAQ ≥1

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Degr

ee o

f Disa

bilit

y*af

ter 5

Year

s

<6 months(n = 60)

6-12 months(n = 47)

>12 months(n = 76)

0.9

2.4 2.3

Objectives

To recognise the disease at an early stage.

To develop a set of rules to be applied in newly patients with

undifferentiated synovitis

• Identify the subset at high risk of chronicity & erosion

• Be used as a basis for initiating disease modifying therapy

ACR /EULAR classification criteria for RA

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

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

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) 3

> 10 joints(at Least one small joint) 5

Sérology (0-3)RF négative ET ACPA négative 0

RF low level (1 à 3 x ULN ) ORACPA low level (1 à 3 x ULN) 2

RF high level(> 3 x ULN) ORACPA high level (> 3 x ULN) 3

Symptoms duration (0-1)< 6 weeks 0

≥ 6 weeks 1

Acute Phase reactants (0-1)CRP normal AND ESR normal 0

CRP abnormal OR ESR abnormal 1

RA: score ≥ 6

≥1 1 swollen joint

Not best explained by another disease

Yes

No

yesNew criteria for RAFulfilled?

No RA

RA

Typical RA erosion on X-ray*

MANAGEMENT

Prevention / arrest of joint damage

Prevention / reversal of disability

Preventionof systemic co-morbidities:CV diseases,osteoporosis….

Sustained Remission

Management of patients with RA

Therapeutic objectives

Remission

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.

EULAR RECOMMENDATIONS FOR THE MANAGEMENT OF RA WITH SYNTHETIC AND BIOLOGICAL DMARDs

Smolen J. et al.Ann Rheum Dis 2010;-69:964-75Combe et al. Ann. Rheum. Dis. 2007; 66: 34-45

Turning recommendations into optimal treatment strategies

12

Early referral

Starting biologic agents

Treat to target

Short & long -term goals

Tight control usingcompositemeasures

Considerpoor

prognosticfactors

Early institution of DMARDs

Pre-determined treatment targets

Remission orLDAS

as soon as possible

Maximising HRQOL for the long-term

Shared decision between

doctorand

patient

Rheumatol-ogists

are primary carers

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

Boers M et al. Lancet. 1997;350:309-318.

Step-downtherapy

SSZ alone

Step-down (MTX + SSZ + Pred)

SSZ

MTX 7.5 mg/week

Weeks16 280

0.0

0.4

0.8

1.2

1.6

Prednisolone 7.5 mg/day

Prednisolone60 mg/day

SSZ 2000 mg/day

Pool

ed In

dex

Systematic literature review: from 1995 to 2008 Meta-analysis of 6 studies

Tight control and predefined strategy

Schipper LG et al Rheumatology 2010;49:2154-64

0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0-0,2-0,4

Tight controlwithout predefined protocol

Fransen, 2005

Fransen, 2003

Van Tuyl, 2008Tight controlwithout predefined protocol

Tight controlwith predefined protocol

Tight controlwith predefined protocol

Verstappen, 2007

Goekoop, 2009

Grigor, 2002

0,25 (IC95 : 0,03-0,46)

0,97 (IC95 : 0,64-1,3)

Mean difference in DAS28 change

Randomised effect model

Traditional DMARDs Are Effective but Do Not Maintain Long-term Response

Retention Rates of DMARDs

Cum

ulat

ive

Ret

entio

n R

ates

0 12 24 36 48 60 72 84 96 108 120

100908070605040302010

0

MethotrexateSulfasalazineChloroquineParenteral GoldOral GoldPenicillamineAzathioprineCyclosporineCombination

Legend:

Time (Months)

18

Taking steps to improve clinical outcome

Smolen J, et al. Ann Rheum Dis 2010;69:631–637.

Active RA

Main target

Alternative target

Adapt therapy according to

disease activity

Remission

Adapt therapy according to disease

activity

Low disease activity

Use a composite measure of disease

activity every 1–3 months

Adapt therapy if state is lost

Sustained remission

Adapt therapy if state is lost

Sustained low disease activity

Assess disease activity about every

3–4 months

Main long-term target

Alternative long-term

target

EULAR RECOMMENDATIONS

Phase I of EULAR RA Management Algorithm

19Smolen JS, et al. Ann Rheum Dis 2010;69:964–75

*The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity

Phase II of EULAR RA Management Algorithm

20

*The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity

Smolen JS, et al. Ann Rheum Dis 2010;69:964–75

Phase III of EULAR RA Management Algorithm

21Smolen JS, et al. Ann Rheum Dis 2010;69:964–75

*The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity

Tracey D, et al. Pharmacology & Therapeutics 117 (2008) 244–279.

Different Biologics for RA

23

APC

Down-regulation of T cell

Adapted from Kremer JM. J Clin Rheumatol. 2005;11:S55–S62.

CD28

T cell

CTLA-4 binding: down-regulation of T cell

Upstream T-cell Modulationwith ORENCIA® (abatacept)

CTLA-4

APC

CD28

MHC

APC

T-cell receptor

ORENCIA

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.

T cell

Forest plot of risk ratios for clinical remission

• RR 1.74; 95% CI (1.54, 1.98)• no heterogeneity I2 0%; p = 0.496

Efficacy of initial MTX vs MTX + biological agent in Early RA

Kuriya B et al. Ann Rheum Dis online first april 26, 2010

Forest plot of risk ratios for radiographic remission

• RR 1.30; 95% CI (1.01, 1.68)• Significant heterogeneity I2 0%; p = 0.001

Efficacy of initial MTX vs MTX + biological agent in Early RA

Kuriya B et al. Ann Rheum Dis online first april 26, 2010

CLINICAL TRIALS FOR ABATACEPT

AGREE study design: patients with early RA and poor

prognostic factors*

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

Inclusion criteria

• Early RA (≤2 years)• MTX-naïve • RF+ and/or anti-CCP2+ • ≥1 erosion

Co-primary endpoints• DAS28 (CRP) <2.6• Total Genant-modified Sharp score

Double-blind period1 Open-label period2

1:1 Randomisation

Screening

Abatacept + MTX**(n=256)

Placebo + MTX**

(n=253)

232

227

Abatacept + MTX

• DAS28 (CRP) • X-Ray progression• HAQ-DI

433

**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.

Day 1 Year 1 Year 2

*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.

AGREE (MTX-naïve)

Significantly greater proportion of abatacept-treated patients achieved

DAS28 remission at Year 1*

Westhovens R, et al. Ann Rheum Dis 2009;68:1870–1877. 28

p<0.001

41.4%

23.3%

*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.

0

10

20

30

40

50

60

70

80

90

100

Prop

ortio

n of

pat

ient

s ac

hiev

ing

DA

S28

rem

issi

on (%

)

Abatacept + MTX (n=256)Placebo + MTX (n=253)

AGREE (MTX-naïve)

Abatacept provides sustained efficacy through 2 years in patients with early RA

(≤2 years)*

Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956. 29

Visit dayAbatacept plus MTX (n=232) MTX alone (n=227) 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 non-responders.

0102030405060708090

100

0 29 85 141 197 253 309 365 449 553 617 729

Year 1Abatacept added to MTX alone group

Prop

ortio

n of

pat

ient

s ac

hiev

ing

DA

S28-

CR

P re

mis

sion

(%, 9

5% C

I)

46.1%

26.9%

44.5%

55.2%

AGREE (MTX-naïve)

Early referral

0.840.65

1.75

1.48

Baseline Year 1 Year 2

Mea

n ch

ange

from

base

line

in S

harp

tota

l sco

re

∆=0.25 Yr 1–2

∆=0.18 Yr 1–2

∆=0.66 BL-Yr 1p<0.001 for ∆Yr 1–2 vs ∆ BL–Yr 1

Patients with X-rays at all timepoints (n=207)

1.0

Adding abatacept to MTX slows the rate of radiographic progression*

Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956. 30

0.0

2.0

Visit dayAbatacept 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.

Abatacept added to MTX alone group

AGREE (MTX-naïve)

Abatacept leads to sustained HAQ normalisation (≤0.5) over 2 years in half of treated patients*

Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956. 31

Abatacept + MTX (n=232)MTX alone (n=227)MTX alone switched to abatacept + MTX (n=227)

*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.

0

10

20

30

40

50

60

70

80

90

100

Year 1

Prop

ortio

n of

pat

ient

s ac

hiev

ing

HA

Q n

orm

alis

atio

n (%

)

Year 2

AGREE (MTX-naïve)

32

Efficacy and Safety of Abatacept or Infliximab Versus Placebo

ATTEST Trial

A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled Trial on the efficacy and safety of abatacept or Infliximab

versus placebo in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate•

Primary Objective

–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

Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

ATTEST

the primary endpoint was not designed to be a head-to-head comparison between Abatacept and infliximab.

Abatacept + MTX and infliximab + MTX ACR20 response rates are similar at Month 3

34

ACR 50AbataceptACR 50Infliximab

ACR 20AbataceptACR 20Infliximab

ACR 70AbataceptACR 70Infliximab

80

Visit day0

10203040506070

1 29 57 85 113141169197225253281309337365

ACR

resp

onse

rat

e (%

)ATTEST

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

Further improvement from Month 6 to 12 was observed with abatacept + MTX in ACR 20 response

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])

35

ATTEST

ACR 50AbataceptACR 50Infliximab

ACR 20AbataceptACR 20Infliximab

ACR 70AbataceptACR 70Infliximab

80

Visit day0

10203040506070

1 29 57 85 113141169197225253281309337365

ACR

resp

onse

rat

e (%

)ATTEST

Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

36

ACR Responses at 6 Months

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

ATTEST

ACR20 ACR50 ACR700.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

59.4

37.0

24.2

41.8

20

9.1

Infliximab + MTX (n=165) Placebo + MTX (n=110)

Pat

ient

s (%

)

‡

‡

‡

ACR20 ACR50 ACR700

10

20

30

40

50

60

70

80

66.7

40.4

20.5

41.8

20

9.1

Abatacept + MTX (n=156) Placebo + MTX (n=110)

Patie

nts

(%)

†

*

*

Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

37

ACR responses at 12 monthsATTEST

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

ACR20 ACR50 ACR700

1020304050607080 72.4

45.5

26.3

55.8

36.4

20.6

Abatacept + MTX (n=156) Infliximab + MTX (n=165)

Perc

enta

ge o

f pat

ient

s

Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

Abatacept+MTX Delivered Sustained Improvements in ACR Responses Over 2 Years

38

0 3 6 9 12 15 18 21 24

Visit (month)

Infliximab patients switched to abatacept

ACR

Resp

onde

rs (%

)

Open label LTE periodDB period

89% (83,94)*

69% (61,77)*

55% (46,64)*

43 (35,52)*

24% (16,31)*

31% (23,39)*

87% (80,93)*84% (78,91)*

71% (63,79)*

61 (52,70)*

41% (32,50)*45% (36,54)*

Data are for patients who entered the open-label period, and had data available at the considered time point (as-observed analysis)

Treatment groups represent treatment received during the double-blind period

*95% confidence intervals

Schiff M and Bessette L Clin Rheum 2010 ; 29: 583-519 9

Abatacept+MTX

Infliximab 3mg/kg + MTX to abatacept

ATTEST-LTE

ABATACEPTSHORT & LONG -TERM EFFICACY

40

Abatacept provides similar short-term efficacy at 6 months compared with other biologic agents

• Placebo-adjusted analysis, based on ACR50 responses

• Mixed populations included:– MTX-IR– DMARD-IR– Anti-TNF-IR

• All biologic agents showed significantly greater efficacy compared with placebo, except anakinra

Singh JA, et al. Cochrane Database Syst Rev 2009;4:CD007848.

Favours Placebo Favours Biologic

Abatacept

Adalimumab

Anakinra

Etanercept

Infliximab

Rituximab

GLIMMIX: Odds Ratio (95% CI)

0.1 1.0 10

COCHRANE META-ANALYSIS

Studies included only approved dosages.

Abatacept short-term efficacy is similar to other biologic agents in real life

Yazici Y, et al. Arthritis Rheum 2011; 63(Suppl 10):S873. Abstract 2233.

Cum

ulati

ve in

cide

nce

of ti

me

to R

APID

≥3.6

re

spon

se*

(%)

Month

0

20

40

60

80

0 6 12 302418

Abatacept

EtanerceptAdalimumab

Infliximab

0 1 2 6543

*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.

Conaghan P, et al. Ann Rheum Dis 2011;70(Suppl 3):151

Abatacept leads to reductions in synovitis and structural damage by Month 4 – MRI data

Synovitis Osteitis Erosion

Adju

sted

mea

n ch

ange

(9

5% co

nfide

nce

inte

rval

)

-1.9

-0.3

0.5

-2.0

-1.0

0.0

1.0

-3.0

2.0

3.0

0.4

1.51.0

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.

Improvements with abatacept seen via sonographic monitoring

Personal communication, Walter Grassi. 43

16 Months

• 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

Conclusion: Excellent responder

LONG TERM GOAL ACHIEVEMENTBY ABATACEPT

An increasing proportion of abatacept patients show sustained LDAS or DAS28 remission over 7 years

Westhovens R, et al. Ann Rheum Dis 2009;68(Suppl3):577. Poster SAT0108. 45

Res

pond

ers

(%)

Year0 0.5

0

302010

4050

7060

80

10090

1 2 3 4 5 6 7

48.2% (37.4, 58.9) n/N=40/83

25.3% (15.9, 34.7) n/N=21/83

69.7% (54.0, 85.4) n/N=23/33

51.5% (34.5, 68.6)n/N=17/33

Response (95% CI)

Remission

LDAS

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.

Double-blindphase Open-label LTE phase

Abatacept has demonstrated increasing reductions in rate of structural damage progression through Year 5

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.

*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

AIM (MTX-IR)

Mea

n ch

ange

from

bas

elin

e in

Gena

nt-m

odifi

ed sh

arp

scor

es (T

S)

0 1 2 3 4 50

0.5

1

1.5

2

2.5

3

3.5

4

Abatacept + MTX Placebo + MTX Placebo + MTX switched to abatacept + MTXYear

Year 1

*0.80

*0.26*0.34

*0.37

*0.41*1.48

*0.29

*0.43

*0.68

*0.74

46

Sustained improvement in physical function with abatacept over 5 years (HAQ-DI response)

Schiff M and Bessette L. Clin Rheum 2010;29:583–591.

100

50

40

30

90

80

70

60

0 0.5 1.0 3.5 5.03.02.52.01.5 4.0 4.5

20

0

74.2%(69.0, 79.4)

71.8%(67.2, 76.4)

Double-blindphase Open-label LTE phase

Data are based on all patients originally randomised to abatacept who entered the long-term extension, with data available at the visit of interest (as-observed analysis).HAQ-DI response ≥ 0.3.

Resp

onde

rs (%

)

Year

AIM (MTX-IR)

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.

Subjects remaining at the end of 4 years of LTE

n/N %

Infliximab1 295/511 62%

Etanercept2 429/581 74%

Adalimumab3 147/262 56%

Abatacept4*(IM101102)

394/539 73%

Abatacept has a retention rate that is comparable with or higher than the anti-TNF agents

• 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).

48

LT- RCT

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

Cumulative (Double-Blind and Open-Label)

Open-Label, UncontrolledN = 2,339

N = 2,688

PlaceboAbatacept

N = 1,955(204)

Double-Blind, Controlled(Biologic Background)

N = 989(134)

BLA/4M

Overview of Patients with Adverse EventsDouble-Blind, Controlled Study Periods

AEs

SAEs

Discontinuation due to AEs

Deaths

AbataceptN = 1955

1736 (88.8)

266 (13.6)

107 (5.5)

10 (0.5)

PlaceboN = 989

840 (84.9)

122 (12.3)

39 (3.9)

6 (0.6)

Number (%) of Patients

Total Patients with Infections

Upper Respiratory Tract Infection

Nasopharyngitis

Sinusitis

Urinary Tract Infection

Influenza

Bronchitis

1051 (53.8)

248 (12.7)

225 (11.5)

125 (6.4)

113 (5.8)

111 (5.7)

101 (5.2)

478 (48.3)

119 (12.0)

90 (9.1)

68 (6.9)

45 (4.6)

52 (5.3)

45 (4.6)

Most Common Infections (≥ 5%) Double-Blind, Controlled Study Periods

Preferred TermAbataceptN = 1955

PlaceboN = 989

Number (%) of Patients

Total Patients with Serious Infections

Pneumonia

Cellulitis

Urinary Tract Infection

Bronchitis

Diverticulitis

Pyelonephritis Acute

Sepsis

Serious Infections (≥ 0.2%) Double-Blind, Controlled Study Periods

58 (3.0)

9 (0.5)

5 (0.3)

4 (0.2)

4 (0.2)

3 (0.2)

3 (0.2)

1 (<0.1)

19 (1.9)

5 (0.5)

2 (0.2)

1 (0.1)

0

0

0

3 (0.3)

Preferred TermAbataceptN = 1955

PlaceboN = 989

Number (%) of Patients

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.

Predictors and Risk of Infection in Rheumatoid Arthritis

TuberculosisCumulative 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

Continued use of abatacept does not increase the risk of malignancy over time

Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–5. Abstract 390. 57

Integrated safety summary

NMSC=non-melanoma skin cancer; Data over a 7-year period; Data lock December 2009. 12,132 p–y of exposure (N=4,149).

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

Malignancies, incidence rate (95% CI)

Malignancies (excluding NMSC)

0.59 (0.19–1.37)

0.69 (0.39–1.11)

0.74 (0.58–0.93)

0.73 (0.58–0.89)

Lymphoma – 0.04 (0.00–0.24)

0.08 (0.04–0.16)

0.07 (0.03–0.14)

Total solid organ (combined)

0.59 (0.19–1.37)

0.60 (0.33–1.01)

0.60 (0.45–0.77)

0.59(0.46–0.75)

Lung cancer – 0.21 (0.07–0.50)

0.13 (0.07–0.23)

0.15 (0.09–0.23)

NMSC 0.82 (0.33–1.70)

0.82 (0.49–1.28)

0.74 (0.58–0.93)

0.73 (0.58–0.90)

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Malignancies: Double-Blind studies

MalignantAbatacept: 29

(1.5%)Placebo: 11

(1.1%%)Non-Melanoma

Skin CAAbatacept: 15

(0.8%)Placebo: 6

(0.5%)

Solid Organ CAAbatacept: 13

(0.7%)Placebo: 5

(0.5%)

HematologicAbatacept: 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

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BIOLOGICS AND PREGNANCYDrug #

casesDevelopmental

toxicity - animalsFetal problems – Humans Drug Discontinuation?

ETA 51 - Preterm , VACTERLVert,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

Ostensen M, Forger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol 2009;5:382-90. UptoDate 2009

*1 case each - CZP, ANA, 0 - GOL and ABA; no animal and human/fetal toxicity reported; drug discontinuation recommended for GOL, CZP, ANA

ConclusionsAbatacept 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

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