010300jt-os.ppt - on-screen 1 tnf differential mechanisms of action, and ifx 6-year safety update...

010300jt-os.ppt - On-screen 1

TNF Differential Mechanisms of TNF Differential Mechanisms of Action, and IFX 6-year Safety Action, and IFX 6-year Safety

updateupdate

Steven P. Petrosino, Ph.D.

Senior Clinical Scientist

Department of Medical Affairs, Immunology

Centocor, Inc


There Are Differences in Clinical Outcomes.There Are Differences in Clinical Outcomes.

1. IFX, but not ETA, is effective and indicated for gastrointestinal disease.1

2. IFX, but not ADA, is effective against Dactylitis and Enthesitis associated with Psoriatic Arthritis. 4

3. IFX consistently induces higher PASI-75 & PASI-100 scores in PsA patients compared to either of the other TNF blockers.4

4. Shown to Date:1. IFX is the only TNF blocker proven to have

radiographic benefit following switch from another TNF blocker.2

2. IFX is the only TNF blocker shown to induce drug-free remission in RA.3

3. IFX is the only TNF blocker shown to induce endoscopically-proven mucosal healing in UC and Crohn’s disease. 5

Clinical DifferentiationClinical Differentiation

Background:

1Pharmaceutical package inserts: Enbrel, Humira, & Remicade; 2OPPOSITE Trial; 3BeSt, & Quinn et al. Arthritis & Rheum 2005; 52:27-35; 4IMPACT II Trial 5ACCENT I (subanalysis) and ACT I Trial


Gastrointestinal Gastrointestinal diseasedisease


TNF-Blockade in AS-associated Co-morbidities:TNF-Blockade in AS-associated Co-morbidities:No Class Effect No Class Effect

1-3 Hanauer et al. Lancet 2002; 359:1541-1549. Sands et al. N. Engl. J. Med. 2004;350:876-85. Doubremelle et al. Gastroenterol. Clin. Biol. 2002; 26:973-979.

4-7 Akobeng et al. Cochrane Database Syst Rev. 2004; 1:CD003574. Van den Brande et al. Gastroenterology 2003; 124:1774-1785. Marzo-Ortega et al. Ann. Rheum. Dis. 2003;62:74-76. Sandborn W.J. et al. Gastroenterology 2001;121:1088-1094.

8-9 Van den Bosch et al. Lancet 2000; 356:1821-1822. Generini et al. Ann. Rheum. Dis. 2004, 63:1664-9.10-13 Marzo-Ortega H. et al. Ann. Rheum. Dis. 2003;62:74-76., Oh et al J Rheum 2005;32:752-3, Davis et al Arthritis

Rheum; 2003:48:3230-36, Brandt et al. Rheum 2005;44:342-4814-15 Rutgeerts et al. DDW 2005 abstract 689, Sandborn et al. DDW 2005 abstract 688.16 Lupascu et al. Dig. Liv. Dis. 2004; 36:423-425.

disease ETA IFX

Efficacy in Crohn’s disease No 4-7 Yes 1-3

Efficacy in Crohn’s disease related to SpA No reports Yes 8-9

Crohn’s disease flares in AS/PsA patients on treatment Observed 10,11,12,13 Not observed

Efficacy in Ulcerative Colitis No reports Yes 14-15, *

Efficacy in Ulcerative Colitis associated to AS

No reports Yes 16

* Data filed for approval


• Like ifx, ada Induces apoptosis in vitro

• Adalimumab achieves a similar response to infliximab at the highest dose (2x to 4x RA Dose):

Mimicking infusion/high Cmax?

Week 4 results

1824

12

36

0

20

40

60

Remission CDAI < 150

Placebo 40/20 mg ada

80/40 mg ada 160/80 mg ada

Hanauer et al. DDW2004 late breaking session

Adalimumab

Importance of High Cmax?Importance of High Cmax? Adalimumab for CDAdalimumab for CD


Study DesignStudy Design

• Multicenter, randomized, double-blind, placebo-controlled, parallel-treatment group trial

• Conducted globally at 62 sites

• 364 subjects with moderately to severely active ulcerative colitis were randomized and treated:

– 121 in the placebo treatment group– 121 in the REMICADE® (infliximab) 5 mg/kg

treatment group– 122 in the REMICADE 10 mg/kg treatment group

ACT 1

Data on File, Centocor, Inc.


Patient PopulationPatient Population

• Subjects with:– Moderately to severely active ulcerative colitis

(UC):• Mayo score 6 points (on 12 point scale)• Endoscopy subscore 2 points

• Subjects must meet at least 1 of the following criteria:– Current treatment with > 1 of the following:

• Oral corticosteroids, 6‑mercaptopurine (6-MP), or azathioprine (AZA)

– Have failed to successfully taper, tolerate, or respond to corticosteroids within the past 18 months

– Have failed to tolerate or respond to 6-MP or AZA within the previous 5 years

ACT 1



Endoscopy Photo: Sample ScoresEndoscopy Photo: Sample Scores

Endoscopy Score 0

Endoscopy Score 1

Endoscopy Score 2

Endoscopy Score 3

Endoscopic pictures used with the permission of Dr. Paul Rutgeerts, Academisch Ziekenhuis Gasthuisberg, Leuven, Belgium


Mucosal Healing at Week 8 and Week 30Mucosal Healing at Week 8 and Week 30ACT 1

REMICADE US Package Insert.

Intent-to-treat AnalysisPatients in all groups with baseline medication were continued on stable doses

3425

62

5059

49

0

10

20

30

40

50

60

70

80

90

100

Week 8 Week 30

Pro

po

rtio

n o

f P

ati

en

ts (

%)

Placebo Infusion 5 mg/kg REMICADE® (infliximab) 10 mg/kg REMICADE

**

*

*p<0.001

*

Clinical Remission Clinical Remission Without Corticosteroids at Week 30Without Corticosteroids at Week 30

ACT 1

Data on File, Centocor, Inc.IN05

724

15

10

22

0

5

10

15

20

25

30

Pro

po

rtio

n o

f P

atie

nts

(%

)

Placebo Combined REMICADE® (infliximab)

*p = 0.039*


Dactylitis and Dactylitis and EnthesitisEnthesitis

Improvement in Dactylitis and Improvement in Dactylitis and EnthesopathyEnthesopathy

REMICADEREMICADE® ® (infliximab)(infliximab)

36%33%

35%

22%23%

42%

0

10

20

30

40

50

33%32%

41%

19%*15%*

40%

0

10

20

30

40

50

† ‡

†p=0.023‡p=0.004

0 14 24 0 14 24

Week Week

Placebo REMICADE 5 mg/kg

REMICADE Significantly ReducedEnthesopathy at Weeks 14 and 24

REMICADE Significantly ReducedDactylitis at Weeks 14 and 24

Pe

rce

nta

ge

of

Pa

tie

nts

wit

h E

nth

es

op

ath

y

Pe

rce

nta

ge

wit

h 1

or

Mo

reD

ac

tyli

tis

Dig

its

†p<0.05

N=200. IMPACT II, ACR 2005


SKIN EFFECTS: PASI SCORESSKIN EFFECTS: PASI SCORESUPDATE FROM ACR 2005UPDATE FROM ACR 2005


Infliximab Inhibits Progression Infliximab Inhibits Progression Of Radiographic Damage Of Radiographic Damage

In Patients With In Patients With Active Psoriatic Arthritis: Active Psoriatic Arthritis:

54 Week Results From IMPACT 254 Week Results From IMPACT 2

D. van der Heijde1, D. Gladman2 A. Kavanaugh3, C. Antoni4, G. G. Krueger5 , C. Guzzo6, B. Zhou6, L. Dooley6, A. Beutler6,

and the IMPACT 2 Study Group

1Department of Rheumatology, University Hospital Maastricht, Maastricht, Netherlands, 2Toronto Western Hospital, University of Toronto, Toronto, Canada

3Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, La Jolla, USA, 4Department of Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany, Schering-Plough, Inc. , 5Department of Dermatology, University of Utah Health

Sciences Center, Salt Lake City, USA, 6Centocor Research & Development, Inc., Malvern, USA


Study Design through Week 54Study Design through Week 54

Week 2

Infusion*

Week 0

Week 14

Week 6

Week 22

Week 16

Week 24

Week 18

IMPACT 2IMPACT 2

Infliximab 5 mg/kgn=100

Placebon=9

5 mg/kgn=47

Placebon=100

Early Escape Early Escape

Week 54

Week 30

Week 38

Week 46

Week 26

X-Ray Evaluation

510 mg/kgn=15

Dose Escalation

* Subjects were stratified by MTX useX-Ray Evaluation

X-Ray Evaluation


Infliximab Treated Patient (Moderate)Infliximab Treated Patient (Moderate)

> 75% improvement in Psoriasis Area and Severity Index


Infliximab Treated Patient (Severe)Infliximab Treated Patient (Severe)

Week 10Week 0> 75% improvement in Psoriasis Area and Severity Index


PASI Response Through Week 24

24

*

0

20

40

60

80

100

Per

cen

t o

f P

atie

nts

% of patients with 50% improvement in PASI

% of patients with 75% improvement in PASI

% of patients with90% improvement in PASI

Placebo (n=87) Infliximab 5 mg/kg (n=83)

2 6 14 22 24 2 6 14 22 24 2 6 14 220 0 0

Weeks WeeksWeeks

** * *

*

* * *

* *

* *

*p<0.001†p=0.011

†

Antoni C, et al. Ann Rheum Dis. 2005; 10.1136/ard.2004.032268.

*

IMPACT 2IMPACT 2

PASI Response at Week 14 and Week 24*

12

6064

0

20

40

60

80

100

Week 14 Week 24

Per

cen

t o

f P

atie

nts

p<0.001 p<0.001

Antoni C, et al. Ann Rheum Dis. 2005; 10.1136/ard.2004.032268.

*Patients with baseline psoriasis BSA ≥3%

0 0

41 39

0

20

40

60

80

100

Week 14 Week 24

p<0.001 p<0.001

PASI75 PASI90

Placebo (n=87) Infliximab 5 mg/kg (n=83)

IMPACT 2IMPACT 224

Proportion of Subjects* That Clear PsoriasisProportion of Subjects* That Clear Psoriasis

0 0

22.9 19.3

0

20

40

60

80

100

Week 14 Week 24

Placebo (n=87) Infliximab (n=83)

Pro

po

rtio

n o

f S

ub

ject

sIMPACT 2IMPACT 2


100% Improvement in PASI Score100% Improvement in PASI Score

*Patients with baseline psoriasis BSA ≥3%

25

p<0.001 p<0.001


Comparison of Selected Therapies (8-16 weeks) Comparison of Selected Therapies (8-16 weeks) for for Moderate-SevereModerate-Severe PsoriasisPsoriasis (PASI 75) (PASI 75)

17

30

45

60

70

70

82

0 10 20 30 40 50 60 70 80 90

Alefacept 15 mg/wk

23Efalizumab 2 mg/kg/wk

22CSA 2.5-3 mg/kg/d

Etanercept 25 mg 2x/wk

Etanercept 50 mg 2x/wk

MTX 15 mg/wk

CSA >5 mg/kg/d

PUVA

Infliximab 5 mg/kg

% Patients Achieving PASI 75

After Stern JAMA 2003;290:3133-5Chen at al. J. Am. Acad. Derm. 2004; 50 (3 Suppl.): P2


PASI 75 SCORES AT 24 WEEKSPASI 75 SCORES AT 24 WEEKS

0

20

40

60

Etanercept Adalimumab Infliximab

PASI 75

3 Phase III trials in PsA - Found the results to be widely different with regards to PASI scores. At 24 weeks, Enbrel's PASI 75 was 23%, Humira's PASI 75 was 42% and Remicade's was 60%. Joint scores at 24 weeks were all in the 50-59% range and suggest no real difference in the response in the joint.

Note: These are NOT head-to-head trials, involve heterogenous patient populations, and this comparison is for illustrative purposes only.


ACR 2005ACR 2005

Improvement in Signs and Symptoms at Improvement in Signs and Symptoms at Week 24 and Week 54: JointsWeek 24 and Week 54: Joints

16

4 2

54

41

27

0

20

40

60

80

100

ACR 20 ACR 50 ACR 70

*

*

*

IMPACT 2

56

40

23

33 33

20

0

20

40

60

80

100

ACR 20 ACR 50 ACR 70

Per

cen

tag

e o

f P

atie

nts

n=100 n=100 n=100 n=100 n=100 n=100 n=91 n=100 n=91 n=100 n=91 n=100

*p<0.001Week 24†† Week 54††

†Missing Data = Nonresponder

Placebo Infliximab 5 mg/kg Placebo Infliximab 5mg/kg

(peak effects) (trough effects)

N=200 D. van der Heijde ACR 2005

Improvement in Signs and Symptoms at Improvement in Signs and Symptoms at Week 24 and Week 54: SkinWeek 24 and Week 54: Skin

IMPACT 2

80

59

40

70

49

39

0

20

40

60

80

100

PASI 50 PASI 75 PASI 90

8

75

60

39

010

20

40

60

80

100

PASI 50 PASI 75 PASI 90

*

*

*

n=87 n=83 n=87 n=83 n=87 n=83 n=80 n=82 n=80 n=82 n=80 n=82

*p<0.001Week 54††

Placebo Infliximab 5 mg/kg Placebo Infliximab 5mg/kg

Week 24††

†Missing Data = LOCF

Per

cen

tag

e o

f P

atie

nts


Total vdH-S Score Total vdH-S Score –– Mean Change from Mean Change from Baseline through Week Baseline through Week 5454

IMPACT 2IMPACT 2T

ota

l vd

H-S

Sco

re

0.82

-0.29

0.53

-0.70

-0.24

-0.94

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

Week 0-24 Week 24-54 Week 0-54

Placebo Infliximab 5 mg/kgPlacebo Infliximab 5 mg/kg

p<0.001 p=0.001Includes 16 weeks on PLACEBO



Sustained Improvement In Clinical Sustained Improvement In Clinical Measures of PsA In Infliximab-Measures of PsA In Infliximab-Treated Patients: 1-Year Results Treated Patients: 1-Year Results

From IMPACT 2From IMPACT 2

Kavanaugh A, et al. ACR 2005


Kavanaugh A et al. (486)Kavanaugh A et al. (486)

• Objective: Report 1 year efficacy and safety of infliximab for arthritic and dermatologic manifestations of PsA

• Methods: IMPACT 2 PsA patients placebo and infliximab 5 mg/kg. Patients could enter early escape at Week 16 and dose escalation at Week 38. Efficacy endpoints included ACR20, PASI75 and dactylitis and enthesopathy assessments.

• Results: At Week 54, 59% achieved ACR20 and 50% achieved PASI75 for infliximab, irrespective of MTX use. The proportion of patients with dactylitis and enthesopathy was significantly lower in infliximab patients vs placebo at Week 24; improvement from baseline maintained at Week 54.

Infliximab resulted in sustained improvement in arthritis, dactylitis, enthesopathy, and psoriasis associated with active PsA over 1 year

Kavanaugh A, et al. ACR 2005. Presentation #486.


Infliximab Therapy Results in Infliximab Therapy Results in Sustained Improvement in Functional Sustained Improvement in Functional Status and Quality of Life in Patients Status and Quality of Life in Patients with Psoriatic Arthritis- Results from with Psoriatic Arthritis- Results from

the IMPACT 2 Studythe IMPACT 2 Study



Kavanaugh A, et al. (487)Kavanaugh A, et al. (487)

• Objective: Report the long-term effect of infliximab on patient functional status and QOL in PsA patients

• Methods: 200 PsA patients, 2 parallel groups placebo and infliximab 5 mg/kg. Function was assessed using HAQ and QOL was assessed using PCS and MCS scores of the SF-36.

• Results: At Week 14 median % improvement from baseline in HAQ, infliximab 42.9% vs 0.0% in the placebo group (p<0.001) and maintained at Week 54 with the median % improvement from baseline in HAQ combined infliximab group 50% vs placebo/infliximab 45.5%

Infliximab results in significant improvements in functional status and QOL that was maintained through 54 weeks in PsA patients



Association between Association between Improvement in Enthesopathy Improvement in Enthesopathy

and Quality of Life: Results from and Quality of Life: Results from the IMPACT 2 Trialthe IMPACT 2 Trial



Kavanaugh A, et al. (488)Kavanaugh A, et al. (488)

• Objective: To assess the relationship between improvement or worsening in enthesopathy and changes in QOL in PsA patients

• Methods: 200 PsA patients. Presence or absence of enthesopathy, HAQ and SF -36 assessed baseline and Week 14. Three categories: improved (present at baseline, but not Week 14), worsened (present at Week 14, but not baseline), and unchanged. Improvements in QOL and function were assessed by enthesopathy status.

• Result(s): 22.2% of infliximab patients had enthesopathy at Week 14 compared with 33.7% placebo (p=0.016). Those who had an improvement in enthesopathy had a greater improvement in functioning and QOL, compared with those who did not.

There is a strong association between improvement in enthesopathy and improvement in function and QOL in PsA patients



Enthesopathy Status

Worsened (n=14)

Unchanged (n=151)

Improved (n=35)

% improvement in HAQ

-46.6 13.1 49.3

Chg in Phys. component SF-36

-0.3 4.5 10.1

Chg in Mental component SF-36

1.5 0.6 4.4

Enthesopathy status and changes in physical function and QOL

• Patients with an improvement in enthesopathy showed a greater improvement in functioning and QOL compared to those who did not.

Kavanaugh A, e al. (488)Kavanaugh A, e al. (488)



Differences in Differences in PharmacokineticsPharmacokinetics



Relative Pharmacokinetic ValuesRelative Pharmacokinetic Values

Kavanaugh et al., 2000; St. Clair et al., 2001; Korth-Bradley et al., 2000; Zhou et al., 2003; Enbrel PI; Humira PI; Remicade PI.

CMAXINFLIXIMAB

ETANERCEPT

INFLIXIMAB

ADALIMUMAB

(Index value for etanercept set = one.)

(Index value for adalimumab set = one.)

IFX 30-165 times greater

IFX 10-90 times greater

20 40 60 80 100 120 140 1600 180

Fold-Magnitude of Difference

ADALIMUMAB

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.00

CMAX(Index value for etanercept set = one.)ETANERCEPT

ADA 1.8-3.2 times greater

CMAX


T1/2

INFLIXIMAB

ADALIMUMAB

3 6 9 12 15 18 21 240

Serum Half-Life (days)

ETANERCEPT


Relative Pharmacokinetic ValuesRelative Pharmacokinetic Values

Kavanaugh et al., 2000; St. Clair et al., 2001; Korth-Bradley et al., 2000; Zhou et al., 2003; Enbrel PI; Humira PI; Remicade PI.

T1/2


BINDING STRENGTH:Affinity (Stickiness of each Binding Site)

HigherAffinity

LowerAffinity

Fc Regions

TNFBinding

Sites

TNFTrimers


Fold-Magnitude of Difference

ETANERCEPT

ADALIMUMAB (Index value for adalimumab set = one.)

0 2 4 6 8 10 12 14 16


AffinityAffinity

1Scallon et al., 2002; 2Granneman et al., 2003; 3Santora et al., 2001; 4Davis et al., 2002; Enbrel PI; Humira PI; Remicade PI.

IFX: 2.44 x 10-11 M1

ADA: (7.05 x 10-11M)2 to (1 x 10-10M)3

ETA: (3.35 x 10-11M)4 to (6.67 x 10-12 M)1

DissociationConstants (Kd)

AffinityINFLIXIMAB

ETANERCEPT

INFLIXIMAB

ADALIMUMAB

(Index value for infliximab set = one.)

ETA 3.7 times greater

IFX 2.9 - 4.1 times greater

0 1 2 3 4 5 6

(Index value for adalimumab set = one.)

ETA 2.1 - 15 times greater


BINDING STRENGTH:Affinity (Stickiness of each Binding Site)

Fc Regions

TNFBinding

Sites

TNFTrimers

but capable of binding to twice as many ligands

HigherAffinity

LowerAffinity


Although etanercept has two TNF-binding arms, a TNF trimer can only be bound by a single etanercept molecule.

From: Scallon et al., 2002

The difference in ability to neutralize TNFThe difference in ability to neutralize TNF is explained in part by stoichiometry.is explained in part by stoichiometry.

An etanercept /TNF complex


Although etanercept has two TNF-binding arms, a TNF trimer can only be bound by a single etanercept molecule.


Etanercept binds quickly, but it also releases quickly.

Without being tethered by other etanercept molecules, a TNF trimer is unable to be neutralized for more than a few minutes.

TNF Trimer



Etanercept binds quickly, but it also releases quickly.

Without being tethered by other etanercept molecules, a TNF trimer is unable to be neutralized for more than a few minutes.


TNF trimer


A single TNF trimer can be bound by up to three infliximab molecules.


An infliximab/ TNF trimer complex



Moreover, each infliximab molecule is capable of binding to more than one TNF trimer.


An infliximab/ TNF complex



Like a TNF trimer being held by multiple infliximab molecules, individual skydivers in this group are kept under control by multiple binding sites.

Release of binding by one hand from any skydiver will not result in anyone floating away.

This illustrates the contribution of higher order complexes involved in IFX/TNF binding.


effective valence

relative equilibriumconstant

http://www-immuno.path.cam.ac.uk/~immuno/part1/lec06/lec6_97.html

BINDING STRENGTH: Functional Affinity(A Synergy of Affinity + Avidity = length of holding time)

Soluble TNF trimers held in complex may emulate a

multi-valent Ag

Tm- or receptor-bound trimers held in complex may emulate

a multi-valent Ag

010300jt-os.ppt - On-screen 52 Scallon et al., JPET 301:418–426, 2002

Differences in the ability to neutralize TNFDifferences in the ability to neutralize TNF

BINDING STRENGTH

sTNF tmTNF

90% dissociation in 2-3 hrs from sTNF

90% dissociation in 20 min. from tmTNF

Undetectable dissociation in 2-3 hrs from either sTNF or tmTNFInfliximab

Etanercept



Stoichiometry

1 TNF trimer:3 IFX molecules

1 IFX molecule:2 TNF trimers

Together, these properties prevent TNF from being freeto bind to TNF receptors that can signal inflammation.


An infliximab/ TNF complex


APOPTOSISAPOPTOSIS


ApoptosisApoptosis

Illustration by Lydia Kibiuk, Copyright © 1996 Lydia Kibiuk.


APOPTOSIS: This form of pre-programmed cell death appears to be the normal way cells are renewed in every tissue. The cells condense, become round or spherical, separate from other cells, fragment and are phagocytized by histiocytes. This is the way lumina develop in tubular structures, limbs are fashioned, organs are reabsorbed in the metamorphosis of larvae and tails are lost by tadpoles. The cells become dehydrated, and retain their organelles. There is no inflammatory reaction.

http://www.meddean.luc.edu/lumen/MedEd/orfpath/cellch.htm

blebs


ApoptosisApoptosisClinical DifferentiationClinical Differentiation


ApoptosisApoptosisClinical DifferentiationClinical Differentiation

• Adalimumab and infliximab, but not etanercept, have been shown to induce apoptosis in cultured monocytes1.

• Infliximab induces apoptosis in lamina propria T cells of CD patients, while apoptosis of lamina propria T cells cannot be shown with etanercept2.

• Human in vivo studies with labeled annexin V have confirmed that apoptosis is an important mechanism of action of infliximab in Crohn’s Disease3.

1Shen et al., Aliment Pharmacol Ther. 2005 Feb 1;21(3):251-8. 2van den Brande et al., J Rheumatol Suppl. 2005 Mar;74:26-30. 3Hommes & van Deveneter., Curr Opin Gastroenterol. 2003 Jul;19(4):350-7.


TelomeresTelomeres


Cell LysisCell Lysis


Cell LysisCell LysisClinical DifferentiationClinical Differentiation

NECROSIS: Pale stained swollen, "ballooned" cells, edematous with swollen nuclei, undergoing lytic necrosis and accompanied by inflammatory reaction.

http://www.meddean.luc.edu/lumen/MedEd/orfpath/cellch.htm


ADCC


http://mcb.berkeley.edu/courses/mcb150/Lect18/Notes18.pdf



ADCC CDC


• Structures of Infliximab, Etanercept, and Adalimumab

Baker D, et al., Rev Gastroenterol Dis. 2004;4(4):196–210.


Adalimumab

Complement binding region

L ch

ain

H ch

ain

S SSS

SS SS

Fab

Fc


L ch

ain

H ch

ain

S SSS

SS SS

Fab

Fc

L ch

ain


H ch

ain

S SSS

SS SS

Fab

Fc

L ch

ain


H ch

ain

S SSS

SS SS

Fab

Fc


H ch

ain

S SSS

SS SS

Fab

Fc

H ch

ain

S SSS

SS SS

Fab

Fc

Infliximab

SSSS


Fc

Human p75 TNF receptor

Site of FusionSSSS


Fc

Human p75 TNF receptor

Site of Fusion

Etanercept


Route of Administration: Route of Administration: PK ParametersPK ParametersClinical DifferentiationClinical Differentiation

Recommended Doses in RARecommended Doses in RA

Scallon et al., JPET 301:418–426, 2002

25 mg ENBREL®

every 8 weeks i.v.


• Like ifx, ada Induces apoptosis in vitro

• Adalimumab achieves a similar response to infliximab only with very high dose (2-4x RA Dose):

Mimicking infusion/high Cmax?

Week 4 results

1824

12

36

0

20

40

60

Remission CDAI < 150

Placebo 40/20 mg ada

80/40 mg ada 160/80 mg ada

Hanauer et al. DDW2004 late breaking session

Adalimumab

Importance of High Cmax?Importance of High Cmax? Adalimumab for CDAdalimumab for CD


Route of Administration: Route of Administration: Patient CompliancePatient ComplianceClinical DifferentiationClinical Differentiation

1Schwartzman S. and Morgan, G.J. Jr., Arthritis Res Ther 2004, 6(Suppl 2):S19-S23.

•“Medication adherence (compliance) is possibly the most important factor in maintaining the benefits of anti-TNF therapy.”1



Route of Administration: Route of Administration: Patient CompliancePatient Compliance

Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.

MediCalMediCal Study: Objective and DesignStudy: Objective and Design

Key Objective:

• To determine whether patients with RA treated with TNF-inhibitors continue on this therapy longer than methotrexate, a “gold-standard” conventional DMARD

• To investigate the difference in persistence between infliximab and etanercept

Study Design:

• Claims Analysis based on California Medicaid data with RA diagnosis between January 1, 1999 to December 31, 2002– 2,700 patients on anti-TNF

1,251 for infliximab 1,449 for etanercept

• Analysis restricted to patients who were “new drug starts”Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.




MediCal Study: OutcomeMediCal Study: Outcome

• Between 1999 to 2002, 41.3% of infliximab patients discontinued vs. 78.1% of etanercept patients (p<0.001).


4.5364.582.3Methotrexate (n=8224)

12.8461.241.3Infliximab(n=1251)

11.841378.1Etanercept (n=1449)

10.4460.761.1TNF inhibitors(n=2700)

Standard error

Mean time to discontinuation

(days)Percentage

discontinued






Compliance:

- Infliximab: 207/1278 misse d two continuous scripts

- Etanercept: 826/1565 misse d two continuous scripts

Non-complia nce approx:

- 53% with etanercept

- 16% with inflix imab

When controlled for eta nercept shortage:

– 785/1482 (53%) patients missed two continuous scripts

2.6

13.7

0

5

10

15

20

25

Sw

itch

Ra

tes

(%)

Infliximab Etanercept

p<0.05

Tandon, Singh, Mithal, Kavanaugh. Poster presentati on I SPOR 2003.


Compliance:

- Infliximab: 207/1278 missed two continuous scripts

- Etanercept: 826/1565 missed two continuous scripts

Non-compliance approx:


- 16% with infliximab

When controlled for etanercept shortage:


0

5

10

15

20

25

p<0.05



Compliance:








0

5

10

15

20

25

p<0.05




Compliance:








p<0.05



Compliance:








p<0.05




Compliance:








0

5

10

15

20

25

p<0.05



Compliance:








0

5

10

15

20

25

p<0.05



SAFETYSAFETY

010300jt-os.ppt - on-screen 1 tnf differential mechanisms of action, and ifx 6-year safety update...

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