010300jt-os.ppt - on-screen 1 tnf differential mechanisms of action, and ifx 6-year safety update...
TRANSCRIPT
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
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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
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Gastrointestinal Gastrointestinal diseasedisease
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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
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• 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
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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.
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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
Data on File, Centocor, Inc.
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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
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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*
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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
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SKIN EFFECTS: PASI SCORESSKIN EFFECTS: PASI SCORESUPDATE FROM ACR 2005UPDATE FROM ACR 2005
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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
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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
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Infliximab Treated Patient (Moderate)Infliximab Treated Patient (Moderate)
> 75% improvement in Psoriasis Area and Severity Index
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Infliximab Treated Patient (Severe)Infliximab Treated Patient (Severe)
Week 10Week 0> 75% improvement in Psoriasis Area and Severity Index
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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
Data on File, Centocor, Inc.
100% Improvement in PASI Score100% Improvement in PASI Score
*Patients with baseline psoriasis BSA ≥3%
25
p<0.001 p<0.001
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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
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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.
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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
N=200 D. van der Heijde ACR 2005
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
N=200 D. van der Heijde ACR 2005
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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
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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.
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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. ACR 2005
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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
Kavanaugh A, et al. ACR 2005. Presentation #487.
010300jt-os.ppt - On-screen 36
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. ACR 2005
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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
Kavanaugh A, et al. ACR 2005. Presentation #488.
010300jt-os.ppt - On-screen 38
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)
Kavanaugh A, et al. ACR 2005. Presentation #488.
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Differences in Differences in PharmacokineticsPharmacokinetics
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Clinical DifferentiationClinical Differentiation
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
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T1/2
INFLIXIMAB
ADALIMUMAB
3 6 9 12 15 18 21 240
Serum Half-Life (days)
ETANERCEPT
Clinical DifferentiationClinical Differentiation
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
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BINDING STRENGTH:Affinity (Stickiness of each Binding Site)
HigherAffinity
LowerAffinity
Fc Regions
TNFBinding
Sites
TNFTrimers
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Fold-Magnitude of Difference
ETANERCEPT
ADALIMUMAB (Index value for adalimumab set = one.)
0 2 4 6 8 10 12 14 16
Clinical DifferentiationClinical Differentiation
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
010300jt-os.ppt - On-screen 44
BINDING STRENGTH:Affinity (Stickiness of each Binding Site)
Fc Regions
TNFBinding
Sites
TNFTrimers
but capable of binding to twice as many ligands
HigherAffinity
LowerAffinity
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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
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Although etanercept has two TNF-binding arms, a TNF trimer can only be bound by a single etanercept molecule.
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.
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
010300jt-os.ppt - On-screen 47
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.
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.
010300jt-os.ppt - On-screen 48
TNF trimer
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.
A single TNF trimer can be bound by up to three infliximab molecules.
From: Scallon et al., 2002
An infliximab/ TNF trimer complex
010300jt-os.ppt - On-screen 49
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.
Moreover, each infliximab molecule is capable of binding to more than one TNF trimer.
From: Scallon et al., 2002
An infliximab/ TNF complex
010300jt-os.ppt - On-screen 50
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.
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.
010300jt-os.ppt - On-screen 51
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
010300jt-os.ppt - On-screen 53
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.
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.
From: Scallon et al., 2002
An infliximab/ TNF complex
010300jt-os.ppt - On-screen 55
APOPTOSISAPOPTOSIS
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ApoptosisApoptosis
Illustration by Lydia Kibiuk, Copyright © 1996 Lydia Kibiuk.
Clinical DifferentiationClinical Differentiation
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
010300jt-os.ppt - On-screen 57
ApoptosisApoptosisClinical DifferentiationClinical Differentiation
010300jt-os.ppt - On-screen 58
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.
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TelomeresTelomeres
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Cell LysisCell Lysis
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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
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ADCC
Cell LysisCell LysisClinical DifferentiationClinical Differentiation
http://mcb.berkeley.edu/courses/mcb150/Lect18/Notes18.pdf
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Cell LysisCell LysisClinical DifferentiationClinical Differentiation
ADCC CDC
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• Structures of Infliximab, Etanercept, and Adalimumab
Baker D, et al., Rev Gastroenterol Dis. 2004;4(4):196–210.
Cell LysisCell LysisClinical DifferentiationClinical Differentiation
Adalimumab
Complement binding region
L ch
ain
H ch
ain
S SSS
SS SS
Fab
Fc
Complement binding region
L ch
ain
H ch
ain
S SSS
SS SS
Fab
Fc
L ch
ain
Complement binding region
H ch
ain
S SSS
SS SS
Fab
Fc
L ch
ain
Complement binding region
H ch
ain
S SSS
SS SS
Fab
Fc
Complement binding region
H ch
ain
S SSS
SS SS
Fab
Fc
H ch
ain
S SSS
SS SS
Fab
Fc
Infliximab
SSSS
Complement binding region
Fc
Human p75 TNF receptor
Site of FusionSSSS
Complement binding region
Fc
Human p75 TNF receptor
Site of Fusion
Etanercept
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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.
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• 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
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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
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Clinical DifferentiationClinical Differentiation
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.
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Route of Administration: Route of Administration: Patient CompliancePatient ComplianceClinical DifferentiationClinical Differentiation
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).
Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.
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
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Route of Administration: Route of Administration: Patient CompliancePatient ComplianceClinical DifferentiationClinical Differentiation
Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.
MediCal Study: OutcomeMediCal Study: Outcome
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.
MediCal Study: OutcomeMediCal Study: Outcome
Compliance:
- Infliximab: 207/1278 missed two continuous scripts
- Etanercept: 826/1565 missed two continuous scripts
Non-compliance approx:
- 53% with etanercept
- 16% with infliximab
When controlled for etanercept shortage:
– 785/1482 (53%) patients missed two continuous scripts
0
5
10
15
20
25
p<0.05
Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.
MediCal Study: OutcomeMediCal Study: Outcome
Compliance:
- Infliximab: 207/1278 missed two continuous scripts
- Etanercept: 826/1565 missed two continuous scripts
Non-compliance approx:
- 53% with etanercept
- 16% with infliximab
When controlled for etanercept shortage:
– 785/1482 (53%) patients missed two continuous scripts
0
5
10
15
20
25
p<0.05
Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.
Route of Administration: Route of Administration: Patient CompliancePatient ComplianceClinical DifferentiationClinical Differentiation
MediCal Study: OutcomeMediCal Study: Outcome
Compliance:
- Infliximab: 207/1278 missed two continuous scripts
- Etanercept: 826/1565 missed two continuous scripts
Non-compliance approx:
- 53% with etanercept
- 16% with infliximab
When controlled for etanercept shortage:
– 785/1482 (53%) patients missed two continuous scripts
p<0.05
Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.
MediCal Study: OutcomeMediCal Study: Outcome
Compliance:
- Infliximab: 207/1278 missed two continuous scripts
- Etanercept: 826/1565 missed two continuous scripts
Non-compliance approx:
- 53% with etanercept
- 16% with infliximab
When controlled for etanercept shortage:
– 785/1482 (53%) patients missed two continuous scripts
p<0.05
Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.
Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.
MediCal Study: OutcomeMediCal Study: Outcome
Compliance:
- Infliximab: 207/1278 missed two continuous scripts
- Etanercept: 826/1565 missed two continuous scripts
Non-compliance approx:
- 53% with etanercept
- 16% with infliximab
When controlled for etanercept shortage:
– 785/1482 (53%) patients missed two continuous scripts
0
5
10
15
20
25
p<0.05
Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.
MediCal Study: OutcomeMediCal Study: Outcome
Compliance:
- Infliximab: 207/1278 missed two continuous scripts
- Etanercept: 826/1565 missed two continuous scripts
Non-compliance approx:
- 53% with etanercept
- 16% with infliximab
When controlled for etanercept shortage:
– 785/1482 (53%) patients missed two continuous scripts
0
5
10
15
20
25
p<0.05
Tandon, Singh, Mithal, Kavanaugh. Poster presentation ISPOR 2003.
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SAFETYSAFETY