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The Pharmacology of TNF Inhibitors
Clinical Investigator Consultant/Lecturer
 Amgen/Wyeth
 Centocor
 NIH (GAIT)
 LaJolla Pharmaceuticals
 ISIS
 Genentech/IDEC
 Aventis
Aventis
Centocor
Amgen/Immunex
Wyeth-Ayerst
Pharmacia
Abbott
Astra Zeneca
Cytokine Inhibitors: Current Indications
Enbrel
Remicade
Humira
Kineret
Target
TNF
TNF
TNF
IL-1
RA
Yes
Yes
Yes
Yes
Crohns
-
Yes
Clinical
Trials
-
JRA
Yes
Clinical Trials
Clinical
Trials
Clinical
Trials
Psoriatic
arthritis
Yes
Clinical Trials
-
-
Ankylosing
Spondylitis
Yes
Clinical Trials
Clinical
Trials
-
Kavanaugh A, Cohen S, Cush J
Inhibitors of tumor necrosis factor (TNF) in
Rheumatoid Arthritis: Will that dog hunt? J
Rheumatol 1998;25:2049
Global Safety and Efficacy of Etanercept in RA
Klareskog, L, Moreland L, Cohen S. ACR 2002
Discontinuations
100
~80%
Early RA (U.S.)
Advanced RA (U.S.)
% Remaining on Study
Advanced RA (Europe)
80
Reason:
Loss of efficacy 8 %
Adverse event 9 %
Patient decision 5 %
Protocol issues 2 %
Lost to follow up 1 %
Other
3%
Total
29%
60
40
20
0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51
Months
DMARD Durability in RA Patients
Azathioprine
(n = 56)
Hydroxychloroqui
ne(n = 228)
Methotrexate
(n = 253)
Oral gold
(n = 84)
Estimated Continuation
1.0
0.8
0.6
0.4
Parenteral gold
(n = 269)
Penicillamine
(n = 193)
0.2
0
0
10
20
30
Months
Pincus T, et al. J Rheumatol. 1992;19:1885–1894.
40
50
60
Withdrawal of Methotrexate and Prednisone
Change at 3 Years
p<0.001*
MTX
10
15
9.3
10
5
0
Prednisone
p<0.001
17.6
Mean Predinsone
dose (mg/d)
Mean MTX
dose (mg/wk)
20
*paired-rank sum` test (n=68)
Baseline
Increased
Decreased or D/C
Discontinued
Year 3
6.4
5
2.3
0
Baseline
Year 3
Methotrexate
3%
68%
Prednisone
3%
85%
39%
59%
TNF Antagonists:
Other Indications and Clinical Investigations
Confirmed Efficacy in Trials
Under Investigation
►
Crohn’s disease
►
Vasculitis: Wegener’s, GCA, PAN
►
Spondyloarthropathies
►
Scleroderma
Psoriatic arthritis
►
Graft-versus-host disease
Psoriasis
►
Inflammatory myositis
Ankylosing spondylitis
►
Interstitial lung disease
►
Sjögren’s syndrome
►
Inflammatory eye and ear disease
►
Asthma
►
Hepatitis C
►
Sarcoidosis
►
Behçet’s syndrome
►
Pyoderma gangrenosum
►
►
Juvenile rheumatoid
arthritis
Adult Still’s disease
Psoriatic Arthritis: Improved Skin
Lesions
Baseline
12 Weeks
Elbow of patient 577; 50% improvement in target lesion.
Nail Responses with Etanercept
Baseline
Week 2
Week 8
Week 12
Cytokine Signaling Pathways
Involved in RA
RF
IL-4
IL-6
IL-10
Plasma
cell
IL-4
IL-10
Th2
Macrophage
Th0
IFNg Interferon g
IL-12
B cell
Synovium
CD4 + T cell
CD11
CD69
OPGL
CD69CD11
Osteoclast
Fibroblast
Chondrocyte
Production of metalloproteinases and
other effector molecules
Migration of polymorphonuclear cells
Erosion of bone and cartilage
Choy EH, Panayi GS. N Engl J Med. 2001;344:907–
916.
TNF
IL-1
IL-6
Anti-inflammatory
TIMPs
Proinflammatory
TGFb
MMPs
IL-1, TNF
GM-CSF, IFNg
IL-6, IL-8
IL-15, IL-16
IL-17, IL-18
Autoimmune diseases
Adapted from Arend WP. Arthritis Rheum. 2001;45:101–
106.
IL-1Ra
sIL-1RII
IL-1 Ra
MAb to IL-6R
MAb to TNF
sTNFR, IL-4, IL-10
IL-11, IL-13, IL-18 BP
Key Actions Attributed to TNF
TNF
(VEGF)
Inhibition of Cytokines
Normal interaction
Neutralization of cytokines
Inflammator
y cytokine
Monoclonal
antibody
Cytokin
e
receptor
Inflammator
y signal
Soluble
receptor
No signal
Receptor blockade
Monoclonal
antibody
Receptor
antagonist
No signal
Activation of
anti-inflammatory pathways
Antiinflammatory
cytokine
Suppression of
inflammatory
cytokines
Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.
TNF Antagonists
etanercept
infliximab
adalimumab
nerelimomab
CDP-571
CDP
afelimomab
Murine sequences
Human sequences
PEG
Evolution of TNF Blocking Therapies
Characteristic
Etanercept
(ENBREL)
Infliximab
(REMICADE)
Adalimumab
(HUMIRA™)
Class
sTNFR
TNF MAb
TNF MAb
Construct
Recombinant
fusion protein
Chimeric MAb
Recombinant
human MAb
Half-life
4 days
8–10 days
10–20 days
Binding target
TNF/LT
TNF
TNF
Administration
25 mg
SC
Twice weekly
3–10 mg/kg
IV with MTX
Every 4–8 weeks
40 mg
SC
Every other
week*
*Some patients not taking concomitant MTX may derive additional benefit from
increasing the dosing frequency of adalimumab to 40 mg every week
Synthesis and Actions of TNF
Chimeric A2 (cA2) Monoclonal Antibody
Infliximab
Mouse
(Binding Site for TNF)
Human (IgG)
 Chimeric (mouse/human)
IgG1 monoclonal
antibody
k
k
 Binds to TNF with high
affinity and specificity Knight DM, et al. Mol Immunol. 1993; 30(16):1443-53.
Mechanisms for Antibody Neutralization of TNF
Effect of Anti-TNF Antibody on Established
Collagen-Induced Arthritis in Mice
Effect on Clinical Progression
* p < 0.05 vs. control
Indicates injections
Adapted from Williams RO, et al. Proc Natl Acad Sci.
Inhibitory Effect of Infliximab on Synovial Cell
IL-1 Production
Brennan FM, et al. Lancet. 1989; ii:244-47.
Haworth C, et al. Eur J Immunol. 1991; 21:2575-79.
Butler D, et al. Eur Cytokine Network. 1995; 6:225-30.
Infliximab (Anti-TNF mAb) in Patients
with Active RA
Serum VEGF and Serum E-selectin
Paleolog EM, et al. Arthritis Rheum. 1995; 38 (suppl.):Abstract S757.
Binding Characteristics: TNF Inhibitors
Etanercept
Association
Rate (Ka)
Infliximab
Adalimumab
7.9 x 106 M-1 Sec- 1.4 x 106 M-1 Sec-1 1.9 x 105 M-1 Sec1
1
Dissociation
Rate (Kd)
2.4 x 10-4 Sec-1
2.7 x 10-4 Sec-1
8.8 x 10-5 Sec-1
Affinity
Constants (Ka)
33.9 x 109 M-1
5.8 x 109 M-1
2.2 x 109 M-1
Infliximab IV: 9.5 Day Half-Life
Percent of Maximum Serum Concentration
at Steady State
55-fold Variation
120
100
80
% 60
40
20
0
0
1.81%
60
120
Days
Dosed every 8 weeks
180
240
Adalimumab SQ: 14 Day HalfLife
Percent of Maximum Serum Concentration at
Steady State
150
1.5-fold Variation
%
100
50
0
0
14
28
Days
Dosed every 2 weeks
42
56
Etanercept SQ: 4.8 Day Half-Life
Percent of Maximum Serum Concentration at
Steady State
1.5-fold Variation
150
%
100
50
0
0
30
Days
Dosed twice a week
60
Safety Considerations With Biologics
► Serious
infections
► Opportunistic
infections (TB)
► Malignancies
► Demyelination
► Hematologic
abnormalities
► Administration
► Congestive
reactions
heart failure
► Autoantibodies
and lupus
TOTAL Opportunistic Infections
Etanercept
130,000
38
Infliximab
365,000
277
Adalimumab
2468
13
(32/68)
52%
4
1
(31/69)
30-45%
38
30
(23/77)
40%
3
Listeriosis
Atypical mycobacteria
2
10
28
26
1
Aspergillus
Cytomegalovirus
Systemic Candidiasis
5
5
7
24
16
13
2
-
Crypto3,
sporo1
Cocci 13
Nocardia 1
# Exposed
M. Tuberculosis
(%US/%EU)
Extrapulmonary/miliary
Pneumocystis carnii
Histoplasmosis*
Others
TNF and Mycobacterial Infection
► Active
TB arises in 10% of patients infected
► 1/3 of world infected with m.Tbc
► Many patients develop latent Tb harboring dormant by
viable tubercle bacilli
► Nitric oxide & TNF (less so IL-1) play an essential role:
activation of macrophages and granuloma formation
resulting in containment of persistent Tb infection
► Animal models, TNF inhibition fatal reactivation of
latent Tb
► TNF deficient mice: resistant to endotoxin, succeptable
to Candida albicans, Listeria monocytogenes, M. TB
► Anti-TNF therapy is anti-granulomatous therapy!
 (Tbc cases, Sarcoid, Wegeners, pyoderma gangr., etc)
Tbc – Differences between TNF inhibitors
Infliximab
Etanercept
210 hrs
102 hrs
Off Rate
Slow
Fast
Lymphotoxin inhibition
None
Yes
Apoptosis
Yes
No
Cell Lysis in vitro
Yes
No
42 %
<25%
1/3  dose
>90% 1.6
vials per week
Pharmacokinetic(1/2 life)
Age > 65 yrs
Dose escalation
Tuberculosis & TNF Antagonists
► Patients
should be evaluated for latent TB
infection with a tuberculin skin test prior to
initiation of TNF antagonist therapy1
► Obtain CXR? Not Routinely advocated in USA
 If PPD positive
 If Signs/Sxs present
 Recent/known TB Contact
► If
latent TB: initiate INH prior to or with
TNF inhibitor therapy
► If active TB infection, treat 4 drugs, delay
intiation of TNF inhibitor therapy
1Furst,
et al, Ann Rheum Dis, 2002;61:(Suppl II):ii-ii7
TNF Inhibitors & Antibody
Formation
Infliximab
Etanercept
► ANA
22,43,63%
11%
► dsDNA
8,14,10,16
4,7,9,15%
► Ab to Rx
HACA 8.3,17,25,50%
< 1%
► Drug-induced lupus
4 pts (0.2%)
4 pts +
► Etiology ? IL-10?
► HACA: directed against murine component
 Crohns; 13% HACA+ > more likely to have infusion rxn
 Lower HACA levels: MTX, 6MP, AZA; higher dose (10mg)
Maini’99
1mg 3mg 10mg
HACA
-MTX
53% 21% 7%
+MTX
15% 7% 0%
Safety Considerations: Immunogenicity
Anti-Drug Antibodies During RA Clinical Trials
% of Patients Developing
Anti-drug Antibodies
Etanercept
5
Infliximab
10
Adalimumab
Anakinra
FDA Arthritis Advisory Committee meeting. August 17,
2001.
5
1
Safety Issue:
Administration Reactions
Incidence
Injection-site reactions
Etanercept
Anakinra
Adalimumab
D/C
37%
<2%
71%
7%
18.5% 0.3%
Infusion reactions
Infliximab
22%
1.9%
Enbrel® (etanercept) [package insert]. 2002; Remicade® (infliximab) [package insert]. 2002;
Kineret™ (anakinra) [package insert]. 2002; Keystone E et al. Ann Rheum Dis. 2001;60 (suppl 1):67. [Abstract];
van de Putte LBA et al. Ann Rheum Dis. 2002;61(suppl 1):168. [Abstract]; Schiff M et al.
Ann Rheum Dis. 2002;61(suppl 1):169. [Abstract]
Autoantibodies and TNF Inhibitors
ANA (+) dsDNA(+)
RA
Drug-induced
lupus
30-40%
0-4%
0
Etanercept
11%
15%
4
Infliximab
62%
15%
6
12.9%
5.6%
1
Adalimumab
►PreScreen/Monitoring
►Safe
ANA & dsDNA Not Necessary!
to use TNF inhibitors in ANA+ RA patients
►Caution
with lupus like patients (Thalidomide used in LE)
Safety Concerns With TNF Inhibitors
Most adverse events have beenidentified in RA and Crohn’s patients.
The frequency of these events in AS & SpA has not been studied.
► Use: RCT* = 5068; Worldwide post-marketing+ > 515,000 patients
►
Etanercept Infliximab Adalimumab
Serious infections*
Tuberculosis+
Lymphoma*
New MS/Optic neuritis
CHF+
0.04/pt-yr 0.03/pt-yr
38
+
277
9
+
4
17/11+$
21/34
0.04/pt-yr
13*
10
+
3 clinical trials (2E, 1I) were d/c for
lack effect; dose related hosp/death
1/1*
ND
D/C for Admin. Rxn*
<2%
1.9%
0.3%
(+)dsDNA*
15%
15%
5.7%
4 pts+
1 pt.*
Drug induced Lupus
4 pts
+
The TNF Market
► Estimates
are that 10-20% of patients are on
TNF inhibitors
► Infliximab Sales grew by >316% from 1999
to 2000
► Feb 2002 15% of etanercept Rxs by PCP
► 2003 TNF inhibitors on the market in 2003
 Infliximab, etanercept, adalimumab
► Potential
Market = $21 Billion
► Current Market ~ $2 Billion
► 2004 Market Estimated @ $4 billion in sales
Decision Making and Newly Released Drugs
Discomfort
Comfort
Safety
Efficacy
QOL
Less Data
More Data
TNF Inhibitors
Characteristic
Etanercept
Infliximab
Adalimumab
Class
sTNFR
TNF mAb
TNF mAb
Construct
Recombinant Chimeric MAb Recombinant
fusion protein
human MAb
Half-life
4 days
8–10 days
10–20 days
Binding target
TNF LT
TNF
TNF
Administration
SC BIW
IV q 8 wk
SC EOW
Exposure
43 mos
230,000
55 mos
365,000
6 mos
~40,000
Comparison of New Agents
Etanercept
Infliximab
Anakinra
Arava
Administration
BIW, SC
q4-8 wk IV
with MTX
QD, SC
PO
Half-life
102 hrs
210 hrs
5.9 hr
15-18d
RA, JRA, ERA
RA, Crohns
RA
RA
ACR20
60-73%
42-80%
38-49%
50-52%
ACR70
10-15%
10%
10%
15%
>90%
>90%
??
60*
*Born Again RA?
60-75%
60-75%
(5%)
5%
Costs
$15,436
$13940-30287
$12,800
$2938
Indications
*Practice20
TNF Antagonists: Relative
Contraindications
► SLE
► Multiple
sclerosis, optic neuritis
► Current
active serious infections
► Chronic/recurrent
infections
► Immunosuppression
► History
of TB or positive PPD (untreated)
► Congestive
heart failure