The Pharmacology of TNF Inhibitors

1
The Pharmacology of TNF Inhibitors

• Clinical Investigator
• Amgen/Wyeth
• Centocor
• NIH (GAIT)
• LaJolla Pharmaceuticals
• ISIS
• Genentech/IDEC
• Aventis

• Consultant/Lecturer
• Aventis
• Centocor
• Amgen/Immunex
• Wyeth-Ayerst
• Pharmacia
• Abbott
• Astra Zeneca

2
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 -
3
Kavanaugh A, Cohen S, Cush J Inhibitors of tumor
necrosis factor (TNF) in Rheumatoid Arthritis
Will that dog hunt? J Rheumatol 1998252049
4
Global Safety and Efficacy of Etanercept in
RAKlareskog, L, Moreland L, Cohen S. ACR 2002
Discontinuations
Early RA (U.S.)
80
100
Advanced RA (U.S.)
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
Remaining on Study
40
20
0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
Months
5
DMARD Durability in RA Patients
Azathioprine (n 56) Hydroxychloroquine
(n 228) Methotrexate (n 253) Oral
gold (n 84) Parenteral gold
(n 269) Penicillamine (n 193)
1.0
0.8
0.6
Estimated Continuation
0.4
0.2
0
Months
Pincus T, et al. J Rheumatol. 19921918851894.
6
Enbrel Efficacy in Rheumatoid Arthritis
ACR20
ACR50
ACR70
Etanercept vs Placebo (Moreland NEJM 1997)
80
75
72
71
70
Etanercept vs Placebo (Moreland Ann Int Med 1999)
70
59
Etanercept vs Placebo (Euro Etan Invest AR 1999)
57
60
Etan/Mtx vs Placebo/Mtx (Weinblatt NEJM 1999)
50
49
of Patients
40
39
40
Etanercept vs Mtx (Bathon NEJM 2000)
34
30
25
20
20
15
15
13
10
0
ACR Responses at Endpoint
7
Geborek DMARD1 Continuation Swedish Multicenter
RA Registry2
100
90
Etanercept
80
70
Infliximab
60
Percentage remaining on DMARD
50
40
Leflunomide
30
20
10
0
0
3
6
12
18
Time (months)
1. Disease modifying anti-rheumatic drug 2.
Geborek et al., Ann RheumDis.61 793, 2002
8
Withdrawal of Methotrexate and Prednisone Change
at 3 Years
paired-rank sum test (n68)
Prednisone
MTX
Methotrexate Prednisone
Increased 3 3
Decreased or D/C 68 85
Discontinued 39 59
9
TNF Antagonists Other Indications and Clinical
Investigations

• Confirmed Efficacy in Trials
• Crohns disease
• Spondyloarthropathies
• Psoriatic arthritis
• Psoriasis
• Ankylosing spondylitis
• Juvenile rheumatoid arthritis
• Adult Stills disease

• Under Investigation
• Vasculitis Wegeners, GCA, PAN
• Scleroderma
• Graft-versus-host disease
• Inflammatory myositis
• Interstitial lung disease
• Sjögrens syndrome
• Inflammatory eye and ear disease
• Asthma
• Hepatitis C
• Sarcoidosis
• Behçets syndrome
• Pyoderma gangrenosum

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Psoriatic Arthritis Improved Skin Lesions
12 Weeks
Baseline
Elbow of patient 577 50 improvement in target
lesion.
11
Nail Responses with Etanercept
Week 2
Baseline
Week 8
Week 12
12
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Cytokine Signaling Pathways Involved in RA
RF
IL-4 IL-10
IL-4 IL-6 IL-10
Th2
Macrophage
Plasmacell
Th0
IFNg IL-12
Interferon g
B cell
CD4 T cell
CD11
CD69
OPGL
TNF IL-1 IL-6
CD11
CD69
Synovium
Chondrocyte
Osteoclast
Fibroblast
Production of metalloproteinases andother
effector molecules
Migration of polymorphonuclear cells
Erosion of bone and cartilage
Choy EH, Panayi GS. N Engl J Med.
2001344907916.
14
-
IL-1Ra sIL-1RII IL-1 Ra MAb to IL-6R MAb to TNF
TIMPs
TGFb
MMPs
sTNFR, IL-4, IL-10 IL-11, IL-13, IL-18 BP
IL-1, TNF GM-CSF, IFN?? IL-6, IL-8 IL-15,
IL-16 IL-17, IL-18
Autoimmune diseases
Adapted from Arend WP. Arthritis Rheum.
200145101106.
15
Key Actions Attributed to TNF?
TNF?
(VEGF)
16
Inhibition of Cytokines
Adapted with permission from Choy EH, Panayi GS.
N Engl J Med. 2001344907916.
17
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TNF Antagonists
etanercept
infliximab
19
Update on Etanercept
John J. Cush, MD Chief, Rheumatology Clinical
Immunology Presbyterian Hospital of
Dallas Clinical Professor of Internal
Medicine The University of Texas Southwestern
Medical School
20
Infliximab and Etanercept
Murine/Human Chimeric IgG1
sTNF-RII / Ig
21
Evolution of TNF Blocking Therapies
Etanercept Infliximab Adalimumab Characteris
tic (ENBREL?) (REMICADE?) (HUMIRA)
Class sTNFR TNF MAb TNF MAb Construct Recombina
nt Chimeric MAb Recombinant fusion
protein human MAb Half-life 4 days 810
days 1020 days Binding target TNF/LT?
TNF TNF Administration 25 mg 310 mg/kg 40
mg SC IV with MTX SC Twice weekly Every 48
weeks Every other week
Some patients not taking concomitant MTX may
derive additional benefit fromincreasing the
dosing frequency of adalimumab to 40 mg every week
22
Synthesis and Actions of TNF?
23
Chimeric A2 (cA2) Monoclonal Antibody
Infliximab


Human (IgG?)
k

• Chimeric (mouse/human) IgG1 monoclonal antibody
• Binds to TNFa with high affinity and specificity

k
Knight DM, et al. Mol Immunol. 1993
30(16)1443-53.
24
Mechanisms for Antibody Neutralization of TNF?
25
Effect of Anti-TNF Antibody on Established
Collagen-Induced Arthritis in Mice
Effect on Clinical Progression
p lt 0.05 vs. control Indicates injections
Adapted from Williams RO, et al. Proc Natl Acad
Sci. 1992 899784-88.
26
Inhibitory Effect of Infliximab on Synovial Cell
IL-1 Production
Brennan FM, et al. Lancet. 1989 ii244-47.
Haworth C, et al. Eur J Immunol. 1991
212575-79. Butler D, et al. Eur Cytokine
Network. 1995 6225-30.
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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.
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Binding Characteristics TNF Inhibitors
Etanercept Infliximab Adalimumab
Association Rate (Ka) 7.9 x 106 M-1 Sec-1 1.4 x 106 M-1 Sec-1 1.9 x 105 M-1 Sec-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
29
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
1.81
0
60
120
180
240
Days
Dosed every 8 weeks
30
Adalimumab SQ 14 Day Half-Life
Percent of Maximum Serum Concentration at
Steady State
150
1.5-fold Variation
100

50
0
0
28
56
14
42
Days
Dosed every 2 weeks
31
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
60
Days
Dosed twice a week
32
Safety Considerations With Biologics

• Serious infections
• Opportunistic infections (TB)
• Malignancies
• Demyelination
• Hematologic abnormalities
• Administration reactions
• Congestive heart failure
• Autoantibodies and lupus

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TOTAL Opportunistic Infections
Etanercept Infliximab Adalimumab
Exposed 130,000 365,000 2468
M. Tuberculosis 38 277 13
(US/EU) (32/68) (31/69) (23/77)
Extrapulmonary/miliary 52 30-45 40
Pneumocystis carnii 4 38 -
Histoplasmosis 1 30 3
Listeriosis 2 28 -
Atypical mycobacteria 10 26 1
Aspergillus 5 24 2
Cytomegalovirus 5 16 -
Systemic Candidiasis 7 13 -
Others Crypto3, sporo1 Cocci 13 Nocardia 1
34
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)

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Tbc Differences between TNF inhibitors
Infliximab Etanercept
Pharmacokinetic(1/2 life) 210 hrs 102 hrs
Off Rate Slow Fast
Lymphotoxin inhibition None Yes
Apoptosis Yes No
Cell Lysis in vitro Yes No
Age gt 65 yrs 42 lt25
Dose escalation 1/3 ? dose gt90 1.6 vials per week
36
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, 200261(Suppl
II)ii-ii7
37
PPD Positivity and Remicade
34 yr.old Korean female RA x 8 mos PPD 19mm
(no Sxs, neg CXR)
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Algorithm for TB Testing
TNF patient has office visit
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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 lt 1
• Drug-induced lupus 4 pts (0.2) 4 pts
• Etiology ? IL-10?
• HACA directed against murine component
• Crohns 13 HACA gt more likely to have infusion
  rxn
• Lower HACA levels MTX, 6MP, AZA higher dose
  (10mg)
• Maini99 1mg 3mg 10mg
• -MTX 53 21 7
• MTX 15 7 0

HACA
40
Safety Considerations ImmunogenicityAnti-Drug
Antibodies During RA Clinical Trials
of Patients Developing Anti-drug Antibodies
Etanercept ? 5
Infliximab 10
Adalimumab 5
Anakinra ? 1
FDA Arthritis Advisory Committee meeting. August
17, 2001.
41
Safety IssueAdministration Reactions

• Injection-site reactions
• Etanercept 37 lt2
• Anakinra 71 7
• Adalimumab 18.5 0.3
• Infliximab 22 1.9

Incidence D/C
Infusion reactions
Enbrel (etanercept) package insert. 2002
Remicade (infliximab) package insert. 2002
Kineret (anakinra) package insert. 2002
Keystone E et al. Ann Rheum Dis. 200160 (suppl
1)67. Abstract van de Putte LBA et al. Ann
Rheum Dis. 200261(suppl 1)168. Abstract
Schiff M et al. Ann Rheum Dis. 200261(suppl
1)169. Abstract
42
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Remicade Infusion Reactions

• Infusion reactions uncommon
• N/V, Headache, chills
• pruritis, urticaria, rash, flushing
• tachycardia, SOB, chest tightness
• Hold -gt assess -gt slow infusion rate (Related to
  speed of delivery gt2hrs)
• When to premedicate?
• Rare Hypotension, bronchospasm, anaphyllaxis,
  feeling impending doom
• Crohns
• Intermittent or delayed therapy
• D/C or Desensitization?

44
Autoantibodies and TNF Inhibitors
ANA () dsDNA() Drug-induced lupus
RA 30-40 0-4 0
Etanercept 11 15 4
Infliximab 62 15 6
Adalimumab 12.9 5.6 1
PreScreen/Monitoring ANA dsDNA Not Necessary! PreScreen/Monitoring ANA dsDNA Not Necessary! PreScreen/Monitoring ANA dsDNA Not Necessary! PreScreen/Monitoring ANA dsDNA Not Necessary!
Safe to use TNF inhibitors in ANA RA patients Safe to use TNF inhibitors in ANA RA patients Safe to use TNF inhibitors in ANA RA patients Safe to use TNF inhibitors in ANA RA patients
Caution with lupus like patients (Thalidomide used in LE) Caution with lupus like patients (Thalidomide used in LE) Caution with lupus like patients (Thalidomide used in LE) Caution with lupus like patients (Thalidomide used in LE)
45
Autoantibodies RA Clinical Trials
Etanercept PBO Infliximab PBO Adalimumab PBO
ANA titers ( of patients) 11 5 62 27 12 7
Anti-dsDNA Ab ( of patients) 15 4 15 0 3 0.2
Lupus-like syndrome (No. of reported cases) N/A N/A 3 0 1 0
ANA anti-nuclear antibody ANA titer
considered positive if gt 180 dsDNA
double-stranded DNA PBO placebo ENBREL
(etanercept) package insert. Seattle, WA Immunex
Corporation 2002 REMICADE (infliximab) package
insert. Malvern, PA Centocor, Inc. 2002
HUMIRA (adalimumab) package insert. Abbott
Park, IL Abbott Laboratories 2002.
46
Safety Concerns With TNF Inhibitors

• Most adverse events have beenidentified in RA and
  Crohns patients. The frequency of these events
  in AS SpA has not been studied.
• Use RCT 5068 Worldwide post-marketing gt
  515,000 patients

Etanercept Infliximab Adalimumab
Serious infections 0.04/pt-yr 0.03/pt-yr 0.04/pt-yr
Tuberculosis 38 277 13
Lymphoma 9 4 10
New MS/Optic neuritis 17/11 21/34 1/1
CHF 3 clinical trials (2E, 1I) were d/c for lack effect dose related hosp/death 3 clinical trials (2E, 1I) were d/c for lack effect dose related hosp/death ND
D/C for Admin. Rxn lt2 1.9 0.3
()dsDNA 15 15 5.7
Drug induced Lupus 4 pts 4 pts 1 pt.
47
TNF Inhibitor Lymphoma RA Pt Profiles
Etanercept Infliximab Adalimumab
N(Pt-yrs) 3389 1298 2468
Lymphomas 9 4 10
SIR Lymphoma 3.47 6.35 5.52
Onset Interval (d) 630 (4-1403) (30wks-19mo) 540 d (57-1265)
Mean Age 62 63 63
48
The TNF Market

• Estimates are that 10-20 of patients are on TNF
  inhibitors
• Infliximab Sales grew by gt316 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 _at_ 4 billion in sales

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Decision Making and Newly Released Drugs
Discomfort
Comfort
Safety
Efficacy
QOL
Less Data
More Data
50
TNF Inhibitors
51
Comparison of New Agents
Etanercept Infliximab Anakinra Arava Administrati
on BIW, SC q4-8 wk IV QD, SC PO with
MTX Half-life 102 hrs 210 hrs 5.9 hr
15-18d Indications RA, JRA, ERA RA,
Crohns RA RA ACR20 60-73 42-80 38-49 50-52 ACR
70 10-15 10 10 15 Practice20 gt90 gt90 ?? 60
Born Again RA? 60-75 60-75 (5) 5 Costs 15,4
36 13940-30287 12,800 2938
52
Comparison of New Agents
Etanercept Infliximab Anakinra Arava Common
AE ISR Infusion Rxn ISR GI Reason W/D ISR
Infusion Rxn ISR GI Pregnancy Category B B B X UR
I 30 32 13 21-25 Serious Infection 1 8 2 2
Tbc/Opportunistic 11/23 92/47 0/0 0/0 LFTs-ALT
(w/MTX) ND (32) ND 10(25) dsDNA 15 10 0 0 Neu
tralizing Abs lt5 13 lt1 ND Consumer Ads print gt
TV TV print - (print)
53
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