The Pharmacology of TNF The Pharmacology of TNF InhibitorsInhibitors

Clinical Investigator

Amgen/WyethCentocorNIH (GAIT)LaJolla

Pharmaceuticals ISISGenentech/IDECAventis

Consultant/LecturerAventisCentocorAmgen/ImmunexWyeth-AyerstPharmaciaAbbottAstra Zeneca

Cytokine Inhibitors: Current IndicationsCytokine Inhibitors: Current IndicationsEnbrel Remicade Humira Kineret

Target TNF TNF TNF IL-1

RA Yes Yes Yes Yes

Crohns - YesClinical Trials

-

JRA Yes Clinical TrialsClinical Trials

Clinical Trials

Psoriatic arthritis

Yes Clinical Trials - -

Ankylosing Spondylitis

Yes Clinical TrialsClinical 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 Global Safety and Efficacy of Etanercept in RARA

Klareskog, L, Moreland L, Cohen S. ACR 2002Klareskog, L, Moreland L, Cohen S. ACR 2002

Early RA (U.S.)Advanced RA (U.S.)Advanced RA (Europe)

Months

Reason: Loss of efficacy 8 %Adverse event 9 %Patient decision 5 %Protocol issues 2 %Lost to follow up 1 %Other 3 %Total 29%

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

% R

em

ain

ing

on

Stu

dy

DiscontinuationsDiscontinuations~80%

DMARD Durability in RA DMARD Durability in RA PatientsPatients

DMARD Durability in RA DMARD Durability in RA PatientsPatients

Pincus T, et al. J Rheumatol. 1992;19:1885–1894.Pincus T, et al. J Rheumatol. 1992;19:1885–1894.

Azathioprine (n = 56)

Hydroxychloroquine(n = 228)

Methotrexate (n = 253)

Oral gold (n = 84)

Parenteral gold (n = 269)

Penicillamine (n = 193)

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

00

00 1010 2020 3030 4040 5050 6060

MonthsMonths

Est

imat

ed C

on

tin

uat

ion

Est

imat

ed C

on

tin

uat

ion

*paired-rank sum` test (n=68)

Withdrawal of Methotrexate and PrednisoneWithdrawal of Methotrexate and PrednisoneChange at 3 YearsChange at 3 Years

0

5

10

15

20

Mean

MTX

d

ose (

mg

/wk)

Baseline Year 3

17.6

9.3

p<0.001*

0

5

10

Baseline Year 3M

ean

Pre

din

son

e

dose (

mg

/d)

6.4

2.3

p<0.001

Methotrexate Prednisone

Increased 3% 3%

Decreased or D/C

68% 85%

Discontinued 39% 59%

MTX Prednisone

TNF Antagonists: TNF Antagonists: Other Indications and Clinical Other Indications and Clinical

InvestigationsInvestigations

TNF Antagonists: TNF Antagonists: Other Indications and Clinical Other Indications and Clinical

InvestigationsInvestigationsConfirmed Efficacy in

Trials► Crohn’s disease ► Spondyloarthropathies

Psoriatic arthritisPsoriasisAnkylosing spondylitis

► Juvenile rheumatoid arthritis

► Adult Still’s disease

Under Investigation► Vasculitis: Wegener’s, GCA, PAN► Scleroderma► Graft-versus-host disease► Inflammatory myositis► Interstitial lung disease► Sjögren’s syndrome► Inflammatory eye and ear disease► Asthma► Hepatitis C► Sarcoidosis► Behçet’s syndrome► Pyoderma gangrenosum

Psoriatic Arthritis: Improved Psoriatic Arthritis: Improved Skin LesionsSkin Lesions

12 Weeks12 WeeksBaselineBaseline

Elbow of patient 577; 50% improvement in target lesion.Elbow of patient 577; 50% improvement in target lesion.

Nail Responses with Etanercept

Baseline

Week 8 Week 12

Week 2

Cytokine Signaling Pathways Cytokine Signaling Pathways Involved in RAInvolved in RA

Cytokine Signaling Pathways Cytokine Signaling Pathways Involved in RAInvolved in RA

Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.

TNFIL-1IL-6

IFNIL-12

IL-4IL-10

Macrophage

RF

IL-4IL-6

IL-10Plasmacell

B cell

Interferon

Th0

Th2

Synovium

OPGL

CD4 + T cell

CD69CD11

CD11CD69

Osteoclast FibroblastChondrocyte

Production of metalloproteinases andother effector molecules

Migration of polymorphonuclear cells

Erosion of bone and cartilage

ProinflammatoryTGF

MMPs

TIMPs

sTNFR, IL-4, IL-10IL-11, IL-13, IL-18 BP

Adapted from Arend WP. Arthritis Rheum. 2001;45:101–106.Adapted from Arend WP. Arthritis Rheum. 2001;45:101–106.

Autoimmune diseases

-Anti-inflammatory

IL-1RasIL-1RIIIL-1 RaMAb to IL-6RMAb to TNF

IL-1, TNFGM-CSF, IFNIL-6, IL-8IL-15, IL-16IL-17, IL-18

Key Actions Attributed to TNFKey Actions Attributed to TNF

TNFTNF(VEGF)

Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.

Inhibition of CytokinesInhibition of Cytokines

Activation ofanti-inflammatory pathways

Anti-inflammatorycytokineSuppression ofinflammatorycytokines

Neutralization of cytokines

Soluble receptor

Monoclonal antibody

No signal

Receptor blockade

Monoclonal antibody

Receptor antagonist

No signal

Inflammatory cytokine

Normal interaction

Cytokine receptorInflammatory signal

TNF AntagonistsTNF Antagonists

infliximabetanercept

adalimumab

Murine sequences

Human sequences

nerelimomabCDP-571

afelimomabCDP-870

PEG

Evolution of TNF Blocking TherapiesEvolution of TNF Blocking Therapies

*Some patients not taking concomitant MTX may derive additional benefit fromincreasing the dosing frequency of adalimumab to 40 mg every week*Some patients not taking concomitant MTX may derive additional benefit fromincreasing the dosing frequency of adalimumab to 40 mg every week

Etanercept Infliximab Adalimumab

Characteristic (ENBREL) (REMICADE) (HUMIRA™)

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 25 mg 3–10 mg/kg 40 mg

SC IV with MTX SC

Twice weekly Every 4–8 weeks Every other week*

Etanercept Infliximab Adalimumab

Characteristic (ENBREL) (REMICADE) (HUMIRA™)

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 25 mg 3–10 mg/kg 40 mg

SC IV with MTX SC

Twice weekly Every 4–8 weeks Every other week*

Synthesis and Actions of TNFSynthesis and Actions of TNF

Human (IgG)

Mouse(Binding Site for TNF)

Knight DM, et al. Mol Immunol. 1993; 30(16):1443-53.

Chimeric (mouse/human) IgG1 monoclonal antibody

Binds to TNF with high affinity and specificity

Chimeric A2 (cA2) Monoclonal AntibodyChimeric A2 (cA2) Monoclonal Antibody

InfliximabInfliximab

Mechanisms for Antibody Neutralization of TNFMechanisms for Antibody Neutralization of TNF

Effect of Anti-TNF Antibody on Established Collagen-Induced Arthritis in Mice

Effect of Anti-TNF Antibody on Established Collagen-Induced Arthritis in Mice

* p < 0.05 vs. control Indicates injections

Adapted from Williams RO, et al. Proc Natl Acad Sci. 1992; 89:9784-88.

Effect on Clinical ProgressionEffect on Clinical Progression

Inhibitory Effect of Infliximab on Synovial Cell IL-1 Production

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

Infliximab (Anti-TNF mAb) in Patients with Active RA

Paleolog EM, et al. Arthritis Rheum. 1995; 38 (suppl.):Abstract S757.

Serum VEGF and Serum E-selectinSerum VEGF and Serum E-selectin

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

Infliximab IV: 9.5 Day Half-Infliximab IV: 9.5 Day Half-LifeLife

Percent of Maximum Serum Concentration Percent of Maximum Serum Concentration at Steady Stateat Steady State

002020404060608080

100100120120

00 6060 120120 180180 240240

DaysDays

Dosed every 8 weeksDosed every 8 weeks

55-fold Variation55-fold Variation

1.81%1.81%

%%

Adalimumab SQ: 14 Day Adalimumab SQ: 14 Day Half-LifeHalf-Life

Percent of Maximum Serum Concentration atPercent of Maximum Serum Concentration at Steady StateSteady State

00

5050

100100

150150

00 2828 5656

DaysDays

Dosed every 2 weeksDosed every 2 weeks

1.5-fold Variation1.5-fold Variation

%%

1414 4242

Etanercept SQ: 4.8 Day Half-Etanercept SQ: 4.8 Day Half-LifeLife

Percent of Maximum Serum Concentration atPercent of Maximum Serum Concentration at Steady StateSteady State

00

5050

100100

150150

00 3030 6060

DaysDays

Dosed twice a weekDosed twice a week

1.5-fold Variation1.5-fold Variation

%%

Safety Considerations With Safety Considerations With BiologicsBiologics

Safety Considerations With Safety Considerations With BiologicsBiologics

► Serious infections

► Opportunistic infections (TB)

► Malignancies

► Demyelination

► Hematologic abnormalities

► Administration reactions

► Congestive heart failure

► Autoantibodies and lupus

TOTAL Opportunistic InfectionsTOTAL Opportunistic InfectionsEtanercept Infliximab Adalimuma

b

# 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

TNF and Mycobacterial TNF and Mycobacterial InfectionInfection► 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 Tbc – Differences between TNF inhibitorsinhibitors

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 > 65 yrs 42 % <25%

Dose escalation 1/3 dose>90% 1.6 vials per

week

Tuberculosis & TNF Tuberculosis & TNF AntagonistsAntagonists

►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 presentRecent/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 therapy1Furst, et al, Ann Rheum Dis, 2002;61:(Suppl II):ii-ii7

TNF Inhibitors & Antibody TNF Inhibitors & Antibody Formation 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

-MTX 53% 21% 7%+MTX 15% 7% 0%

HACA

Safety Considerations: ImmunogenicityAnti-Drug Antibodies During RA Clinical Trials

Safety Considerations: ImmunogenicityAnti-Drug Antibodies During RA Clinical Trials

% of Patients Developing% of Patients DevelopingAnti-drug AntibodiesAnti-drug Antibodies

EtanerceptEtanercept 55

InfliximabInfliximab 1010

AdalimumabAdalimumab 55

AnakinraAnakinra 11

FDA Arthritis Advisory Committee meeting. August 17, 2001.FDA Arthritis Advisory Committee meeting. August 17, 2001.

Safety Issue:Safety Issue:Administration ReactionsAdministration Reactions

Injection-site reactions Etanercept 37% <2%

Anakinra 71% 7% Adalimumab 18.5% 0.3% 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]

Incidence D/C

Infusion reactions

Autoantibodies and TNF InhibitorsAutoantibodies 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!►Safe to use TNF inhibitors in ANA+ RA patients►Caution with lupus like patients (Thalidomide used in LE)

Safety Concerns With TNF Safety Concerns With TNF InhibitorsInhibitors► 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*

0.04/pt-yr

0.03/pt-yr

0.04/pt-yr

Tuberculosis+ 38 + 277 + 13*

Lymphoma* 9 4 10New 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

ND

D/C for Admin. Rxn*

<2% 1.9% 0.3%

(+)dsDNA* 15% 15% 5.7%

Drug induced Lupus

4 pts + 4 pts+ 1 pt.*

The TNF MarketThe 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

Safety EfficacyQOL

Less Data More Data

ComfortDiscomfort

Decision Making and Newly Released Drugs

TNF InhibitorsTNF InhibitorsTNF InhibitorsTNF InhibitorsCharacteristic Etanercept Infliximab Adalimumab

Class sTNFR TNF mAb TNF mAb

Construct Recombinant Chimeric MAb Recombinantfusion 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 55 mos 6 mos230,000 365,000 ~40,000

Comparison of New AgentsComparison of New AgentsEtanerceptEtanercept InfliximabInfliximab AnakinraAnakinra AravaArava

AdministrationAdministration BIW, SCBIW, SC q4-8 wk IVq4-8 wk IV QD, SCQD, SC POPOwith MTXwith MTX

Half-lifeHalf-life 102 hrs102 hrs 210 hrs210 hrs 5.9 hr 5.9 hr 15-18d15-18d

IndicationsIndications RA, JRA, ERARA, JRA, ERA RA, CrohnsRA, Crohns RARA RARA

ACR20ACR20 60-73%60-73% 42-80%42-80% 38-49%38-49% 50-52%50-52%

ACR70ACR70 10-15%10-15% 10%10% 10%10% 15%15%

*Practice20*Practice20 >90%>90% >90%>90% ???? 60*60*

*Born Again RA?*Born Again RA? 60-75%60-75% 60-75%60-75% (5%)(5%) 5%5%

CostsCosts $15,436$15,436 $13940-30287$13940-30287 $12,800$12,800 $2938$2938

TNF Antagonists: Relative TNF Antagonists: Relative ContraindicationsContraindications

TNF Antagonists: Relative TNF Antagonists: Relative ContraindicationsContraindications

►SLE

►Multiple sclerosis, optic neuritis

►Current active serious infections

►Chronic/recurrent infections

► Immunosuppression

►History of TB or positive PPD (untreated)

►Congestive heart failure