ENBRELetanercept:

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• ENBREL(etanercept)
• EXPOSURE RESPONSE
• RELATIONSHIP
• Dr. Ivan Nestorov
• Amgen Inc.

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Talk Summary

• Introduction to Enbrel.
• Defining Enbrels therapeutic window.
• Why study Enbrels exposure - response.
• Site of action vs Systemic exposure.
• Enbrel exposure - response in RA and psoriasis.
• Enbrel exposure - response challenges.

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TNF

• Pro-inflammatory cytokine, produced primarily by
  activated monocytes macrophages.
• Many conditions are characterized by increased
  levels of TNF both systemically and locally (at
  the inflammation sites).
• Compensating the TNF surplus is desirable.

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ELEVATED TNF LEVELS

• Rheumatoid Arthritis
• Serum TNF levels elevated.
• Synovial fluid TNF levels even higher.
• Crohns Disease
• Serum TNF levels elevated.
• Gut mucosa TNF levels elevated.
• Psoriasis
• TNF is released by injured keratinocytes.
• TNF is increased in psoriatic lesional skin.
• Serum TNF levels elevated.

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Etanercept Structure
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Etanercept Mechanism of Action
Etanercept
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THE TNF THERMOMETER

• Normal cytokine balance
• TNF? and LT? in balance with sTNF receptors
• No excess TNF? or LT? activity
• No chronic inflammation
• Immunocompetent

High TNF?
Low TNF?
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THE TNF THERMOMETER

• Abnormal cytokine balance
• TNF? and LT? overwhelm soluble TNF receptors
• Excess TNF? or LT? activity
• Chronic inflammation and joint destruction
• Immunocompetence impaired

High TNF?
Low TNF?
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THE CYTOKINE THERMOMETER

• Abnormal cytokine balance
• Low TNF? levels
• Inadequate TNF? activity
• Chronic inflammation reduced
• Immunosuppressed
• Risk for opportunistic infections

Low TNF?
High TNF?
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DEFINING ENBRELS THERAPEUTIC WINDOW
THERAPEUTIC WINDOW

• Therapeutic goal is to normalize the TNF? levels
  without suppressing the immunocompetence.
• Thus a therapeutic window is defined.

High TNF?
Low TNF?
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DEFINING ENBRELS THERAPEUTIC WINDOW
SAFETY CONCERNS
THERAPEUTIC WINDOW
EFFICACY CONCERNS
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ENBREL REMICADE
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ENBREL REMICADE
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ENBREL REMICADE
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EXPOSURESERUM AND/OR SITE OF ACTION?

• TNF elevated both in serum and SoA.
• Complex distribution and elimination processes of
  large molecules.
• Site of Action seldom considered.
• SoA still important!!!

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ENBREL TISSUE EXPOSURE
CROHNS DISEASE
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ENBREL PopPKPD MODEL in RA(H. Lee, H.C. Kimko,
M. Rogge, D. Wang, I. Nestorov, C.C. Peck.
Population pharmacokinetic (PK) and
pharmacodynamic (PD) modeling of Etanercept using
logistic regression analysis. Clin. Pharmacol.
Ther.)

• One compartment Pop PK model
• Covariates - WT, GENDER, RACE - weak
• Significant IOC variability
• Sequential PK/PD modeling.
• Logistic regression PD model on ACR20
• Sum of placebo and active
• Exposure - cumulative AUC

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Tumor Necrosis Factor (TNF) and Psoriasis

• Efficacy in psoriasis measured by PASI
• Psoriasis Area and Severity Index (PASI) score
  correlates with TNF expression
• Serum and lesional TNF levels
• Decrease after effective therapy
• Correlate with extent of clinical improvement

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PASI 75
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PASI Clinical Response
PASI
Baseline
18.7
12 Weeks
7.6
24 Weeks
2.5
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ENBREL PK/PD MODELING CHALLENGES

• Which response variable to use?
• Which exposure variable to use?
• TNF secretion, TNF and Enbrel tissue distribution
  and binding linked to effect in a complex
  exposure-response model
• Integrated Enbrel clinical database and
  definitive Pop PK/PD model

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WHICH RESPONSE VARIABLE?

• ACR is a composite criterion
• Improvement in SJC TJC
• Improvement in 3 of 5 components
• ACR20 is a binary variable
• ? INFORMATION IS BEING LOST
• Alternative
• Model on each of the ACR components
• Compose the ACR after the model

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EXPOSURE CUMULATIVE AUC or Css?
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COMPLEX INTEGRATED EXPOSURE-RESPONSE MODEL
ENDOGENOUS PROCESSES MODEL(S)
PK MODEL
BINDING MODEL
EFFECT COMPARTMENT
(INDIRECT) PD MODEL
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HUGE ENBREL DATABASE

• Lot of research preclinical data
• More than 150,000 patients treated
• PK/PD data from at least 1500 RA subjects, 1500
  psoriasis subjects, constantly expanding
• Various populations - juvenile, elderly,
  Japanese, special cases etc.

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BACKUP SLIDES
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ENBREL REMICADE
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REMICADE
ENBREL

• Dosing
• RA 3 mg/kg IV inf.
• Crohns 5 mg/kg IV inf.
• MW 150 kD
• HL 8 - 10 days
• Vd 5 - 6 L
• TB warning

• Dosing
• RA 25 mg BIW SC
• Crohns failed
• MW 150 kD
• HL 4.5 days
• Vd 6 10 L
• No TB warning

WHY?
MOA BASED ON BINDING OF EXCESS TNF
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ENBREL REMICADE
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DIFFERENTIATIONMECHANISM OF ACTION

• Remicade and Enbrel share a common MoA
• Safety
• PK/PD for Tox studies - 16.0501/2/4/6
• Antigenicity issues - in virtually all clinical
  studies
• Understanding variability - PopPK, SA
• Efficacy
• Exposure at sites of action - WBA TD studies
• Biomarkers (cytokines)

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DIFFERENTIATIONDISTRIBUTION in humans
REMICADE Vss
ENBREL Vss

• 3 - 5 L in serum
• 2.5 L serum volume
• ?
• 0.5 - 2.5 L outside serum

• 7 - 12 L in serum
• 2.5 L serum volume
• ?
• 4.5 - 9.5 L outside serum

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DIFFERENTIATIONBINDING

• Remicade and Enbrel (?MW) share a common MoA
  based on binding
• In vitro studies - in Discovery Research
• Binding affects distribution
• Use binding parameters in models

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INDEPENDENT CONFIRMATION J.M.H. van der Brande et
al. Infliximab but not Etanercept induces
apoptosis in Lamina Propria T-lymphocytes from
patients with Crohns disease. Gastroenterology,
1241774-1785 (2000).
Figure 1. Both (A) infliximab and (B) etanercept
neutralized recombinant human TNF- effectively at
concentrations of 1 g/mL and 0.25 g/mL,
respectively, as assayed by transcription of an
NF-Bdriven reporter construct..