EMEA EFPIA Workshop 19Dec08 Integrating Pgx Early into Drug - - PowerPoint PPT Presentation

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EMEA EFPIA Workshop 19Dec08 Integrating Pgx Early into Drug - - PowerPoint PPT Presentation

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EMEA EFPIA Workshop 19Dec08 Integrating Pgx Early into Drug Development: PK as a working example 1 EMEA-EFPIA Workshop on PGx 19 Dec 2008 - CASE 4 Overview: 4 Sessions over a DAY Workshop Goal: Collaborative efforts on future paper or

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EMEA-EFPIA Workshop on PGx 19 Dec 2008 - CASE 4

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EMEA EFPIA Workshop 19Dec08

Integrating Pgx Early into Drug Development: PK as a working example

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EMEA-EFPIA Workshop on PGx 19 Dec 2008 - CASE 4

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Overview: 4 Sessions over a DAY

Workshop Goal: Collaborative efforts on future paper or guidance

  • Session 1 Set the Scene from EMEA ‘Pts to Consider’:

3 speakers (Experts from Regulatory Authority, Industry, Medical Practice)

  • Session 2 Set the Science (PK & PGx):

– ADME Panel (PGx expert) – Core Case: Building blocks for Session 3

  • Session 3 Parallel Small Groups on Cases to Design:

Design the next drug development phase on the pipeline: – Case 1: Phase 1 – Case 2: Phase 2a – Case 3: Standardised Formats – Case 4: Phase 2b

  • Session 4

Agree areas for consensus & next actions to work together

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EMEA-EFPIA Workshop on PGx 19 Dec 2008 - CASE 4

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Workshop Attendees:

  • Choose 1 Case (out of 4)
  • Become the Project Team during the case:
  • Identify who you are and your Expertise
  • Volunteer for Project Team Leader (to a team decision)
  • Volunteer for Decision-Table to work with Debriefer, in order to

generate 1-2 slides for debrief on key messages which arose during the case discussion

Core Case Panel :

  • Are the experts who developed the case and will be on the Team as:
  • Project Team Manager (to time session and facilitate process)
  • Data expert
  • Debriefer after Session 3

For Each Case

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EMEA-EFPIA Workshop on PGx 19 Dec 2008 - CASE 4

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Case 4 Background Drug A is in Early Development

Company ABC is developing a second-in-class Drug A for a serious, chronic disease, Diabetes Mellitus Type 2, for which many patients are insufficiently controlled.

  • Drug A is an antagonist which shows no major

toxicities in animals at exposures expected to provide >80% receptor occupancy.

  • Limiting toxicity is elevated body temperature in dogs.
  • A narrow therapeutic margin is expected in patients.
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EMEA-EFPIA Workshop on PGx 19 Dec 2008 - CASE 4

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EMEA-EFPIA PGx in PK Workshop

Case 4

Goal: What does team plan for Phase 2b trial?

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Case 4: Plan for Phase 2b

Situation: Project team has data from Phase 1 & Phase 2a Target: Plan for Phase 2b Given:

  • Observed PK variability in Phase 1
  • Observed PK variability in Phase 2a

Data: see next slides (Phase 2a)

  • Phase 2a is dose finding and initial drug effect

Drug A Effect is assessed by % glycosylated hemoglobin (HbA1c)

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Phase 2A study – PK results

PK - Drug A 25 mg 50 mg 100 mg

50 100 150 200 250 300 350

Daily dose

AUC 24hr (µg.hr/mL)

PK - Drug A 25 mg 50 mg 100 mg

50 100 150 200 250 300 350

Daily dose

AUC 24hr (µg.hr/mL)

Phase 2A study design:

  • N = 120 => n = 30 / treatment arm
  • Four treatment arms: 0 mg (placebo), 25 mg, 50 mg, 100 mg (daily dose)
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DNA samples collected for n = 100 subjects (special informed consent)

Phase 2A study – PK results by CYP2C8 genotype

PK of Drug A - per genotype

AA AB BB AA AB BB AA AB BB 50 100 150 200 250 300 350

25 mg 50 mg 100 mg Daily dose Genotype AUC 24hr (µg.hr/mL)

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Case 4: Plan for Phase 2b

Situation: Project team has data from Phase 1 & Phase 2a Target: Plan for Phase 2b Given:

  • Observed PK variability in Phase 1
  • Observed PK variability in Phase 2a
  • Some effect data from Phase 2a

The key question in drug development: Does PK variability predict Drug Response ?

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Drug effect assessed by change in % glycosylated hemoglobin (HbA1c)

Phase 2A study – HbA1c results

Target effect range HbA1C = 4-7% Overall effect 0 mg 25 mg 50 mg 100 mg

3 4 5 6 7 8 9 10 11 12

Daily dose

HbA1c (%)

Overall effect 0 mg 25 mg 50 mg 100 mg

3 4 5 6 7 8 9 10 11 12

Daily dose

HbA1c (%)

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Target effect range

Phase 2A study –

PK-PD relationship

PK versus PD

50 100 150 200 250 300 350 400 3 4 5 6 7 8 9 10 11 12

0 mg 25 mg 50 mg 100 mg

AUC-24hr (µg.hr/mL) HbA1c (%)

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Scenario 1:

Phase 2A study – HbA1c results by CYP2C8 genotype

Target effect range

Effect per genotype

AA AB BB AA AB BB AA AB BB AA AB BB 3 4 5 6 7 8 9 10 11 12

25 mg 50 mg 100 mg Daily dose Genotype 0 mg

HbA1c (%)

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Perform exploratory studies (incl.

  • ther genes,

convert EM to PM by inhibitor)

/

/ Genotype ADME panel pro- spectively in Ph-2B Do no PGx

Next Team steps > Scenario: v

Only collect DNA Genotype XX pro- spectively in Ph-2B +why Enrich Ph- 2B study for specific XX genotype Other proposals

1: CYP2C8 associates with PK / CYP2C8 associates with effect

Case 4 – Options for Project Team Decision on its next step: Design of Phase 2B Clinical Trial

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Scenario 1: (Ideal or ‘dream’ situation)

Phase 2A study – HbA1c results by CYP2C8 genotype

Target effect range

Effect per genotype

AA AB BB AA AB BB AA AB BB AA AB BB 3 4 5 6 7 8 9 10 11 12

25 mg 50 mg 100 mg Daily dose Genotype 0 mg

HbA1c (%)

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Phase 2A study – HbA1c results by CYP2C8 genotype

Scenario 2: This is actually what the team observed

Target effect range

Effect per genotype

AA AB BB AA AB BB AA AB BB AA AB BB 3 4 5 6 7 8 9 10 11 12

25 mg 50 mg 100 mg Daily dose Genotype 0 mg

HbA1c (%)

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Perform exploratory studies (incl.

  • ther genes,

convert EM to PM by inhibitor)

/ /

/ Genotype ADME panel pro- spectively in Ph-2B Do no PGx

Next Team steps > Scenario: v

Only collect DNA Genotype XX pro- spectively in Ph-2B +why Enrich Ph- 2B study for specific XX genotype Other proposals

1: CYP2C8 associates with PK / CYP2C8 associates with effect 2: CYP2C8 associates with PK / CYP2C8 does not associate with effect

Case 4 – Options for Project Team Decision on its next step: Design of Phase 2B Clinical Trial

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Project Team conclusion (scenario 2):

  • Variability in effect of drug A on HbA1c

is partially explained by PK and weakly by CYP2C8

As in real life, emerging data unfolds… => Scenario 3

Project Team reviews Ph1 and 2a data

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Effect of Drug IMPROVISTA on blood sugar in elderly diabetes patients (n=60)

CC CT TT

50 100 150 200 250

Genotype gene Z

n=35 n=20 n=5

p<0.001 p<0.01

Blood sugar (mg/dL)

  • Drug IMPROVISTA is already on the market

(first-in-class), and targets the same protein as Drug A.

  • The protein encoded by Gene Z is known to be

part of the signalling pathway downstream of the target protein, but its exact role in the signalling cascade is not yet understood.

  • The functional effect of the examined

polymorphism on the protein function is unknown.

  • The publication does not report on possible

effects of Gene Z genotype on the PK profile of drug IMPROVISTA. Anon Y. Mus et al, Lancet 2008 Pharmacogenetic effect of Gene Z genotype on response to IMPROVISTA therapy in diabetes mellitus patients.

Results of the following study are published in the public domain literature at the time when the phase 2B study design is discussed.

Case 4:

Scenario 3

(builds further on Scenario 2)

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3: Published Gene Z with efficacy of first-in- class competitor / CYP2C8 does not associate with effect (drug A)

Perform exploratory studies (incl.

  • ther genes,

convert EM to PM by inhibitor)

Not appl. Not appl.

Genotype XX and YY prospective ly in Ph-2B Genotype ADME panel pro- spectively in Ph-2B Do no PGx

Next Team steps > Scenario: v

Only collect DNA Genotype XX pro- spectively in Ph-2B +why Enrich Ph- 2B study for specific XX genotype Other proposals

1: CYP2C8 associates with PK / CYP2C8 associates with effect 2: CYP2C8 associates with PK / CYP2C8 does not associate with effect

Case 4 – Options for Project Team Decision on its next step: Design of Phase 2B Clinical Trial

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As in real life, emerging drug development decisions unfold…

  • Executives in the Company decide that the first-in-class drug

data (Lancet publication) has enough biological plausibility to also apply for second-in-class Drug A

  • As it happens, consented DNA samples from Phase 2A are

available to generate Gene Z genotyping data with Drug A (retrospective analysis) within the Company.

Case 4: Scenario 4

(builds further on Scenario 3)

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Gene Z genotype and effect of Drug A

CC CT TT CC CT TT CC CT TT CC CT TT 3 4 5 6 7 8 9 10 11 12

25 mg 50 mg 100 mg Daily dose Genotype 0 mg

HbA1c (%)

Project Team reviews Phase 2a data with gene Z (retrospective analysis)

P<0.05 N.S. N.S. N.S.

Target effect range

Case 4: Scenario 4

(builds further on Scenario 3)

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3: Published Gene Z with efficacy of first-in- class competitor / CYP2C8 does not associate with effect drug A 4: Internal data of Gene Z on Drug A in Ph-2A study confirms literature / CYP2C8 does not associate with effect drug A

Perform exploratory studies (incl.

  • ther genes,

convert EM to PM by inhibitor)

Not appl. Not appl.

Genotype XX and YY prospective ly in Ph-2B Genotype ADME panel pro- spectively in Ph-2B Do no PGx

Next Team steps > Scenario: v

Only collect DNA Genotype XX pro- spectively in Ph-2B +why Enrich Ph- 2B study for specific XX genotype Other proposals

1: CYP2C8 associates with PK / CYP2C8 associates with effect 2: CYP2C8 associates with PK / CYP2C8 does not associate with effect

Case 4 – Options for Project Team Decision on its next step: Design of Phase 2B Clinical Trial