Case 4 Goal: What does team plan for Phase 2b trial? Phase 2A study - - PowerPoint PPT Presentation

EMEA-EFPIA PGx in PK Workshop

Case 4

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

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)

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 (%)

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

2

Perform exploratory studies (incl.

• ther genes,

convert EM to PM by inhibitor) Genotype XX and YY prospective ly in Ph-2B

2

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

Next Team steps > Scenario: v

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

1: CYP2C8 associates with PK / CYP2C8 associates with effect

7 4 2

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

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 (%)

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

2 2

Perform exploratory studies (incl.

• ther genes,

convert EM to PM by inhibitor)

1

Genotype XX and YY prospective ly in Ph-2B

1 2

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

Next Team steps > Scenario: v

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

1: CYP2C8 associates with PK / CYP2C8 associates with effect

7 4 2

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

8 3

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

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)

3 5 3 5

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

2 2

Perform exploratory studies (incl.

• ther genes,

convert EM to PM by inhibitor)

1

Genotype XX and YY prospective ly in Ph-2B

1 2

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

Next Team steps > Scenario: v

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

1: CYP2C8 associates with PK / CYP2C8 associates with effect

7 4 2

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

8 3

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

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)

3 5 3 5

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

7 2 8 1

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

2 2

Perform exploratory studies (incl.

• ther genes,

convert EM to PM by inhibitor)

1

Genotype XX and YY prospective ly in Ph-2B

1 2

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

Next Team steps > Scenario: v

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

1: CYP2C8 associates with PK / CYP2C8 associates with effect

7 4 2

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

8 3

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

Conclusions

• Decision depends on context and data

available from earlier studies

• DNA should always be collected as

minimum for all scenarios

– Complete agreement from participants – Vital in change of view from Scen. 3 to 4

• Pharmacogenetics should not be

considered in isolation

– Effect of age, toxicity data, different efficacy markers