1. Pharmacogenetics (PGx) of Irinotecan: Scientific and Clinical Impact of UGT Polymorphism: Background Clinical Pharmacology Subcommittee of ACPS November 3, 2004 Lawrence J. Lesko, Ph.D., FCP Director, Office of Clinical Pharmacology and Biopharmaceutics Center for Drug Evaluation and Research Food and Drug Administration

2. Labeling Regulations “If evidence is available to support the safety and effectiveness of the drug only in selected subgroups of the larger population with a disease, the labeling shall describe the evidence and identify specific tests needed for selection and monitoring of patients who need the drug.” - 21 CFR 201.57

3. PGx Information in Drug Product Labels No barriers to including PGx information in product labels No barriers to including PGx information in product labels –Herceptin (trastuzumab) ~ most well known –35% of approved drugs  PGx information in labels –Thioridazine: black box warning based on PGx (avoid in 2D6 PMs) –Atomoxetine: PGx in 7 different sections of the label (differences between 2D6 PM and EM) –Cetuximab: includes receptor positivity information (EGFR inhibitor) –6MP, azathioprine: updated labels to include TPMT information in multiple sections

4. 6MP and TPMT Polymorphism Labeling – absence of PGx information in label discussed at CPSC and Pediatric Oncology Subcommittee in 4/03 and 7/03 Labeling – absence of PGx information in label discussed at CPSC and Pediatric Oncology Subcommittee in 4/03 and 7/03 New labeling - revised by sponsors in consultation with FDA- includes data on increased risk of severe myelosuppression TPMT activity-deficient genotypes New labeling - revised by sponsors in consultation with FDA- includes data on increased risk of severe myelosuppression TPMT activity-deficient genotypes Informs clinicians about option of using TPMT testing to guide treatment with 6MP Informs clinicians about option of using TPMT testing to guide treatment with 6MP

5. General Process for Updating Labels with PGx Information Develop the appropriate questions Develop the appropriate questions Capture the relevant evidence Capture the relevant evidence Abstract and summarize the evidence Abstract and summarize the evidence Evaluate the quality of studies Evaluate the quality of studies Assess the overall strength of evidence Assess the overall strength of evidence Consider other factors in relabeling decision Consider other factors in relabeling decision Determine specific language for label Determine specific language for label

6. Current Understanding of PGx and Neutropenia GroupPrevalence Risk of Toxicity All Patients -----10% Patients That Are 7/7 10%50% Patients That Are 6/7 40%12.5% Patients That Are 6/6 50%0% Based on data from Innocenti et al (2004)

7. Potential of UGT Testing to Guide Treatment All Patients with Same Diagnosis (10% risk) PGx profile for high risk (50%): treat with alternative drug or dose PGx Profile for moderate risk (12.5%): treat with alternative drug or dose PGx Profile for low risk (0%): treat with conventional dose

8. Objectives for Today Discuss the scientific and clinical evidence linking UGT1A1 polymorphism (7/7 genotype) with severe neutropenia Discuss the scientific and clinical evidence linking UGT1A1 polymorphism (7/7 genotype) with severe neutropenia Discuss the role that UGT1A1 testing can play in identifying patients predisposed to severe toxicity Discuss the role that UGT1A1 testing can play in identifying patients predisposed to severe toxicity

9. Sponsor-FDA Interactions Committed to providing informative and understandable labeling Committed to providing informative and understandable labeling Agree that information on UGT polymorphism and risk of toxicity in the label is of great importance Agree that information on UGT polymorphism and risk of toxicity in the label is of great importance Agree to update label to fully inform prescribers and patients about PGx Agree to update label to fully inform prescribers and patients about PGx Specific wording of the new label is not the topic for discussion today Specific wording of the new label is not the topic for discussion today

10. Pharmacogenetics of Irinotecan: Scientific and Clinical Impact of UGT Polymorphism – Questions for the Committee 1. Is the scientific and clinical evidence presented sufficient to demonstrate that homozygous UGT1A1*28 genotypes (7/7 genotype) are at significantly greater risk for developing a) neutropenia, and b) acute and delayed diarrhea from irinotecan therapy?

11. Pharmacogenetics of Irinotecan: Scientific and Clinical Impact of UGT Polymorphism – Questions for the Committee 2. Based on what is known about the relationship between various irinotecan-containing regimens and grade 3/4 toxicities, for UGT1A1*28 genotypes- a) Do we know enough to recommend the starting dose of irinotecan in the single-agent and in the combination therapy? b) What would be the risks and benefits of the recommended starting dose? c) What is an appropriate study to evaluate dosing for UGT1A1*28 patients?

12. Pharmacogenetics of Irinotecan: Scientific and Clinical Impact of UGT Polymorphism 3. How can information about genotype be used in combination with bilirubin levels, prior pelvic and abdominal radiotherapy, performance status, and age in clinical decision-making? 4. Is the measurement of UGT1A1*28 sufficiently robust in terms of sensitivity and specificity to be used as a response predictor test for irinotecan dosing?