1. AprepitantAprepitant Division of Gastrointestinal and Coagulation Drug Products Division of Gastrointestinal and Coagulation Drug Products Center for Drug Evaluation and Research

2. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 2 Gary Della’Zanna, D.O. M.Sc. Division of Gastrointestinal and Coagulation Drug Products Wen-Jen Chen, Ph.D. Division of Biometrics II Venkat Jarugula, Ph.D. Division of Pharmaceutical Evaluation II Gary Della’Zanna, D.O. M.Sc. Division of Gastrointestinal and Coagulation Drug Products Wen-Jen Chen, Ph.D. Division of Biometrics II Venkat Jarugula, Ph.D. Division of Pharmaceutical Evaluation II

3. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 3OverviewOverview Background Indication Efficacy Highly emetogenic chemotherapy Safety -5-HT 3 antagonists -Chemotherapy Background Indication Efficacy Highly emetogenic chemotherapy Safety -5-HT 3 antagonists -Chemotherapy

4. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 4BackgroundBackground New Drug Application -September 27, 2002 New molecular entity First in a new therapeutic class -NK 1 - receptor antagonist Priority review New Drug Application -September 27, 2002 New molecular entity First in a new therapeutic class -NK 1 - receptor antagonist Priority review

5. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 5 Proposed Indication In combination with other antiemetics Prevention of acute and delayed nausea and vomiting Highly emetogenic chemotherapy In combination with other antiemetics Prevention of acute and delayed nausea and vomiting Highly emetogenic chemotherapy

6. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 6 Efficacy Results Phase III Primary endpoint: Complete Response -overall phase (0 - 120 hours) Secondary endpoints: -Complete Response –acute (0 - 24 hours) –delayed phase (25 - 120 hours) -Nausea -Vomiting Primary endpoint: Complete Response -overall phase (0 - 120 hours) Secondary endpoints: -Complete Response –acute (0 - 24 hours) –delayed phase (25 - 120 hours) -Nausea -Vomiting

7. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 7 Successful Endpoints Primary endpoint: Complete Response -overall phase Secondary endpoints: -Complete Response -acute, delayed phases -Vomiting -overall, acute, delayed phases Primary endpoint: Complete Response -overall phase Secondary endpoints: -Complete Response -acute, delayed phases -Vomiting -overall, acute, delayed phases

8. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 8 No Nausea (Secondary Endpoint)

9. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 9 Nausea Endpoints Use of rescue therapy: -28% standard therapy -18% aprepitant group Time to analysis -first use of rescue therapy later in aprepitant group Use of rescue therapy: -28% standard therapy -18% aprepitant group Time to analysis -first use of rescue therapy later in aprepitant group

10. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 10 Highly Emetogenic Cisplatin Ondansetron approval -Cisplatin dose >100 mg/m 2 Protocol dose  70 mg/m 2 Cisplatin -20% of patients <70 mg/m 2 Cisplatin >50 mg/m 2 Cisplatin (high or moderate) Ondansetron approval -Cisplatin dose >100 mg/m 2 Protocol dose  70 mg/m 2 Cisplatin -20% of patients <70 mg/m 2 Cisplatin >50 mg/m 2 Cisplatin (high or moderate)

11. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 11 Drug-Drug Interaction Cytochrome P450 3A4 (CPY3A4) -Substrate -Moderate inhibitor -Inducer Cytochrome P450 2C9 (CYP2C9) -Inducer Cytochrome P450 3A4 (CPY3A4) -Substrate -Moderate inhibitor -Inducer Cytochrome P450 2C9 (CYP2C9) -Inducer

12. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 12 Treatment Regimen 5-HT 3 Antagonists Ondansetron and granisetron -metabolized by CYP3A4 -first pass metabolism effect Dolasetron -metabolized by carbonyl reductase -no exposure data -QTc and cardiac warnings Ondansetron and granisetron -metabolized by CYP3A4 -first pass metabolism effect Dolasetron -metabolized by carbonyl reductase -no exposure data -QTc and cardiac warnings

13. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 13 Drug-Drug Interaction Chemotherapy -CYP3A4 Docetaxel study -5 patients -no effect on PK Dexamethasone -metabolized by CYP3A4 -50% dose reduction Chemotherapy -CYP3A4 Docetaxel study -5 patients -no effect on PK Dexamethasone -metabolized by CYP3A4 -50% dose reduction

14. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 14 Safety Chemotherapy (CYP3A4) Exposure

15. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 15 Serious Adverse CYP3A4 Chemotherapy Phase III Studies (Cycle 1)

16. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 16 Serious Adverse Experiences CYP3A4

17. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 17 Serious Adverse Experiences CYP3A4

18. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 18 Vinorelbine Deaths Aprepitant: 7 deaths (9%) -4 respiratory insufficiency -2 septic shock -1 cardiopulmonary arrest Standard Therapy: 2 deaths (3%) -1 pulmonary emboli -1 unknown Aprepitant: 7 deaths (9%) -4 respiratory insufficiency -2 septic shock -1 cardiopulmonary arrest Standard Therapy: 2 deaths (3%) -1 pulmonary emboli -1 unknown

19. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 19 Serious Adverse Experiences CYP3A4

20. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 20 Safety Chemotherapy (CYP3A4) (limited or no exposure)

21. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 21 Precaution Section “EMEND should be used with caution in patients receiving concomitant medicinal products that are primarily metabolized through CYP3A4; some chemotherapy agents are metabolized by CYP3A4.”