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

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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

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

Gastrointestinal Drugs Advisory Committee Meeting March 6, BackgroundBackground 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

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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

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

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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

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

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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)

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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

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

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

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

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

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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

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

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

Gastrointestinal Drugs Advisory Committee Meeting March 6, 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.”