1 FDA Advisory Committee March 6, 2003 Dennis M. Erb, PhD Regulatory Affairs Merck Research Laboratories EMEND ® (aprepitant)

2 An Unmet Medical Need Prevention of Chemotherapy-Induced Nausea and Vomiting Over one million cancer patients receive chemotherapy each year –20% highly emetogenic chemotherapy (HEC) Chemotherapy-induced nausea and vomiting (CINV) –Among the most distressing side effects of chemotherapy –Disrupt patients’ daily lives –Patients may even delay scheduled chemotherapy J Clin Oncol 1997;15(1):103-9 American Cancer Society. Cancer Facts & Figures 2001

3 J Clin Oncol 1997;15(1):103-9 Prevention of Chemotherapy-Induced Nausea and Vomiting No single class of drugs is fully effective Current therapy guideline: 5-HT 3 receptor antagonist plus corticosteroid –Greater than 50% of patients still experience nausea and vomiting –Delayed emesis (>24 hours) remains a serious problem Symptoms often occur for several days Prevention of CINV is an important goal of healthcare providers and their patients Need for new therapies –More effective prevention with multiple day protection An Unmet Medical Need

4 EMEND ® (aprepitant): Addressing the Need First new approach to CINV prevention in over a decade Novel mechanism of action –Blocks substance P at the Neurokinin-1 receptor in the brain Distinct efficacy profile against CINV –Acts throughout the period when symptoms may occur Acute (0-24 hr) and delayed (>24 hr) phases –Improves the effectiveness of current regimens Fewer patients experience acute or delayed CINV May alter an enduring perception of cancer chemotherapy –Nausea and vomiting need not be inevitable

5 Development Program: Results Prevented nausea and vomiting due to highly emetogenic chemotherapy –Superior to Standard Therapy alone –Significant benefit in acute and delayed phases –Advantage maintained in subsequent cycles Improved patients’ daily lives Demonstrated a favorable safety profile –Similar to Standard Therapy alone –Well-characterized drug interaction profile EMEND plus Standard Therapy:

6 Proposed Indication EMEND, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.

7 Consultants Pharmacology Dr. Paul Andrews Professor of Comparative Physiology St. George’s Hospital Medical School, London, UK Dr. Merrill J. Egorin Professor of Medicine and Pharmacology University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania Dr. Malcolm Rowland Research Professor, School of Pharmacy & Pharmaceutical Sciences University of Manchester, Manchester, UK Statistics Dr. Janet Wittes President Statistics Collaborative, Inc., Washington, DC

8 Consultants Clinical Research Dr. Ronald De Wit Associate Professor Rotterdam Cancer Institute and Erasmus University Hospital Rotterdam, The Netherlands Dr. Steven Grunberg Professor of Medicine University of Vermont, Burlington, Vermont Dr. Paul Hesketh Professor of Medicine Tufts University School of Medicine, Boston, Massachusetts Dr. Loren Laine Professor of Medicine University of Southern California, Los Angeles, California

9 Agenda Dr. Kevin Petty, Clinical Pharmacology –Background and Rationale –Clinical Pharmacology Dr. Kevin Horgan, Clinical Research –Clinical Efficacy Dr. Scott Reines, Clinical Research –Clinical Safety –Summation and Conclusions

10 Background and Rationale & Clinical Pharmacology EMEND ® (aprepitant) Kevin J. Petty, MD, PhD Clinical Pharmacology Merck Research Laboratories

11 Aprepitant Pharmacology: Summary Novel antiemetic mechanism of action –Blockade of (substance P) NK 1 receptors in CNS –Effective against both acute and delayed emesis in ferrets Favorable pharmacokinetics/pharmacodynamics –Once daily oral dosing –No dose adjustment in special populations Well characterized drug interaction potential –Generally modest effects with regimen for CINV –Low potential for interaction with chemotherapy

12 Aprepitant Pharmacology: Overview Pathophysiology of chemotherapy-induced nausea and vomiting Nonclinical pharmacology –Properties of aprepitant –Efficacy in nonclinical models Clinical pharmacology –Pharmacokinetics –Drug interaction

13 Mechanisms of Chemotherapy-Induced Nausea and Vomiting Chemotherapy Central Peripheral

14 Mechanisms of Chemotherapy-Induced Nausea and Vomiting Enterochromaffin cell Serotonin release Chemotherapy Peripheral

15 Mechanisms of Chemotherapy-Induced Nausea and Vomiting Enterochromaffin cell Serotonin release Vagal afferent 5-HT 3 receptors Chemotherapy Peripheral

16 Chemotherapy Mechanisms of Chemotherapy-Induced Nausea and Vomiting Dorsal vagal complex Area postrema Enterochromaffin cell Serotonin release Vagal afferent 5-HT 3 receptors Peripheral Central

17 Chemotherapy Mechanisms of Chemotherapy-Induced Nausea and Vomiting Brainstem NK 1 receptors Substance P Dorsal vagal complex Area postrema Enterochromaffin cell Serotonin release Vagal afferent 5-HT 3 receptors Peripheral Central

18 Pharmacological Properties of Aprepitant Antagonist for NK 1 (substance P) receptor Specific, high affinity human NK 1 receptor binding (IC 50 = 0.12 nM) –>8000 fold selective for NK 1 receptors over known receptors mediating antiemetic activity Dopamine D 2, serotonin 5-HT 3, corticosteroid, and opiate receptors No findings in nonclinical toxicology studies that preclude use of aprepitant in humans

19 Aprepitant Pharmacology: Novel Antiemetic Mechanism of Action Nonclinical pharmacology –Antiemetic efficacy in nonclinical models Chemotherapy-induced emesis in ferrets –Pathophysiology similar to humans –Used in discovery of 5-HT 3 receptor antagonists

20 NK 1 Antagonists Have a Broad Preclinical Antiemetic Profile Site of Action Central Peripheral Central/peripheral Emetogen Apomorphine Morphine Nicotine Loperamide Radiation Cyclophosphamide Ipecacuanha Copper sulfate Cisplatin NK HT 3 ––––+++++––––+++++ Antagonist

21 Aprepitant Protects Against Chemotherapy- Induced Emesis in Ferrets Profile similar to humans (acute + delayed phases) Retches and Vomits Acute Delayed Vehicle Cisplatin

22 Aprepitant Protects Against Chemotherapy- Induced Emesis in Ferrets Profile similar to humans (acute + delayed phases) Retches and Vomits Acute + delayed effects blocked by aprepitant Vehicle Aprepitant (1 mg/kg/day) Cisplatin Cisplatin Acute Delayed

23 Aprepitant Protects Against Chemotherapy- Induced Emesis in Ferrets Profile similar to humans (acute + delayed phases) Retches and Vomits Acute + delayed effects blocked by aprepitant Vehicle Aprepitant (1 mg/kg/day) Aprepitant (2 mg/kg/day) Cisplatin Cisplatin Cisplatin Acute Delayed

24 Preclinical Assessment of Aprepitant Antiemetic Activity Prevents cisplatin-induced emesis in the well established ferret model –Requirement for central NK 1 receptor antagonism Additive with established antiemetic agents (dexamethasone, 5-HT 3 receptor antagonists) Active against both acute and delayed phases –Distinct and novel profile –Efficacy with once-daily dosing

25 Aprepitant Pharmacology: Overview Clinical pharmacology –Pharmacokinetics Once-daily oral dosing No dose adjustment needed: –Age, gender, race, body weight –Renal or hepatic insufficiency Brain penetrant

26 Regimen for Chemotherapy-Induced Nausea and Vomiting Provides Consistent Daily Plasma Exposure 125 mg Time Postdose (hr) N=12 Aprepitant Plasma Concentration (ng/mL)

27 Regimen for Chemotherapy-Induced Nausea and Vomiting Provides Consistent Daily Plasma Exposure 125 mg80 mg N=12 Time Postdose (hr) Aprepitant Plasma Concentration (ng/mL)

28 Regimen for Chemotherapy-Induced Nausea and Vomiting Provides Consistent Daily Plasma Exposure 125 mg80 mg Time Postdose (hr) N=12 Aprepitant Plasma Concentration (ng/mL)

29 Aprepitant Blocks Brain NK 1 Receptors in Humans Binding of PET tracer to NK 1 receptors prior to aprepitant dosing Low High Tracer Binding

30 Aprepitant Blocks Brain NK 1 Receptors in Humans Binding of PET tracer to NK 1 receptors prior to aprepitant dosing Blockade of NK 1 receptors after aprepitant dosing Low High Tracer Binding

31 Aprepitant Blocks Brain NK 1 Receptors in Humans Binding of PET tracer to NK 1 receptors prior to aprepitant dosing Blockade of NK 1 receptors after aprepitant dosing Aprepitant Plasma Trough Concentration (ng/mL) Brain NK 1 Receptor Occupancy (%) Low High Tracer Binding

32 Aprepitant Blocks Brain NK 1 Receptors in Humans Binding of PET tracer to NK 1 receptors prior to aprepitant dosing Blockade of NK 1 receptors after aprepitant dosing Aprepitant Plasma Trough Concentration (ng/mL) Brain NK 1 Receptor Occupancy (%) Mean (± SD) Plasma Trough Concentrations of the Aprepitant 3-Day Regimen Low High Tracer Binding

33 Aprepitant Pharmacology: Overview Clinical pharmacology –Well characterized drug interaction potential Generally modest effects with regimen for chemotherapy-induced nausea and vomiting Low potential for interaction with chemotherapy –Supported by Phase III safety data

34 Aprepitant Is a Moderate CYP3A4 Inhibitor 2-fold5-fold16-fold StrongModerateWeak KetoconazoleItraconazoleClarithromycin Inhibition of CYP3A4 Ranked According to Fold Increase in Oral Midazolam AUC

35 Aprepitant Is a Moderate CYP3A4 Inhibitor Inhibition of CYP3A4 Ranked According to Fold Increase in Oral Midazolam AUC StrongModerateWeak KetoconazoleItraconazoleClarithromycin Erythromycin Diltiazem Verapamil Grapefruit juice

36 Aprepitant Is a Moderate CYP3A4 Inhibitor Aprepitant regimen for CINV produces CYP3A4 inhibition comparable to grapefruit juice and widely used drugs (e.g., diltiazem, verapamil). Inhibition of CYP3A4 Ranked According to Fold Increase in Oral Midazolam AUC StrongModerateWeak KetoconazoleItraconazoleClarithromycin Erythromycin Diltiazem Verapamil Grapefruit juice Aprepitant (125 mg Day 1; 80 mg/d Days 2 to 5) Day: 1 5

37 Effects of Aprepitant on Other Drugs Evaluation of Potential Drug Interactions with Aprepitant Regimen Coadministered antiemetics –Dexamethasone –Methylprednisolone –Ondansetron –Granisetron Narrow therapeutic index drugs –Chemotherapy Docetaxel (CYP3A4) –Digoxin (P-glycoprotein) –Warfarin

38 Aprepitant Increases Plasma Concentration of Dexamethasone Dexamethasone: 20 mg P.O. Day 1, 8 mg/d P.O. Days 2-5 Aprepitant: 125 mg Day 1, 80 mg/d Days 2-5 N=12 per treatment Dexamethasone Plasma Concentration (ng/mL)

39 Aprepitant Increases Plasma Concentration of Dexamethasone Dexamethasone Dose Adjustment in Phase III Studies Ensured Efficacy Not Confounded by Variable Steroid Exposure N=12 per treatment Dexamethasone: 20 mg P.O. Day 1, 8 mg/d P.O. Days 2-5 Aprepitant: 125 mg Day 1, 80 mg/d Days 2-5 Dexamethasone Plasma Concentration (ng/mL)

40 Aprepitant Has a Small Effect on I.V. Methylprednisolone N=8 Aprepitant: 125 mg P.O. Methylprednisolone: 125 mg I.V.

41 Aprepitant Does Not Affect 5-HT 3 Antagonists Ondansetron 32 mg I.V. + Aprepitant 375 mg (N=15) No dose adjustment of ondansetron or granisetron required Ondansetron Plasma Concentration (ng/mL)

42 No dose adjustment of ondansetron or granisetron required Aprepitant Does Not Affect 5-HT 3 Antagonists Ondansetron 32 mg I.V. + Aprepitant 375 mg (N=15) Granisetron 2 mg P.O. + Aprepitant 125 mg (N=18) P.O. Granisetron Plasma Concentration (ng/mL) Ondansetron Plasma Concentration (ng/mL)

43 Effects of Aprepitant on Other Drugs Evaluation of Potential Drug Interactions with Aprepitant Regimen Coadministered antiemetics –Dexamethasone –Methylprednisolone –Ondansetron –Granisetron Narrow therapeutic index drugs –Chemotherapy Docetaxel (CYP3A4) –Digoxin (P-glycoprotein) –Warfarin

44 Aprepitant Does Not Affect Docetaxel Pharmacokinetics (Ongoing Trial, N=5) Plasma Concentration Profiles of Docetaxel Docetaxel AUC of individual patients Docetaxel Plasma Concentration (mcg/mL)

45 Aprepitant Does Not Affect Steady State Pharmacokinetics of the P-glycoprotein Substrate Digoxin No dose adjustment of digoxin required N=11 Aprepitant Digoxin Plasma Concentration (ng/mL)

46 Aprepitant Has Low Potential to Affect I.V. Chemotherapeutic Agents Pharmacokinetics of chemotherapeutic agents frequently modulated by CYP3A4 and/or P-glycoprotein –Aprepitant has Weak to no effect on I.V. CYP3A4 substrates –Methylprednisolone –Ondansetron –Docetaxel No effect on a P-glycoprotein substrate (digoxin) Low potential to interact with chemotherapy as supported by Phase III safety data

47 Aprepitant Slightly Induces Warfarin Metabolism Small inductive effect on warfarin warrants closer monitoring of INR N=11-12

48 Aprepitant Slightly Induces Warfarin Metabolism Small inductive effect on warfarin warrants closer monitoring of INR N=11-12

49 Aprepitant Pharmacology: Summary Novel antiemetic mechanism of action –Blockade of (substance P) NK 1 receptors in CNS –Effective against both acute and delayed emesis in ferrets Favorable pharmacokinetics/pharmacodynamics –Once-daily oral dosing –No dose adjustment in special populations Well characterized drug interaction potential –Generally modest effects with regimen for chemotherapy- induced nausea and vomiting –Low potential for interaction with chemotherapy

50 Conclusions The pharmacokinetics of aprepitant and the potential for clinically meaningful drug interactions with aprepitant have been well characterized Appropriate guidance can be provided for safe and effective use in the intended patient population

51 Clinical Efficacy Kevin J. Horgan, MD Clinical Research Merck Research Laboratories EMEND ® (aprepitant)

52 An unmet medical need J Clin Oncol ;17(9): , 1999 Prevention of Nausea and Vomiting with Highly Emetogenic Chemotherapy Highly emetogenic chemotherapy evokes nausea and vomiting in the vast majority of patients in the absence of preventive therapy Current therapy consists of a 5-HT 3 receptor antagonist and a corticosteroid Despite current therapy many (>50%) patients still have symptoms following highly emetogenic chemotherapy

AcuteDelayed Overall 120 Administration of Chemotherapy Day Hours0 Time Course of Nausea and Vomiting Following Chemotherapy

54 Current Standard Therapy Corticosteroid Therapy+5-HT 3 Receptor Antagonist Augments efficacy of 5-HT 3 receptor antagonist in preventing acute symptoms Some efficacy as monotherapy in preventing delayed symptoms Not approved as antiemetic Prevents acute symptoms in ~50% of patients Equivocal efficacy preventing delayed symptoms Approved only for acute symptoms Highly Emetogenic Chemotherapy

55 Aprepitant Program Objective To define the potential role of aprepitant in the prevention of nausea and vomiting associated with highly emetogenic chemotherapy

56 Aprepitant Program Overview Does aprepitant work alone as an antiemetic?

57 Aprepitant Program Overview Does aprepitant work alone as an antiemetic? Is a regimen including aprepitant more effective than current standard therapy?

58 Aprepitant Program Overview Does aprepitant work alone as an antiemetic? Is a regimen including aprepitant more effective than current standard therapy? What is the optimum aprepitant dose?

59 Aprepitant Program Overview Does aprepitant work alone as an antiemetic? Is a regimen including aprepitant more effective than current standard therapy? What is the optimum aprepitant dose? Confirm that the Phase III aprepitant regimen is safe and effective.

60 Cisplatin Is Prototypic Highly Emetogenic Chemotherapy Cornerstone of therapy for common cancers (e.g., lung, ovarian) Most emetogenic chemotherapy –  50 mg/m 2 infused over  3 hours is highly emetogenic Predictable and well characterized pattern of emesis Benchmark for evaluation and approval of novel antiemetic therapies –5-HT 3 receptor antagonists: Ondansetron, granisetron, dolasetron –Dopamine D 2 receptor antagonist: Metoclopramide Antiemetic efficacy with cisplatin predictive of antiemetic efficacy with other agents (e.g., carboplatin, doxorubicin, cyclophosphamide)

61 Key Elements of the Clinical Trials All studies double-blind versus appropriate control All patients cisplatin näive All patients to receive high dose cisplatin –  70 mg/m 2 infused over  3 hours on Day 1 –Additional emetogenic chemotherapy permitted on Day 1 Randomization stratified – Gender – Additional emetogenic chemotherapy “Rescue” therapy allowed for established nausea or vomiting

62 Key Elements of the Clinical Trials Daily patient diary –All emetic events –All use of rescue therapy –Nausea assessments Primary efficacy assessments –Initial cycle of cisplatin chemotherapy –Modified intention-to-treat population

63 Efficacy Endpoints Primary endpoint –Complete Response: No emesis and no rescue Reflects control of both emesis and nausea Primary endpoint in ondansetron and dolasetron development programs Other key endpoints –Frequency of emetic events –Use of rescue therapy –Nausea –Impact of nausea and vomiting on daily life

64 Aprepitant Program Overview Does aprepitant work alone as an antiemetic? Is a regimen including aprepitant more effective than current standard therapy? What is the optimum aprepitant dose? Confirm that the Phase III aprepitant regimen is safe and effective.

65 Eur J Cancer 37: , 2001 Aprepitant as Monotherapy Day 1 Aprepitant I.V. prodrug 60 or 100 mg Ondansetron I.V. 32 mg Protocol 004

66 Complete Response: Acute and Delayed Phases Aprepitant as Monotherapy Protocol % 48% 17% p<0.05 N=

67 Aprepitant as Monotherapy † Cancer 78: , 1996 Historical Data † (Untreated) p<0.05 Complete Response: Acute and Delayed Phases Protocol % 48% 17% N=

68 Protocol 004 Conclusions Aprepitant as Monotherapy Aprepitant is an effective antiemetic –In both acute and delayed phases Distinctive efficacy profile relative to 5-HT 3 receptor antagonists –Significantly superior efficacy in delayed phase Distinctive efficacy profile implied potential for better efficacy by combining with a 5-HT 3 receptor antagonist

69 Aprepitant Program Overview Does aprepitant work alone as an antiemetic? Is a regimen including aprepitant more effective than current standard therapy? What is the optimum aprepitant dose? Confirm that the Phase III aprepitant regimen is safe and effective.

70 Aprepitant Regimen Study Aprepitant loading dose strategy –Day 1: 400 mg P.O. –Days 2-5: 300 mg P.O. Control regimen contains “Standard Therapy” –Day 1 only: Granisetron 10 µg/kg I.V. Dexamethasone 20 mg P.O. Protocol 007 Design Features

71 P Aprepitant Regimen Study Day 1Days 2 to 5 Primary Treatment Groups Protocol 007 G D Control Group G=granisetron; D=dexamethasone; A=aprepitant; P=placebo P

72 Aprepitant Regimen Study Group Control Day 1Days 2 to 5 G D A A G=granisetron; D=dexamethasone; A=aprepitant; P=placebo PP P Aprepitant 1-Day Aprepitant 5-Day Primary Treatment Groups Protocol 007

73 Aprepitant Regimen Study N Engl J Med 340: 190-5: 1999 Complete Response: Acute and Delayed Phases Aprepitant 5-Day Aprepitant 1-Day Control 77% 57% 52% 16% p<0.05 p<0.01 N= % 43% p<0.01 Protocol 007

74 Aprepitant Regimen Study Aprepitant enhances the efficacy of a “Standard Therapy” regimen –Acute and delayed nausea and vomiting Aprepitant is more effective when administered for multiple days –Delayed nausea and vomiting Even when a very high dose is administered on Day 1 Conclusions Protocol 007

75 Aprepitant Program Overview Does aprepitant work alone as an antiemetic? Is a regimen including aprepitant more effective than current standard therapy? What is the optimum aprepitant dose? Confirm that the Phase III aprepitant regimen is safe and effective.

76 Dose Finding Study Primary Endpoint: Complete Response –Overall (Days 1 to 5) = Acute + Delayed Evolution of “Standard Therapy” –Day 1: Ondansetron + dexamethasone –Days 2 to 5:Dexamethasone Transition from tablet to capsule formulation –Formulation for all subsequent studies and for market Protocol 040/042 Design Features

77 Dose Finding Study Initiated with two aprepitant dose regimens –Day 1: 375 mg Days 2 to 5: 250 mg –Day 1: 125 mg Days 2 to 5: 80 mg Capsule formulation had better than anticipated bioavailability –Both 375/250 mg and 125/80 mg regimens were predicted to have similar clinical efficacy In order to explore the dose response adequately –375/250 mg regimen discontinued after 35 patients –40/25 mg regimen added Protocol 040/042 Design Features

78 Dose Finding Study Day 1Days 2 to 5 ODD Protocol 040/042 Primary Treatment Groups O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo Group Control PP

79 Dose Finding Study Day 1Days 2 to 5 ODAAD Protocol 040/042 Primary Treatment Groups O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo Group Aprepitant 40/25 Control PP 4025

80 Dose Finding Study Group Control Day Days 2 to O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo ODAAD PP Aprepitant 40/25 Aprepitant 125/80 Protocol 040/042 Primary Treatment Groups

81 Dose Finding Study Overall Complete Response Aprepitant 125/80 Aprepitant 40/25 Control N= % 44% 71% p<0.05 p<0.01 Protocol 040/042

82 Dose Finding Study Overall Complete Response Aprepitant 125/80 Aprepitant 40/25 Control N= % 44% 71% Protocol 040/042 p<0.05

83 Dose Finding Study Complete Response: Acute and Delayed Phases Aprepitant 125/80 Aprepitant 40/25 Control N= % 76% 83% 71% 73% 45% p<0.05 p<0.01 Protocol 040/042

84 Dose Finding Study Time to First Emesis or Rescue Protocol 040/042

85 Dose Finding Study Time to First Emesis or Rescue Protocol 040/042

86 Dose Finding Study Time to First Emesis or Rescue Protocol 040/042

87 Dose Finding Study Aprepitant 125/80 mg regimen is effective –40/25 mg less effective –375/250 mg adds no apparent benefit Almost all initial therapy failures occur within 72 hours –3-day dosing likely to provide full benefit Phase III aprepitant regimen: 125 mg on Day 1 followed by 80 mg on Days 2 and 3 Conclusions Protocol 040/042

88 Two large multinational studies, both with multiple cycle extensions, in patients receiving high-dose cisplatin chemotherapy Phase III Primary Hypothesis: Cycle 1 Compared to Standard Therapy: –The aprepitant regimen will provide superior control of nausea and vomiting as measured by the proportion of patients with an Overall Complete Response No emesis and no rescue In the 120 hours following the initiation of cisplatin

89 Phase III Studies Aprepitant regimen refinements –3-day aprepitant dosing –Dexamethasone dose reduced to provide plasma exposure similar to control Protocols 052 and 054 Design Features

90 Phase III Studies Aprepitant Control GroupDay Day Days ODADDA O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo PP Protocols 052 and 054 Primary Treatment Groups

91 Phase III Studies Inclusion Criteria –Cisplatin dose  70 mg/m 2 Exclusion Criteria –Laboratory value parameters AST or ALT  2.5 x upper limit of normal (ULN) Neutrophil count <1500/mm 3 and WBC <3000/mm 3 Bilirubin >1.5 x ULN; Creatinine >1.5 x ULN –Concomitant or very recent use of Strong CYP3A4 inhibitors CYP3A4 inducers Design Features Protocols 052 and 054

92 Phase III Studies Protocols 052 and 054 Combined Patient Demographics (N=549) (N=554) Aprepitant Control

93 Phase III Studies Aprepitant (N=549) Control (N=554) Protocols 052 and 054 Combined Primary Cancer Diagnoses

94 Phase III Studies Protocols 052 and 054 Combined Concomitant Chemotherapy Aprepitant (N=549) Control (N=554)

95 Phase III Studies: Cycle 1 p< % N=260 73% Primary Endpoint: Overall Complete Response Protocol 052

96 Phase III Studies: Cycle 1 p<0.001 N=260 63% 43% p< Protocol 054Protocol 052 Primary Endpoint: Overall Complete Response 52% 73%

97 Phase III Studies: Cycle 1 89% 78% 75% 56% N= p< % 68% 47% 68% p<0.001 Protocol 052 Complete Response: Acute and Delayed Phases Protocol 054

98 Phase III Studies: Cycle 1 Time to First Emesis or Rescue APR N=260 Control N=260 APR N=260 Control N=263

99 Phase III Studies: Cycle 1 N= % 55% 81% 71% 66% 45% 82% 73% p<0.01 Components of Primary Endpoint: Overall Protocol 052Protocol 054

100 Nausea is a particularly important symptom for patients A validated 100 mm visual analog scale (VAS) was used Patient places a vertical mark corresponding to level of nausea Prespecified endpoints (Days 1 to 5) –No Nausea: Maximum VAS <5 mm –No Significant Nausea: Maximum VAS <25 mm How much nausea have you had over the past 24 hours? No nause a Nausea as bad as it could be Phase III Studies: Cycle 1 0 mm 100 mm Nausea Assessment

101 Phase III Studies: Cycle 1 48% 44% 73% 66% 49% 39% 71% 64% N= p<0.05 No Nausea and No Significant Nausea: Overall Protocol 052Protocol 054

102 Phase III Studies: Cycle 1 48% 42% 72% 65% N = p<0.05 No Nausea and No Significant Nausea: Overall Protocols 052 and 054 Combined

103 Phase III Studies: Cycle 1 Complete Protection = Complete Response + No Significant Nausea –Aprepitant statistically superior in both protocols 052 and 054 Total Control = Complete Response + No Nausea –Aprepitant statistically superior in protocol 054 No Impact on Daily Life –Validated nausea- and vomiting-specific questionnaire –Aprepitant statistically superior in both protocols 052 and 054 Other Prespecified Endpoints

104 Phase III Studies: Cycle 1 Protocols 052 and 054 Combined: Overall (Post-hoc Analysis) Aprepitant (N=70) Control (N=72) p< % 26% Concomitant Emetogenic Chemotherapy (Cyclophosphamide and/or Doxorubicin)

105 Phase III Studies: Cycle 1 Conclusions Aprepitant highly effective in two replicate clinical trials –Overall 20% fewer patients vomited or required rescue medications for established nausea or emesis (p<0.001) Superiority of aprepitant evident –In both acute and delayed phases –For both components of primary endpoint: Emesis and use of rescue medications –In patients taking cisplatin plus other emetogenic chemotherapy (post-hoc analysis) Consistent advantage for aprepitant regimen on nausea endpoints – More rescue medications used in control group

106 Phase III Studies: Multiple Cycles Up to 5 additional cycles of blinded treatment – 68 out of 71 sites participated Multiple cycle efficacy data collection – Two questions at Day 6 to 8 clinic visit in cycles 2 to 6 Did you have 1) Emesis? 2) Significant nausea interfering with daily life? Protocols 052 and 054

107 Protocols 052 and 054 Combined N= N= Observed Proportion of Patients without Emesis and without Significant Nausea Phase III Studies: Multiple Cycles

108 Proportion of Patients Symptom Free by Cycle Phase III Studies: Multiple Cycles Protocols 052 and 054 Combined N= N= N= N= Chemotherapy Cycle

109 Aprepitant Efficacy Conclusions Addition of aprepitant to a regimen of a 5-HT 3 receptor antagonist and a corticosteroid is beneficial in the prevention of nausea and vomiting due to highly emetogenic chemotherapy The benefit is –Clinically important –Evident during both the acute and delayed phases –Sustained during multiple cycles of chemotherapy

110 Clinical Safety Scott A. Reines, MD, PhD Clinical Research Merck Research Laboratories EMEND ® (aprepitant)

111 Number of Patients Receiving Aprepitant Phase I clinical pharmacology studies Studies in non-cancer patients Studies in patients receiving cancer chemotherapy Phase II915 Phase III Total 3342 Clinical Development Program

112 APR 125/80 (N=544) % Control (N=550) % Adverse experiences (AEs) Drug-related AEs Serious AEs Discontinuations due to AEs Deaths Percent of Patients with: Phase III: Cycle 1 Clinical Adverse Experience Summary

113 Most Common Serious Clinical AEs Control (N=550) % Percent of Patients with: Serious adverse experiences Neutropenia Dehydration Febrile neutropenia Respiratory insufficiency Pulmonary embolism Thrombocytopenia Pneumonia Cardiac arrest Leukopenia Phase III: Cycle 1 APR 125/80 (N=544) % (Incidence  0.7%)

114 Control (N=543) % APR 125/80 (N=539) % Laboratory adverse experiences Drug-related laboratory AEs Serious laboratory AEs Discontinuations due to lab AEs Percent of Patients with: Phase III: Cycle 1 Laboratory Adverse Experience Summary

115 Evaluation of Toxicity Due to Concomitant Therapies Cisplatin-induced toxicity –Serum creatinine –Neurotoxicity, ototoxicity Other chemotherapy-induced toxicity –Neutropenia categorized using NCI Common Toxicity Criteria –Hematologic adverse experiences –Fever, infection, febrile neutropenia, dehydration Glucocorticoid-induced toxicity –Hypertension, hyperglycemia, hypokalemia Chemotherapy metabolized by CYP3A4

116 Day 6 to 8 APR 125/80 (N=501) % Control (N=507) % Day 19 to 29 APR 125/80 (N=482) % Control (N=495) % > Upper Limit of Normal (ULN) > ULN to 1.5 x ULN > 1.5 to 3.0 x ULN > 3.0 to 6.0 x ULN > 6.0 x ULN Serum Creatinine (NCI Criteria) Phase III: Cycle 1 Serum Creatinine by NCI Criteria Cisplatin-Induced Toxicity

117 Cisplatin-Induced Toxicity Serum Creatinine by NCI Criteria No differences in nephrotoxicity as indicated by serum creatinine Day 6 to 8 APR 125/80 (N=501) % Control (N=507) % Day 19 to 29 APR 125/80 (N=482) % Control (N=495) % > Upper Limit of Normal (ULN) > ULN to 1.5 x ULN > 1.5 to 3.0 x ULN > 3.0 to 6.0 x ULN > 6.0 x ULN Serum Creatinine (NCI Criteria) Phase III: Cycle 1

118 No differences in nephrotoxicity as indicated by serum creatinine Cisplatin-Induced Toxicity No differences in neurotoxicity or ototoxicity between groups Serum Creatinine by NCI Criteria Day 6 to 8 APR 125/80 (N=501) % Control (N=507) % Day 19 to 29 APR 125/80 (N=482) % Control (N=495) % > Upper Limit of Normal (ULN) > ULN to 1.5 x ULN > 1.5 to 3.0 x ULN > 3.0 to 6.0 x ULN > 6.0 x ULN Serum Creatinine (NCI Criteria) Phase III: Cycle 1

119 Neutropenia Severity by NCI Criteria Chemotherapy-Induced Toxicity Any neutropenia < 2000/mm 3  1500 < 2000/mm 3  1000 < 1500/mm 3  500 < 1000/mm 3 < 500/mm 3 Neutropenia Severity (NCI Criteria) Day 6 to 8 APR 125/80 (N=481) % Control (N=489) % Day 19 to 29 APR 125/80 (N=462) % Control (N=477) % Phase III: Cycle 1

120 No evidence of differences in hematological toxicity Chemotherapy-Induced Toxicity Neutropenia Severity by NCI Criteria Any neutropenia < 2000/mm 3  1500 < 2000/mm 3  1000 < 1500/mm 3  500 < 1000/mm 3 < 500/mm 3 Neutropenia Severity (NCI Criteria) Day 6 to 8 APR 125/80 (N=481) % Control (N=489) % Day 19 to 29 APR 125/80 (N=462) % Control (N=477) % Phase III: Cycle 1

121 APR 125/80 (N=544) % Control (N=550) % Percent of Patients with: Infections Dehydration Neutropenia Thrombocytopenia Anemia Fever Leukopenia Febrile neutropenia Hypokalemia Hypertension Hyperglycemia Phase III: Cycle 1 Prespecified Adverse Experiences Chemotherapy-induced Glucocorticoid-induced Chemotherapy or Glucocorticoid-Induced Toxicity

122 (Etoposide, Vinca Alkaloids, Taxanes, Irinotecan, Ifosfamide) Safety of Aprepitant in Patients Receiving Chemotherapy Metabolized by CYP3A4 Overall summary of adverse events –Clinical –Laboratory Hematological toxicity –All chemotherapy metabolized by CYP3A4 –Individual chemotherapies Etoposide, vinorelbine, paclitaxel

123 APR 125/80 (N=266) % Control (N=251) % Percent of Patients with: Clinical adverse experiences Prespecified AEs Serious clinical AEs Serious laboratory AEs Phase III: Cycle 1 (Etoposide, Vinca Alkaloids, Taxanes, Irinotecan, Ifosfamide) AE Summary in Patients Receiving Concomitant Chemotherapy Metabolized by CYP3A4

124 Neutropenia in Patients Receiving Concomitant Chemotherapy Metabolized by CYP3A4 (Etoposide, Vinca Alkaloids, Taxanes, Irinotecan, Ifosfamide) All patients < 2000 mm 3  1500 < 2000 mm 3  1000 < 1500 mm 3  500 < 1000 mm 3 < 500 mm 3 Neutropenia Severity (NCI Criteria) Phase III: Cycle 1 Day 6 to 8 APR 125/80 (N=237) % Control (N=221) % Day 19 to 29 APR 125/80 (N=234) % Control (N=222) %

125 Day 6 to 8 APR 125/80 (N=237) % Control (N=221) % Day 19 to 29 APR 125/80 (N=234) % Control (N=222) % Neutropenia in Patients Receiving Concomitant Chemotherapy Metabolized by CYP3A4 All patients < 2000 mm 3  1500 < 2000 mm 3  1000 < 1500 mm 3  500 < 1000 mm 3 < 500 mm 3 Neutropenia Severity (NCI Criteria) Phase III: Cycle 1 No change in hematological toxicity of chemotherapy metabolized by CYP3A4 (Etoposide, Vinca Alkaloids, Taxanes, Irinotecan, Ifosfamide)

126 Percent of Patients with Neutrophil Counts <1500/mm 3 (Day 19 to 29) Percent of Patients N= Individual Chemotherapies Metabolized by CYP3A Phase III: Cycle 1

127 N= Percent of Patients Phase III: Cycle Percent of Patients with Neutropenia Adverse Experiences Individual Chemotherapies Metabolized by CYP3A4

128 Conclusions Safety of Aprepitant in Patients Receiving Chemotherapy Metabolized by CYP3A4 Extensive evaluation of clinical and laboratory safety –Over 250 patients per treatment group No pattern of clinically important changes –Overall incidences of adverse experiences Serious AEs Prespecified AEs –Neutropenia NCI criteria, adverse events

129 Safety of Aprepitant in Patient Subgroups Demographic variables assessed during Phase III, Cycle 1 –Age –Gender –Race –Primary cancer diagnosis Aprepitant displayed a consistent, favorable safety profile

130 Safety Evaluation During Multiple Chemotherapy Cycles Treatment up to 6 total cycles of chemotherapy Data collection –Drug-related AEs –Serious AEs –Discontinuations due to AEs –Laboratory evaluations

131 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle APR 125/80 N Control N Phase III Numbers of Patients Entered into Multiple Chemotherapy Cycles

132 Drug-related AEs Serious Clinical AEs Discontinuations due to AEs Serious laboratory AEs Deaths Percent of Patients with: APR 125/80 (N=413) % Control (N=438) % Phase III: Cycles 2-6 Safety Summary During Multiple Chemotherapy Cycles

133 Percent of Patients with Neutrophil Counts <1500/mm 3 (Day 19 to 29) Chemotherapy Cycle Percent of Patients N= Chemotherapy-Induced Toxicity: Multiple Cycles

134 Aprepitant Overall Safety Conclusions Incidences of adverse experiences similar to Standard Therapy No significant changes in toxicity of concomitant therapies –Cisplatin –Chemotherapy, whether or not metabolized by CYP3A4 –Glucocorticoids No clinically important differences among patient subgroups –Age, gender, race, primary cancer diagnosis Well tolerated during multiple chemotherapy cycles

135 Summation and Conclusions EMEND ® (aprepitant)

136 A Major Advance in the Supportive Care of Cancer Patients Aprepitant A cancer diagnosis has profound implications –Life-threatening disease –Potentially disruptive and debilitating treatment Daily function can be compromised by nausea and vomiting

137 A Major Advance in the Supportive Care of Cancer Patients Aprepitant A cancer diagnosis has profound implications –Life-threatening disease –Potentially disruptive and debilitating treatment Daily function can be compromised by nausea and vomiting 5-HT 3 receptor antagonists introduced into clinical practice in 1991 –Quickly recognized as a therapeutic advance

138 A Major Advance in the Supportive Care of Cancer Patients Aprepitant A cancer diagnosis has profound implications –Life-threatening disease –Potentially disruptive and debilitating treatment Daily function can be compromised by nausea and vomiting 5-HT 3 receptor antagonists introduced into clinical practice in 1991 –Quickly recognized as a therapeutic advance Many patients still experience nausea and vomiting despite best available therapy –Ranked among the most distressing symptoms Delayed symptoms remain difficult to treat

139 Patients treated with best therapy available today Many Patients Still Experience Nausea and Vomiting After Highly Emetogenic Chemotherapy Protocol 052Protocol Percent of Patients Percent of Patients Hours Time to First Emesis or Use of Rescue Control N=260N=263

140 Evaluated in 7-year multinational clinical development program –>3000 patients and subjects in total >1400 patients in cancer chemotherapy trials Unique Attributes for Patients Receiving Highly Emetogenic Chemotherapy Aprepitant

141 Evaluated in 7-year multinational clinical development program –>3000 patients and subjects in total >1400 patients in cancer chemotherapy trials Developed for use in conjunction with standard agents –Unprecedented efficacy Benefit sustained over multiple cycles Unique Attributes for Patients Receiving Highly Emetogenic Chemotherapy Aprepitant

142 Evaluated in 7-year multinational clinical development program –>3000 patients and subjects in total >1400 patients in cancer chemotherapy trials Developed for use in conjunction with standard agents –Unprecedented efficacy Benefit sustained over multiple cycles Very well tolerated – Across patient subgroups and concomitant therapies Unique Attributes for Patients Receiving Highly Emetogenic Chemotherapy Aprepitant

Percent of Patients Percent of Patients Protocol 052Protocol 054 Hours APR 125/80 Regimen Time to First Emesis or Use of Rescue Therapy More Patients Benefit with Aprepitant Control APR N=260 Control N=260 APR N=260 Control N=263

144 Aprepitant: Conclusions A new class of antiemetic therapy –First NK 1 receptor antagonist introduced into clinical practice Novel mechanism with distinct clinical benefits Marked reduction in emesis and need for rescue medication –Aprepitant improves the best available antiemetic therapy May alter an enduring perception of cancer chemotherapy –Nausea and vomiting need not be inevitable

145 Proposed Indication EMEND, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.