# Presentation: 042675

## FDA Advisory CommitteeMarch 6, 2003

- Dennis M. Erb, PhD*Regulatory Affairs**Merck Research Laboratories*

- EMEND®  (aprepitant)

## Prevention of Chemotherapy-InducedNausea and Vomiting

- Prevention of Chemotherapy-InducedNausea 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):103-9American Cancer Society. *Cancer Facts & Figures* 2001

## 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 providersand their patients
- Need for new therapies
- More effective prevention with multiple day protection

- An Unmet Medical Need

## 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

## 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:

## 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.

## 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*

## 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*

## 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

## Background and Rationale&Clinical Pharmacology

- EMEND®  (aprepitant)
- Kevin J. Petty, MD, PhD*Clinical Pharmacology**Merck Research Laboratories*

## 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

## Aprepitant Pharmacology: Overview

- Pathophysiology of chemotherapy-inducednausea and vomiting
- Nonclinical pharmacology
- Properties of aprepitant
- Efficacy in nonclinical models
- Clinical pharmacology
- Pharmacokinetics
- Drug interaction

## Mechanisms of Chemotherapy-Induced Nausea and Vomiting

- Chemotherapy

- Central

- Peripheral

## Mechanisms of Chemotherapy-Induced Nausea and Vomiting

- Enterochromaffin cell
- Serotonin release

- Chemotherapy

- Peripheral

## Mechanisms of Chemotherapy-Induced Nausea and Vomiting

- Enterochromaffin cell
- Serotonin release
- Vagal afferent
- 5-HT**3** receptors

- Chemotherapy

- Peripheral

## Mechanisms of Chemotherapy-Induced Nausea and Vomiting

- Chemotherapy

- Dorsal vagal complex
- Area postrema

- Enterochromaffin cell
- Serotonin release
- Vagal afferent
- 5-HT**3** receptors

- Peripheral

- Central

## Mechanisms of Chemotherapy-Induced Nausea and Vomiting

- Chemotherapy

- Brainstem
- NK**1** receptors
- Substance P
- Dorsal vagal complex
- Area postrema

- Enterochromaffin cell
- Serotonin release
- Vagal afferent
- 5-HT**3** receptors

- Peripheral

- Central

## 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

## 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

## NK1 Antagonists Have a Broad Preclinical Antiemetic Profile

## Aprepitant Protects Against Chemotherapy-Induced Emesis in Ferrets

- Profile similar to humans
- (acute + delayed phases)

- 0

- 60

- 120

- 180

- 240

- 300

- Retches and Vomits

- Vehicle

## Aprepitant Protects Against Chemotherapy-Induced Emesis in Ferrets

- Profile similar to humans
- (acute + delayed phases)

- 0

- 60

- 120

- 180

- 240

- 300

- Retches and Vomits

- Acute + delayed effects blocked by aprepitant

- Vehicle

- Aprepitant(1 mg/kg/day)

## Aprepitant Protects Against Chemotherapy-Induced Emesis in Ferrets

- Profile similar to humans
- (acute + delayed phases)

- 0

- 60

- 120

- 180

- 240

- 300

- Retches and Vomits

- Acute + delayed effects blocked by aprepitant

- Vehicle

- Aprepitant(1 mg/kg/day)

- Aprepitant(2 mg/kg/day)

- 0

- 24

- 48

- 72

- Cisplatin

## 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

## 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

## Regimen for Chemotherapy-Induced Nausea and Vomiting Provides Consistent Daily Plasma Exposure

- Aprepitant Plasma Concentration (ng/mL)

## Regimen for Chemotherapy-Induced Nausea and Vomiting Provides Consistent Daily Plasma Exposure

- Aprepitant Plasma Concentration (ng/mL)

## Regimen for Chemotherapy-Induced Nausea and Vomiting Provides Consistent Daily Plasma Exposure

- Time Postdose (hr)

- N=12

- Aprepitant Plasma Concentration (ng/mL)

## Aprepitant Blocks Brain NK1 Receptorsin Humans

- Binding of PET tracer to NK**1** receptors prior to aprepitant dosing

## Aprepitant Blocks Brain NK1 Receptorsin Humans

- Binding of PET tracer to NK**1** receptors prior to aprepitant dosing

- Blockade of
- NK**1** receptorsafter aprepitant dosing

## Aprepitant Blocks Brain NK1 Receptorsin Humans

- Binding of PET tracer to NK**1** receptors prior to aprepitant dosing

- Blockade of
- NK**1** receptorsafter aprepitant dosing

**Aprepitant Plasma Trough Concentration (ng/mL)**

**Brain NK****1**** Receptor Occupancy (%)**

## Aprepitant Blocks Brain NK1 Receptorsin Humans

- Aprepitant Blocks Brain NK**1** Receptorsin Humans

- Binding of PET tracer to NK**1** receptors prior to aprepitant dosing

- Blockade of
- NK**1** receptorsafter aprepitant dosing

**Aprepitant Plasma Trough Concentration (ng/mL)**

**Brain NK****1**** Receptor Occupancy (%)**

**Mean (± SD) Plasma Trough Concentrations of the Aprepitant 3-Day Regimen**

## 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

## Aprepitant Is a Moderate CYP3A4 Inhibitor

- 2-fold

- 5-fold

- 16-fold

- Strong

- Moderate

- Weak

- Ketoconazole

- Itraconazole

- Clarithromycin

- Inhibition of CYP3A4 Ranked According toFold Increase in Oral Midazolam AUC

## Aprepitant Is a Moderate CYP3A4 Inhibitor

- Inhibition of CYP3A4 Ranked According toFold Increase in Oral Midazolam AUC

- Strong

- Moderate

- Weak

- Ketoconazole

- Itraconazole

- Clarithromycin

- Erythromycin

- Diltiazem

- Verapamil

- Grapefruit juice

## 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 toFold Increase in Oral Midazolam AUC

- Strong

- Moderate

- Weak

- Ketoconazole

- Itraconazole

- Clarithromycin

- Erythromycin

- Diltiazem

- Verapamil

- Grapefruit juice

- Aprepitant (125 mg Day 1; 80 mg/d Days 2 to 5)

- Day: 1   5

## 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

## 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)

## 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)

## Aprepitant Has a Small Effect on I.V. Methylprednisolone

- N=8
- Aprepitant: 125 mg P.O.
- Methylprednisolone: 125 mg I.V.

## Aprepitant Does Not Affect 5-HT3 Antagonists

- Ondansetron 32 mg I.V. +
- Aprepitant 375 mg (N=15)

- No dose adjustment of ondansetron or granisetron required

- Ondansetron Plasma Concentration (ng/mL)

## 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)

- Granisetron Plasma Concentration (ng/mL)

## 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

## Aprepitant Does Not Affect Docetaxel Pharmacokinetics (Ongoing Trial, N=5)

- Aprepitant Does Not Affect Docetaxel Pharmacokinetics (Ongoing Trial, N=5)

- Plasma ConcentrationProfiles of Docetaxel

- Docetaxel AUC of individual patients

- Docetaxel Plasma Concentration (mcg/mL)

## Aprepitant Does Not Affect Steady State Pharmacokinetics of the P-glycoprotein Substrate Digoxin

- No dose adjustment of digoxin required

- N=11

- Aprepitant

- Aprepitant

- Digoxin PlasmaConcentration (ng/mL)

## 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

## Aprepitant Slightly InducesWarfarin Metabolism

- Small inductive effect on warfarin warrants closer monitoring of INR

- N=11-12

## Aprepitant Slightly InducesWarfarin Metabolism

- Small inductive effect on warfarin warrants closer monitoring of INR

- N=11-12

## 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

## 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

## Clinical Efficacy

- Kevin J. Horgan, MD*Clinical Research**Merck Research Laboratories*

- EMEND®  (aprepitant)

## Prevention of Nausea and Vomiting withHighly Emetogenic Chemotherapy 

*J Clin Oncol ;*17(9):2971-94, 1999

- Prevention of Nausea and Vomiting withHighly 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

## Time Course of Nausea and Vomiting Following Chemotherapy

## 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

## Aprepitant Program Objective

- To define the potential role of aprepitant in theprevention of nausea and vomiting associatedwith highly emetogenic chemotherapy

## Aprepitant Program Overview

- Does aprepitant work alone as an antiemetic?

## Aprepitant Program Overview

- Does aprepitant work alone as an antiemetic?
- Is a regimen including aprepitant more effective than current standard therapy?

## 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?

## 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.

## 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)

## 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

## 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

## 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

## 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.

## Aprepitant as Monotherapy

- Aprepitant as Monotherapy

- Day 1

- Aprepitant I.V. prodrug60 or 100 mg
- Ondansetron I.V.32 mg

- Protocol  004

## Aprepitant as Monotherapy 

- Complete Response: Acute and Delayed Phases

- Aprepitant as Monotherapy

- Protocol  004

**37%**

**48%**

**48%**

**17%**

- N=

- 30

- 23

- 29

- 23

## Aprepitant as Monotherapy 

- Aprepitant as Monotherapy

-  **†***Cancer* 78:2193-2198, 1996

- HistoricalData**†**(Untreated)

- Complete Response: Acute and Delayed Phases

- Protocol  004

**37%**

**48%**

**48%**

**17%**

- N=

- 30

- 23

- 29

- 23

## Aprepitant as Monotherapy

- Conclusions

- 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

## 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.

## 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

## Aprepitant Regimen Study

- Day 1

- Days 2 to 5

- Primary Treatment Groups

- Protocol  007

- G

- D

- Control

- Group

- G=granisetron; D=dexamethasone; A=aprepitant; P=placebo

- P

## Aprepitant Regimen Study

- Group

- Control

- Day 1

- Days 2 to 5

- G

- D

- A

- A

- G=granisetron; D=dexamethasone; A=aprepitant; P=placebo

- P

- P

- P

- Aprepitant
- 1-Day

- Aprepitant
- 5-Day

**400**

**400**

**300**

- Primary Treatment Groups

- Protocol  007

## Aprepitant Regimen Study 

- 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%**

- N=

- 53

- 50

- 54

- 51

- 54

- 51

**83%**

**43%**

- Protocol  007

## 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

## 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.

## 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

## 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

## Dose Finding Study

- Day 1

- Days 2 to 5

- O

- D

- D

- Protocol 040/042

- Primary Treatment Groups

- O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo

- Group

- Control

- P

- P

## Dose Finding Study

- Day 1

- Days 2 to 5

- O

- D

- A

- A

- D

- Protocol 040/042

- Primary Treatment Groups

- O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo

- Group

- Aprepitant
-     40/25

- Control

- P

- P

**40**

**25**

## Dose Finding Study

- Group

- Control

- Day 1

**125**

**40**

- Days 2 to 5

**80**

**25**

- O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo

- O

- D

- A

- A

- D

- P

- P

- Aprepitant
-     40/25

- Aprepitant
-     125/80

- Protocol 040/042

- Primary Treatment Groups

## Dose Finding Study

- Overall Complete Response

- Aprepitant  125/80

- Aprepitant    40/25

- Control

- N=

- 131

- 126

- 119

**59%**

**44%**

**71%**

- p<0.01

- Protocol 040/042

## Dose Finding Study

- Overall Complete Response

- Aprepitant  125/80

- Aprepitant    40/25

- Control

- N=

- 131

- 126

- 119

**59%**

**44%**

**71%**

- Protocol 040/042

## Dose Finding Study

- Complete Response: Acute and Delayed Phases

- Aprepitant   125/80

- Aprepitant
-    40/25

- Control

- N=

- 131

- 126

- 119

- 132

- 126

- 119

**64%**

**76%**

**83%**

**71%**

**73%**

**45%**

- Protocol 040/042

## Dose Finding Study

- Time to First Emesis or Rescue

- Protocol 040/042

## Dose Finding Study

- Time to First Emesis or Rescue

- Protocol 040/042

## Dose Finding Study

- Time to First Emesis or Rescue

- Protocol 040/042

## 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

## 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

## 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

## Phase III Studies

- Aprepitant

- Control

- Group

- Day 4

**16**

**8**

- Day 1

**12**

**20**

- Days 2-3

**8**

**16**

- O

- D

- A

- D

- D

- A

- O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo

- P

- P

- Protocols 052 and 054

- Primary Treatment Groups

## 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

## Phase III Studies

- Protocols 052 and 054 Combined

- Patient Demographics

## Phase III Studies

- Aprepitant (N=549)

- Control  (N=554)

- Protocols 052 and 054 Combined

- Primary Cancer Diagnoses

## Phase III Studies

- Protocols 052 and 054 Combined

- Concomitant Chemotherapy

## Phase III Studies: Cycle 1

- p<0.001

**52%**

- N=

- 260

- 260

**73%**

- Primary Endpoint: Overall Complete Response

- Protocol 052

## Phase III Studies: Cycle 1

- p<0.001

- N=

- 260

- 260

**63%**

**43%**

- 263

- 260

- Protocol 054

- Protocol 052

- Primary Endpoint: Overall Complete Response

**52%**

**73%**

## Phase III Studies: Cycle 1

**89%**

**78%**

**75%**

**56%**

- N=

- 259

- 260

- 260

- 260

- p<0.001

- p<0.001

**83%**

**68%**

**47%**

**68%**

- 260

- 263

- 261

- 263

- p<0.001

- p<0.001

- Protocol 052

- Complete Response: Acute and Delayed Phases

- Protocol 054

## Phase III Studies: Cycle 1

- Time to First Emesis or Rescue

-  APR N=260     Control N=260

-  APR N=260     Control N=263

## Phase III Studies: Cycle 1

- Phase III Studies: Cycle 1

- N=

- 260

- 260

- 260

- 263

- 260

- 260

- 260

- 263

**78%**

**55%**

**81%**

**71%**

**66%**

**45%**

**82%**

**73%**

- p<0.01

- p<0.01

- p<0.01

- p<0.01

- Components of Primary Endpoint: Overall

- Protocol 052

- Protocol 054

## 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

- 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

- Phase III Studies: Cycle 1

- 0 mm

- 100 mm

- Nausea Assessment

## Phase III Studies: Cycle 1

**48%**

**44%**

**73%**

**66%**

**49%**

**39%**

**71%**

**64%**

- N=

- 257

- 260

- 260

- 263

- 257

- 259

- 260

- 263

- No Nausea and No Significant Nausea: Overall

- Protocol 052

- Protocol 054

## Phase III Studies: Cycle 1

**48%**

**42%**

**72%**

**65%**

- N =

- 517

- 523

- 522

- 517

- No Nausea and No Significant Nausea: Overall

- Protocols 052 and 054 Combined

## 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

## Phase III Studies: Cycle 1

- Protocols 052 and 054 Combined: Overall(Post-hoc Analysis)

- Aprepitant  (N=70)

- Control  (N=72)

- p<0.001

**59%**

**26%**

- Concomitant Emetogenic Chemotherapy (Cyclophosphamide and/or Doxorubicin)

## 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

## 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

## Phase III Studies: Multiple Cycles 

- N= 349	270	184	117	83N= 393	278	180	111	72

- Observed Proportion of Patients without Emesis and without Significant Nausea

- Phase III Studies: Multiple Cycles

## Phase III Studies: Multiple Cycles

- Proportion of Patients Symptom Free by Cycle

- Phase III Studies: Multiple Cycles

- Protocols 052 and 054 Combined

## 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

## Clinical Safety

- Scott A. Reines, MD, PhD*Clinical Research**Merck Research Laboratories*

- EMEND®  (aprepitant)

## Clinical Development Program

## Clinical Adverse Experience Summary

## Most Common Serious Clinical AEs

- (Incidence ****0.7%)

##  Laboratory Adverse Experience Summary

-  Laboratory Adverse Experience Summary

## Evaluation of Toxicity Due toConcomitant Therapies

- Evaluation of Toxicity Due toConcomitant 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

## Cisplatin-Induced Toxicity

- Serum Creatinine by NCI Criteria

## Cisplatin-Induced Toxicity

- Serum Creatinine by NCI Criteria

-   No differences in nephrotoxicity as indicated by serum creatinine

## Cisplatin-Induced Toxicity

-   No differences in nephrotoxicity as indicated by serum creatinine

- No differences in neurotoxicity or ototoxicity between groups

- Serum Creatinine by NCI Criteria

## Chemotherapy-Induced Toxicity

## Chemotherapy-Induced Toxicity

- Neutropenia Severity by NCI Criteria

## Chemotherapy or Glucocorticoid-Induced Toxicity

- 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

## Safety of Aprepitant in Patients Receiving Chemotherapy Metabolized by CYP3A4 

- 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

## AE Summary in Patients Receiving Concomitant Chemotherapy Metabolized by CYP3A4

** **(Etoposide, Vinca Alkaloids, Taxanes, Irinotecan, Ifosfamide)

## Neutropenia in Patients Receiving Concomitant Chemotherapy Metabolized by CYP3A4

** **(Etoposide, Vinca Alkaloids, Taxanes, Irinotecan, Ifosfamide)

## Neutropenia in Patients Receiving Concomitant Chemotherapy Metabolized by CYP3A4

-  No change in hematological toxicity of chemotherapy metabolized by CYP3A4

-  (Etoposide, Vinca Alkaloids, Taxanes, Irinotecan, Ifosfamide)

## Individual Chemotherapies Metabolized by CYP3A4

- Percent of Patients

- N=

- 266

- 251

- 101

- 96

- 82

- 76

- 52

- 58

- Phase III: Cycle 1

## Individual Chemotherapies Metabolized by CYP3A4

- N=

- 106

- 91

- 52

- 58

- 82

- 76

- Percent of Patients

- Phase III: Cycle 1

- 266

- 251

- Percent of Patients with Neutropenia Adverse Experiences

## Safety of Aprepitant in Patients Receiving Chemotherapy Metabolized by CYP3A4 

- 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

## 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

## 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

## Numbers of Patients Entered into Multiple Chemotherapy Cycles 

- Cycle 3
- Cycle 4
- Cycle 5
- Cycle 6

- Phase III

- Numbers of Patients Entered into Multiple Chemotherapy Cycles

## Safety Summary DuringMultiple Chemotherapy Cycles

- Phase III: Cycles 2-6

- Safety Summary DuringMultiple Chemotherapy Cycles

## Chemotherapy-Induced Toxicity: Multiple Cycles 

- Chemotherapy Cycle

- Percent of Patients

- N=

- 462

- 477

- 366

- 377

- 304

- 303

- 219

- 231

- 169

- 173

- 134

- 143

- Chemotherapy-Induced Toxicity: Multiple Cycles

## 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

## Summation and Conclusions

- EMEND®  (aprepitant)

## Aprepitant  

- Aprepitant

- A cancer diagnosis has profound implications
- Life-threatening disease
- Potentially disruptive and debilitating treatment
- Daily function can be compromised by nausea and vomiting

## Aprepitant  

- 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

## Aprepitant  

- 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

- Many Patients Still Experience Nausea andVomiting After Highly Emetogenic Chemotherapy

- Time to First Emesis or Use of Rescue

**Control**

**Control**

- N=260

- N=263

## Evaluated in 7-year multinational clinical development program
>3000 patients  and subjects in total
>1400 patients in cancer chemotherapy trials

- >3000 patients  and subjects in total
- >1400 patients in cancer chemotherapy trials

- Unique Attributes for Patients Receiving Highly Emetogenic Chemotherapy

- Aprepitant

## 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

- >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

## 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

- >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

## More Patients Benefit with Aprepitant

- Protocol 052

- Protocol 054

- Hours

- Hours

**APR 125/80 Regimen**

**APR 125/80 Regimen**

- Time to First Emesis or Use of Rescue Therapy

**Control**

**Control**

-  APR N=260     Control N=260

-  APR N=260     Control N=263

## 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

## 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.