1 FDA Advisory Committee March 6, 2003 Dennis M. Erb, PhD Regulatory Affairs Merck Research...

1

FDA Advisory CommitteeMarch 6, 2003

Dennis M. Erb, PhDRegulatory Affairs

Merck Research Laboratories

EMEND® (aprepitant)

2

An Unmet Medical Need

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

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-HT3 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

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 AndrewsProfessor of Comparative PhysiologySt. George’s Hospital Medical School, London, UK

Dr. Merrill J. EgorinProfessor of Medicine and PharmacologyUniversity of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Dr. Malcolm RowlandResearch Professor, School of Pharmacy & Pharmaceutical SciencesUniversity of Manchester, Manchester, UK

Statistics

Dr. Janet WittesPresidentStatistics Collaborative, Inc., Washington, DC

8

Consultants

Clinical Research

Dr. Ronald De WitAssociate ProfessorRotterdam Cancer Institute and Erasmus University HospitalRotterdam, The Netherlands

Dr. Steven GrunbergProfessor of MedicineUniversity of Vermont, Burlington, Vermont

Dr. Paul HeskethProfessor of MedicineTufts University School of Medicine, Boston, Massachusetts

Dr. Loren LaineProfessor of MedicineUniversity 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


Kevin J. Petty, MD, PhDClinical Pharmacology


11

Aprepitant Pharmacology: Summary

Novel antiemetic mechanism of action– Blockade of (substance P) NK1 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-inducednausea 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


Enterochromaffin cell

Serotonin release

Chemotherapy

Peripheral

15



Serotonin release

Vagal afferent5-HT3 receptors

Chemotherapy

Peripheral

16

Chemotherapy


Dorsal vagal complex

Area postrema


Serotonin release


Peripheral

Central

17

Chemotherapy


BrainstemNK1 receptorsSubstance P

Dorsal vagal complex

Area postrema


Serotonin release


Peripheral

Central

18

Pharmacological Properties of Aprepitant

Antagonist for NK1 (substance P) receptor

Specific, high affinity human NK1 receptor binding (IC50 = 0.12 nM)– >8000 fold selective for NK1 receptors over known receptors

mediating antiemetic activity• Dopamine D2, serotonin 5-HT3, 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-HT3 receptor antagonists

20

NK1 Antagonists Have a Broad Preclinical Antiemetic Profile

Site of Action

Central

Peripheral

Central/peripheral

Emetogen

ApomorphineMorphineNicotineLoperamide

RadiationCyclophosphamideIpecacuanhaCopper sulfate

Cisplatin

NK1

++++

++++

+

5-HT3

––––

++++

+

Antagonist

21

Aprepitant Protects Against Chemotherapy-Induced Emesis in Ferrets

Profile similar to humans(acute + delayed phases)

0

60

120

180

240

300

Ret

ches

and

Vom

its

Acute Delayed

Vehicle

0 24 48 72

Cisplatin

22



0

60

120

180

240

300

Ret

ches

and

Vom

its

Acute + delayed effects blocked by aprepitant

VehicleAprepitant

(1 mg/kg/day)

0 24 48 72

Cisplatin

0 24 48 72

Cisplatin

Acute Delayed

23



0

60

120

180

240

300

Ret

ches

and

Vom

its

Acute + delayed effects blocked by aprepitant

VehicleAprepitant

(1 mg/kg/day)Aprepitant

(2 mg/kg/day)

0 24 48 72

Cisplatin

0 24 48 72

Cisplatin

0 24 48 72

Cisplatin

Acute Delayed

24

Preclinical Assessment of Aprepitant Antiemetic Activity

Prevents cisplatin-induced emesis in the well established ferret model– Requirement for central NK1 receptor antagonism

Additive with established antiemetic agents (dexamethasone, 5-HT3 receptor antagonists)

Active against both acute and delayed phases– Distinct and novel profile– Efficacy with once-daily dosing

25


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

Apr

epita

nt P

lasm

a C

once

ntra

tion

(ng/

mL)

27


125 mg 80 mg

N=12 Time Postdose (hr)

Apr

epita

nt P

lasm

a C

once

ntra

tion

(ng/

mL)

28


125 mg 80 mg 80 mg

Time Postdose (hr)N=12

Apr

epita

nt P

lasm

a C

once

ntra

tion

(ng/

mL)

29

Aprepitant Blocks Brain NK1 Receptorsin Humans

Binding of PET tracer to NK1 receptors prior to aprepitant dosing

Low High

Tracer Binding

30



Blockade of NK1 receptorsafter aprepitant dosing

Low High

Tracer Binding

31




Aprepitant Plasma Trough Concentration (ng/mL)

Bra

in N

K1

Rec

epto

r O

ccu

pan

cy (

%)

0102030405060708090

100

0 1 10 100 1000 10000

Low High

Tracer Binding

32




Aprepitant Plasma Trough Concentration (ng/mL)

Bra

in N

K1

Rec

epto

r O

ccu

pan

cy (

%)

0102030405060708090

100

0 1 10 100 1000 10000

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

Regimen

Low High

Tracer Binding

33


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-fold 5-fold 16-fold

StrongModerateWeak

KetoconazoleItraconazoleClarithromycin

Inhibition of CYP3A4 Ranked According toFold Increase in Oral Midazolam AUC

35

Aprepitant Is a Moderate CYP3A4 InhibitorInhibition of CYP3A4 Ranked According to

Fold Increase in Oral Midazolam AUC

StrongModerateWeak

KetoconazoleItraconazoleClarithromycinErythromycin

DiltiazemVerapamil

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 toFold Increase in Oral Midazolam AUC

StrongModerateWeak

KetoconazoleItraconazoleClarithromycinErythromycin

DiltiazemVerapamil

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 2-5Aprepitant: 125 mg Day 1, 80 mg/d Days 2-5 N=12 per treatment

0 6 12 18 24

Time (hr)

0

50

100

150

200

250

Dex

amet

haso

ne

Day 1

Con

cent

ratio

n (n

g/m

L)

869-41 Dexa D1 Feb. 19, 2003

with Aprepitantwithout Aprepitant

Dex

amet

haso

ne P

lasm

a C

once

ntra

tion

(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 treatmentDexamethasone: 20 mg P.O. Day 1, 8 mg/d P.O. Days 2-5Aprepitant: 125 mg Day 1, 80 mg/d Days 2-5

0 6 12 18 24

Time (hr)

0

50

100

150

200

250

Dex

amet

haso

ne

Day 1

Con

cent

ratio

n (n

g/m

L)

0 6 12 18 240

50

100

150

200

250

869-41 Dexa D1&D5 Feb. 19, 2003

Day 5


Dex

amet

haso

ne P

lasm

a C

once

ntra

tion

(ng/

mL)

40

Aprepitant Has a Small Effect on I.V. Methylprednisolone

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

0 4 8 12 16 20 24

Time (hr)

0

2000

4000

6000

8000M

ethy

lpre

dnis

olon

e P

lasm

a

Con

cent

ratio

n (n

g/m

L)

I.V.


869-acm 67 Meth_(Slide3) IV.axg Feb. 24, 2003

41

Aprepitant Does Not Affect 5-HT3 AntagonistsOndansetron 32 mg I.V. +Aprepitant 375 mg (N=15)

0 4 8 12 16 18 24

Time (hr)

0

100

200

300

400

500

600

Ond

anse

tron

Con

c. (

ng/m

L) I.V.

869-41&50 Anta_(Slide4) a1 Feb. 19, 2003


No dose adjustment of ondansetron or granisetron required

Ond

anse

tron

Pla

sma

Con

cent

ratio

n (n

g/m

L)

42

No dose adjustment of ondansetron or granisetron required

Aprepitant Does Not Affect 5-HT3 AntagonistsOndansetron 32 mg I.V. +Aprepitant 375 mg (N=15)

Granisetron 2 mg P.O. +Aprepitant 125 mg (N=18)

0 4 8 12 16 18 24

Time (hr)

0

100

200

300

400

500

600

Ond

anse

tron

Con

c. (

ng/m

L) I.V.


0 12 24 36 48 60 720

2

4

6

8

10

869-41&50 Anta_(Slide4) Feb. 25, 2003

PO

Gra

nise

tron

Con

c. (

ng/m

L)


P.O.

Gra

nise

tron

Pla

sma

Con

cent

ratio

n (n

g/m

L)

Ond

anse

tron

Pla

sma

Con

cent

ratio

n (n

g/m

L)

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 ConcentrationProfiles of Docetaxel

Docetaxel AUC of individual patients

Without WithAprepitant Aprepitant

0

1

2

3

4

5

869-51 Doce 2 Feb. 25, 2003

Doc

etax

el A

UC

0-

0 4 8 12Time (hr)

0.01

0.1

1

10

Doc

etax

el C

onc.

(m

cg/m

L)


Doc

etax

el P

lasm

a C

once

ntra

tion

(mcg

/mL)

45

0 4 8 12 16 20 24

Time (hr)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Mea

n D

igox

in P

lasm

a

Con

cent

ratio

n (n

g/m

L)

With APRWithout APR

869-47 Digox 1 Feb. 11, 2003

Day 1 (N=11)

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

No dose adjustment of digoxin requiredN=11

AprepitantAprepitant

Dig

oxin

Pla

sma

Con

cent

ratio

n (n

g/m

L)

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 InducesWarfarin Metabolism

Small inductive effect on warfarin warrants closer monitoring of INR

N=11-12

1 2 3 4 5 6 7 8

Day

0.0

0.2

0.4

0.6

0.8

1.0

1.2R

atio

of f

old

chan

ge fr

om b

asel

ine

(AP

R/p

lace

bo)

869-67 INR-R-S GM Ratio a1 Feb. 19, 2003

R(+) Warfarin

S(-) Warfarin

869-67 INR-R-S GM Ratio a1.axg Feb. 19, 2003

APR or PlaceboWarfarin

48

Aprepitant Slightly InducesWarfarin Metabolism

Small inductive effect on warfarin warrants closer monitoring of INR

N=11-12

1 2 3 4 5 6 7 8

Day

0.0

0.2

0.4

0.6

0.8

1.0

1.2R

atio

of f

old

chan

ge fr

om b

asel

ine

(AP

R/p

lace

bo)

869-67 INR-R-S GM Ratio Feb. 19, 2003

R(+) Warfarin

S(-) Warfarin

INR

WarfarinAPR or Placebo

49

Aprepitant Pharmacology: Summary

Novel antiemetic mechanism of action– Blockade of (substance P) NK1 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, MDClinical Research



52

An unmet medical need

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-HT3 receptor antagonist and a corticosteroid

Despite current therapy many (>50%) patients still have symptoms following highly emetogenic chemotherapy

53

24

1 2 3 4 5

Acute Delayed

Overall

120

Administration ofChemotherapy

Day

Hours 0

Time Course of Nausea and Vomiting Following Chemotherapy

54

Current Standard Therapy

Corticosteroid Therapy+5-HT3 Receptor Antagonist

Augments efficacy of 5-HT3 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 theprevention of nausea and vomiting associated

with highly emetogenic chemotherapy

56

Aprepitant Program Overview

Does aprepitant work alone as an antiemetic?

57



Is a regimen including aprepitant more effective than current standard therapy?

58




What is the optimum aprepitant dose?

59





Confirm that the Phase III aprepitant regimen is safe and effective.

60

Cisplatin Is PrototypicHighly Emetogenic Chemotherapy

Cornerstone of therapy for common cancers (e.g., lung, ovarian)

Most emetogenic chemotherapy 50 mg/m2 infused over 3 hours is highly emetogenic

Predictable and well characterized pattern of emesis

Benchmark for evaluation and approval of novel antiemetic therapies– 5-HT3 receptor antagonists: Ondansetron, granisetron, dolasetron– Dopamine D2 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/m2 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






65

Eur J Cancer 37:835-842, 2001

Aprepitant as Monotherapy

Day 1

Aprepitant I.V. prodrug60 or 100 mg

Ondansetron I.V.32 mg

Protocol 004

66

0

20

40

60

80

100

Per

cent

of P

atie

nts

Acute Delayed

AprepitantOndansetron

869 acm 4 ComplResp Feb. 14, 2003

Complete Response: Acute and Delayed PhasesAprepitant as Monotherapy

Protocol 004

37%

48% 48%

17%

p<0.05

N= 30 23 29 23

67

0

20

40

60

80

100

Per

cent

of P

atie

nts

Acute Delayed

AprepitantOndansetron

869 acm 4 ComplResp Feb. 14, 2003

Aprepitant as Monotherapy

†Cancer 78:2193-2198, 1996

HistoricalData†

(Untreated)

p<0.05

Complete Response: Acute and Delayed PhasesProtocol 004

37%

48% 48%

17%

N= 30 23 29 23

68

Protocol 004

ConclusionsAprepitant as Monotherapy

Aprepitant is an effective antiemetic– In both acute and delayed phases

Distinctive efficacy profile relative to 5-HT3 receptor antagonists– Significantly superior efficacy in delayed phase

Distinctive efficacy profile implied potential for better efficacy by combining with a 5-HT3 receptor antagonist

69






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


Day 1 Days 2 to 5

Primary Treatment GroupsProtocol 007

G DControl

Group

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

P

72


Group

Control

Day 1 Days 2 to 5

G D A A

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

P P

PAprepitant 1-Day

Aprepitant 5-Day

400

400 300

Primary Treatment GroupsProtocol 007

73

0

20

40

60

80

100

Per

cent

of P

atie

nts

Acute Delayed

869-7 Acute-Del 1A Feb. 14, 2003


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= 53 50 54 5154 51

83%

43%

p<0.01

p<0.01

Protocol 007

74


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

ConclusionsProtocol 007

75






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 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

79

Dose Finding Study

Day 1 Days 2 to 5

O D A AD

Protocol 040/042



Group

Aprepitant 40/25

Control P P

40 25

80

Dose Finding Study

Group

Control

Day 1

125

40

Days 2 to 5

80

25


O D A AD

P P

Aprepitant 40/25

Aprepitant 125/80

Protocol 040/042


81

Dose Finding StudyOverall Complete Response

0

20

40

60

80

100

Per

cent

of P

atie

nts

869 40-42 Compl Resp 1A Feb. 14, 2003

Aprepitant 125/80

Aprepitant 40/25

Control

N= 131 126119

59%

44%

71%p<0.05

p<0.01

Protocol 040/042

82

Dose Finding StudyOverall Complete Response

0

20

40

60

80

100

Per

cent

of P

atie

nts

869 40-42 Compl Resp 1A Feb. 14, 2003

Aprepitant 125/80

Aprepitant 40/25

Control

N= 131 126119

59%

44%

71%

Protocol 040/042

p<0.05

83

Dose Finding StudyComplete Response: Acute and Delayed Phases

0

20

40

60

80

100P

erce

nt o

f Pat

ient

s

869-acm 40-42 S8A Feb. 14, 2003

Acute DelayedPhase

Aprepitant 125/80

Aprepitant 40/25

Control

N= 131 126119 132 126119

64%

76%83%

71% 73%

45%

p<0.05

p<0.01

p<0.01

Protocol 040/042

84

Dose Finding StudyTime to First Emesis or Rescue

0 24 48 72 96 120

Hours

040

60

80

100

Per

cent

of P

atie

nts

869-acm 40-42 Time Cr3 Feb. 15, 2003

with

Com

plet

e R

espo

nse

Control

Protocol 040/042

85


0 24 48 72 96 120

Hours

040

60

80

100

Per

cent

of P

atie

nts

869-acm 40-42 Time Cr3 Feb. 15, 2003

with

Com

plet

e R

espo

nse

Control

APR 125/80

APR 40/25

Protocol 040/042

86


0 24 48 72 96 120

Hours

040

60

80

100

Per

cent

of P

atie

nts

869-acm 40-42 Time Cr3 Feb. 15, 2003

with

Com

plet

e R

espo

nse

Control

APR 125/80

APR 40/25

APR 375/250

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

ConclusionsProtocol 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

Group Day 4

16

8

Day 1

12

20

Days 2-3

8

16

O D A DD A


P P



91

Phase III Studies

Inclusion Criteria– Cisplatin dose 70 mg/m2

Exclusion Criteria– Laboratory value parameters

• AST or ALT 2.5 x upper limit of normal (ULN)• Neutrophil count <1500/mm3 and WBC <3000/mm3

• Bilirubin >1.5 x ULN; Creatinine >1.5 x ULN– Concomitant or very recent use of

• Strong CYP3A4 inhibitors• CYP3A4 inducers

Design FeaturesProtocols 052 and 054

92

Phase III Studies

Protocols 052 and 054 Combined

Patient Demographics

(N=549)

(N=554)

Aprepitant

Control

0 20 40 60 80 100

Percent of Patients

869-acm 52-54 S8B Feb. 28, 2003

Male

<65

Gender

Age

Additionalemetogenicchemotherapy

93

Phase III Studies

0 20 40 60 80 100

Percent of Patients

Lung

Ovarian

Head and Neck

Esophageal

Gastric

869-acm 52-54 S10 B Feb. 14, 2003

Aprepitant (N=549)

Control (N=554)


Primary Cancer Diagnoses

94

Phase III Studies


Concomitant Chemotherapy

Aprepitant (N=549)

Control (N=554)

0 20 40 60 80 100

Percent of Patients

EtoposideFluorouracilGemcitabineVinorelbinePaclitaxelCyclophosphamideDoxorubicinDocetaxelCisplatin (only)

869-acm 52-54 S11 A Feb. 28, 2003

95

Phase III Studies: Cycle 1

0

20

40

60

80

100

Per

cent

of P

atie

nts

052

869-acm 52-54 S12A1-A2 Sep1 Feb. 13, 2003

AprepitantControl

p<0.001

52%

N= 260 260

73%

Primary Endpoint: Overall Complete Response

Protocol 052

96


0

20

40

60

80

100

Per

cent

of P

atie

nts

052

869-acm 52-54 S12A1-A2 Sep1 Feb. 13, 2003

AprepitantControl

p<0.001

N= 260 260

0

20

40

60

80

100

869-acm 52-54 S12A1-A2 Sep2 Feb. 13, 2003

054

63%

43%

p<0.001

263260

Protocol 054Protocol 052

Primary Endpoint: Overall Complete Response

52%

73%

97


0

20

40

60

80

100

Per

cent

of P

atie

nts

Acute Delayed

052

869-acm 52-54 S12 H1-A Feb. 13, 2003

AprepitantControl

89%

78% 75%

56%

N= 259 260 260 260

p<0.001p<0.001

0

20

40

60

80

100

869-acm 52-54 S12 H1-B Feb. 13, 2003

Acute Delayed

054

83%

68%

47%

68%

260263261 263

p<0.001

p<0.001

Protocol 052

Complete Response: Acute and Delayed Phases

Protocol 054

98


0 24 48 72 96 120Hours

040

60

80

100

Per

cent

of P

atie

nts

Protocol 052

0 24 48 72 96 120Hours

040

60

80

100

869-52-54 Time_1st_Cr Feb. 14, 2003

Protocol 054

ControlAprepitant

Time to First Emesis or Rescue

APR N=260 Control N=260 APR N=260 Control N=263

99

0

20

40

60

80

100

Per

cent

of P

atie

nts

No Emesis No Rescue

052052

0

20

40

60

80

100

No Emesis No Rescue

054054

869-acm 52-54 S14 A3 Feb. 13, 2003

AprepitantControl


N= 260 260 260263260 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

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?

Nonause

a

Nausea as bad as it could be


0 mm 100 mm

Nausea Assessment

101


0

20

40

60

80

100

Per

cent

of P

atie

nts

VAS <5 mm VAS <25 mm

052

0

20

40

60

80

100

869-acm 52-54 S14 B3 Feb. 14, 2003

VAS <5 mm VAS <25 mm

054

AprepitantControl

48% 44%

73%66%

49%

39%

71%64%

N= 257 260 260263257 259 260 263

p<0.05

No Nausea and No Significant Nausea: Overall


102

0

20

40

60

80

100

Per

cent

VAS <5 mmVAS <5 mm0

20

40

60

80

100

869-acm 52-54 S14 C Feb. 14, 2003

VAS <25 mmVAS <25 mm

AprepitantControl


48%42%

72%65%

N = 517 523 522517

p<0.05

p<0.05

No Nausea and No Significant Nausea: OverallProtocols 052 and 054 Combined

103


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


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

0

20

40

60

80

100

Per

cent

of P

atie

nts

869-acm 52-54 S14 D Feb. 14, 2003

with

Com

plet

e R

espo

nse

Aprepitant (N=70)

Control (N=72)

p<0.001

59%

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?


107


2 3 4 5 6

Chemotherapy Cycle

20

40

60

80

100

Per

cent

of P

atie

nts

869-acm 5254 Cycle 11 Feb. 14, 2003

Aprepitant

Control

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

108

Proportion of Patients Symptom Free by Cycle Phase III Studies: Multiple Cycles


1 2 3 4 5 60

20

40

60

80

100

Per

cent

of P

atie

nts

Aprepitant

Control

Time to First Emesis

1 2 3 4 5 6Cycles

0

20

40

60

80

100

869-acm 5254 1Em-1Frzn Feb. 24, 2003

Aprepitant

Control

Time to First Significant Nausea

N=520 256 185 119 70 51 N=523 201 131 80 46 29

N=517 264 183 115 67 46N=522 259 165 108 56 34

Chemotherapy Cycle

109

Aprepitant Efficacy Conclusions

Addition of aprepitant to a regimen of a 5-HT3 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, PhDClinical Research



111

Number of Patients Receiving Aprepitant

Phase I clinical pharmacology studies

Studies in non-cancer patients

Studies in patients receiving cancer chemotherapy

Phase II 915Phase III 544

711

1172

1459

Total 3342

Clinical Development Program

112

APR 125/80(N=544)

%

69.1

17.1

13.4

7.7

3.7

Control (N=550)

%

67.6

12.7

13.6

5.8

3.8

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)

%

13.61.10.91.30.20.50.20.50.70.7


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)

%

13.42.21.81.30.90.70.70.70.40.2

(Incidence 0.7%)

114

Control(N=543)

%

19.5

2.6

0.2

0.7

APR 125/80(N=539)

%

22.3

4.1

0.2

0.4

Laboratory adverse experiences

Drug-related laboratory AEs

Serious laboratory AEs

Discontinuations due to lab AEs


Phase III: Cycle 1

Laboratory Adverse Experience Summary

115

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

116

Day 6 to 8

APR 125/80(N=501)

%

14.4

11.0

3.2

0.2

0.0

Control(N=507)

%

16.2

12.6

3.2

0.4

0.0

Day 19 to 29

APR 125/80(N=482)

%

7.4

6.8

0.6

0.0

0.0

Control(N=495)

%

7.7

6.3

1.2

0.2

0.0

> 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 CriteriaCisplatin-Induced Toxicity

117

Cisplatin-Induced ToxicitySerum Creatinine by NCI Criteria

No differences in nephrotoxicity as indicated by serum creatinine

Day 6 to 8

APR 125/80(N=501)

%

14.4

11.0

3.2

0.2

0.0

Control(N=507)

%

16.2

12.6

3.2

0.4

0.0

Day 19 to 29

APR 125/80(N=482)

%

7.4

6.8

0.6

0.0

0.0

Control(N=495)

%

7.7

6.3

1.2

0.2

0.0


> ULN to 1.5 x ULN

> 1.5 to 3.0 x ULN

> 3.0 to 6.0 x ULN

> 6.0 x ULN


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)

%

14.4

11.0

3.2

0.2

0.0

Control(N=507)

%

16.2

12.6

3.2

0.4

0.0

Day 19 to 29

APR 125/80(N=482)

%

7.4

6.8

0.6

0.0

0.0

Control(N=495)

%

7.7

6.3

1.2

0.2

0.0


> ULN to 1.5 x ULN

> 1.5 to 3.0 x ULN

> 3.0 to 6.0 x ULN

> 6.0 x ULN


Phase III: Cycle 1

119

Neutropenia Severity by NCI CriteriaChemotherapy-Induced Toxicity

Any neutropenia < 2000/mm3

1500 < 2000/mm3

1000 < 1500/mm3

500 < 1000/mm3

< 500/mm3

Neutropenia Severity(NCI Criteria)

Day 6 to 8

APR 125/80(N=481)

%

6.6

3.1

2.3

1.0

0.2

Control(N=489)

%

4.9

2.5

1.4

0.4

0.6

Day 19 to 29

APR 125/80(N=462)

%

24.2

10.8

6.3

5.6

1.5

Control(N=477)

%

28.3

13.4

7.5

5.9

1.5

Phase III: Cycle 1

120

No evidence of differences in hematological toxicity

Chemotherapy-Induced ToxicityNeutropenia Severity by NCI Criteria

Any neutropenia < 2000/mm3

1500 < 2000/mm3

1000 < 1500/mm3

500 < 1000/mm3

< 500/mm3


Day 6 to 8

APR 125/80(N=481)

%

6.6

3.1

2.3

1.0

0.2

Control(N=489)

%

4.9

2.5

1.4

0.4

0.6

Day 19 to 29

APR 125/80(N=462)

%

24.2

10.8

6.3

5.6

1.5

Control(N=477)

%

28.3

13.4

7.5

5.9

1.5

Phase III: Cycle 1

121

APR 125/80(N=544)

%12.5

5.95.04.03.12.92.21.7

2.61.81.7

Control(N=550)

%10.5

5.15.83.52.53.52.41.3

2.71.31.8


InfectionsDehydrationNeutropeniaThrombocytopeniaAnemiaFeverLeukopeniaFebrile neutropenia

HypokalemiaHypertensionHyperglycemia

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)

%

74.1

30.1

15.0

0

Control(N=251)

%

74.5

28.3

13.5

0


Clinical adverse experiences

Prespecified AEs

Serious clinical AEs


Phase III: Cycle 1


AE Summary in Patients Receiving Concomitant Chemotherapy Metabolized by CYP3A4

124

Neutropenia in Patients Receiving Concomitant Chemotherapy Metabolized by CYP3A4


All patients < 2000 mm3

1500 < 2000 mm3

1000 < 1500 mm3

500 < 1000 mm3

< 500 mm3


Phase III: Cycle 1Day 6 to 8

APR 125/80(N=237)

%

6.7

3.0

2.5

0.8

0.4

Control(N=221)

%

6.4

2.7

2.3

0.5

0.9

Day 19 to 29

APR 125/80(N=234)

%

17.1

6.8

3.8

5.6

0.9

Control(N=222)

%

23.5

10.8

6.3

5.0

1.4

125

Day 6 to 8

APR 125/80(N=237)

%

6.7

3.0

2.5

0.8

0.4

Control(N=221)

%

6.4

2.7

2.3

0.5

0.9

Day 19 to 29

APR 125/80(N=234)

%

17.1

6.8

3.8

5.6

0.9

Control(N=222)

%

23.5

10.8

6.3

5.0

1.4

Neutropenia in Patients Receiving Concomitant Chemotherapy Metabolized by CYP3A4

All patients < 2000 mm3

1500 < 2000 mm3

1000 < 1500 mm3

500 < 1000 mm3

< 500 mm3


Phase III: Cycle 1

No change in hematological toxicity of chemotherapy metabolized by CYP3A4


126

Percent of Patients with Neutrophil Counts <1500/mm3

(Day 19 to 29)

0

5

10

15

20

25

30

All CYP3A4 Etoposide Vinorelbine Paclitaxel

APR 125/80

Control

Pe

rce

nt o

f Pa

tien

ts

N= 266 251

Individual Chemotherapies Metabolized by CYP3A4

101 96 82 76 52 58

Phase III: Cycle 1

127

0

5

10

15

20

25

30

All CYP3A4 Etoposide Vinorelbine Paclitaxel

APR 125/80

Control

N= 106 91 52 5882 76

Pe

rce

nt o

f Pa

tien

ts

Phase III: Cycle 1

266 251

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 DuringMultiple 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 6

413

337

250

184

148

APR 125/80N

438

347

255

189

152

ControlN

Phase III

Numbers of Patients Entered into Multiple Chemotherapy Cycles

132

Drug-related AEs

Serious Clinical AEs

Discontinuations due to AEs


Deaths


APR 125/80(N=413)

%

5.6

19.1

12.1

0.8

6.8

Control(N=438)

%

4.1

18.3

9.6

0.7

5.3

Phase III: Cycles 2-6

Safety Summary DuringMultiple Chemotherapy Cycles

133

Percent of Patients with Neutrophil Counts <1500/mm3

(Day 19 to 29)

0

5

10

15

20

25

30

1 2 3 4 5 6

APR 125/80

Control

Chemotherapy Cycle

Pe

rce

nt o

f Pa

tien

ts

N= 462 477 366 377 304 303 219 231 169 173 134 143

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


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


Aprepitant



5-HT3 receptor antagonists introduced into clinical practice in 1991– Quickly recognized as a therapeutic advance

138


Aprepitant



5-HT3 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 andVomiting After Highly Emetogenic Chemotherapy


90

80

70

60

50

400

Per

cent

of P

atie

nts

0 12 24 36 48 60 72 1081209684

100

90

80

70

60

50

400

Per

cent

of P

atie

nts

0 12 24 36 48 60 72 1081209684

Hours Hours

Time to First Emesis or Use of Rescue

ControlControl

N=260 N=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



Developed for use in conjunction with standard agents– Unprecedented efficacy

• Benefit sustained over multiple cycles


Aprepitant

142



Developed for use in conjunction with standard agents– Unprecedented efficacy

• Benefit sustained over multiple cycles

Very well tolerated– Across patient subgroups and concomitant therapies


Aprepitant

143

100

90

80

70

60

50

400

Per

cent

of P

atie

nts

0 12 24 36 48 60 72 1081209684

100

90

80

70

60

50

400

Per

cent

of P

atie

nts

0 12 24 36 48 60 72 1081209684


Hours Hours

APR 125/80 RegimenAPR 125/80 Regimen

Time to First Emesis or Use of Rescue TherapyMore Patients Benefit with Aprepitant

Control Control

APR N=260 Control N=260 APR N=260 Control N=263

144

Aprepitant: Conclusions

A new class of antiemetic therapy

– First NK1 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.

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1 FDA Advisory Committee March 6, 2003 Dennis M. Erb, PhD Regulatory Affairs Merck Research...

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