FDA ACM PowerPoint Template

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Key Anti-emetic Milestones
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Delayed emesis randomized trialDouble-blind
trial with cisplatin (120 mg/m2)
All patients received i.v. metoclopramide,
dexamethasone, and lorazepam day 1
Kris et al, J Clin Oncol 1989 7 108
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Delayed emesis randomized trial Multi-center
trial with 322 patients receiving cisplatin
All patients received ondansetron 8 mg i.v. and
dexamethasone 20 mg i.v. day 1 for acute emesis
Italian Group, J Clin Oncol 1997 15 124
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Incidence of emesis Perception vs
realityModerately emetogenic chemotherapy
All patients received 5HT3 antagonist 84 also
received steroid
Grunberg et al, Proc ASCO 2002 22 996
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Aprepitant Blocks Brain NK1 Receptorsin Humans
Mean ( SD) Plasma Trough Concentrations of the
Aprepitant 3-Day Regimen
Binding of PET tracer to NK1 receptors prior to
aprepitant dosing
Brain NK1 Receptor Occupancy ()
Blockade of NK1 receptorsafter aprepitant dosing
Aprepitant Plasma Trough Concentration (ng/mL)
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Aprepitant Protects Against Chemotherapy-Induced
Emesis in Ferrets
Aprepitant(1 mg/kg/day)
Aprepitant(2 mg/kg/day)
Vehicle
300
240
180
Retches and Vomits
120
60
0
0
24
48
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Cisplatin
Profile similar to humans (acute delayed phases)
Acute delayed effects blocked by aprepitant
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Aprepitant

• 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.

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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

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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

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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

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Aprepitant

• 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.

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Aprepitant as Monotherapy
Protocol 004
Day 1
Aprepitant I.V. prodrug60 or 100 mg Ondansetron
I.V.32 mg
Eur J Cancer 37835-842, 2001
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Aprepitant as Monotherapy
Complete Response Acute and Delayed Phases
Protocol 004
48
48
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N
30
23
29
23
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Aprepitant as Monotherapy
Complete Response Acute and Delayed Phases
Protocol 004
48
48
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HistoricalData(Untreated)
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N
30
23
29
23
Cancer 782193-2198, 1996
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Aprepitant as Monotherapy
Conclusions
Protocol 004

• 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

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Aprepitant

• 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.

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Aprepitant Regimen Study
Design Features
Protocol 007

• 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.

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Aprepitant Regimen Study
Primary Treatment Groups
Protocol 007
Group
Day 1
Days 2 to 5
G
D
A
A
Aprepitant 5-Day
400
300
Aprepitant 1-Day
P
400
Control
P
P
Ggranisetron Ddexamethasone Aaprepitant
Pplacebo
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Aprepitant Regimen Study
Complete Response Acute and Delayed Phases
Protocol 007
83
77
Aprepitant 5-Day
Aprepitant 1-Day
57
52
Control
43
16
N
53
50
54
51
54
51
N Engl J Med 340 190-5 1999
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Aprepitant Regimen Study
Conclusions
Protocol 007

• 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

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Aprepitant

• 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.

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

• 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 regimen125 mg on Day 1
followed by 80 mg on Days 2 and 3
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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

Two large multinational studies, both with
multiple cycle extensions,in patients receiving
high-dose cisplatin chemotherapy
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Phase III Studies
Design Features
Protocols 052 and 054

• Aprepitant regimen refinements
• 3-day aprepitant dosing
• Dexamethasone dose reduced to provide plasma
  exposure similar to control

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Phase III Studies
Primary Treatment Groups
Protocols 052 and 054
Group
Day 4
Day 1
Days 2-3
O
D
A
D
D
A
8
12
8
Aprepitant
P
P
16
20
16
Control
Oondansetron Ddexamethasone Aaprepitant
Pplacebo
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Phase III Studies
Design Features
Protocols 052 and 054

• 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 lt1500/mm3 and WBC lt3000/mm3
• Bilirubin gt1.5 x ULN Creatinine gt1.5 x ULN
• Concomitant or very recent use of
• Strong CYP3A4 inhibitors
• CYP3A4 inducers

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Phase III Studies
Patient Demographics
Protocols 052 and 054 Combined
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Phase III Studies
Primary Cancer Diagnoses
Protocols 052 and 054 Combined
Aprepitant (N549)
Control (N554)
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Phase III Studies
Concomitant Chemotherapy
Protocols 052 and 054 Combined
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Phase III Studies Cycle 1
Primary Endpoint Overall Complete Response
Protocol 052
plt0.001
73
52
N
260
260
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Phase III Studies Cycle 1
Primary Endpoint Overall Complete Response
Protocol 054
Protocol 052
plt0.001
73
63
52
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N
260
260
263
260
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Phase III Studies Cycle 1
Complete Response Acute and Delayed Phases
Protocol 052
Protocol 054
plt0.001
plt0.001
plt0.001
plt0.001
89
83
78
75
68
68
56
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N
259
260
260
260
260
263
261
263
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Phase III Studies Cycle 1
Time to First Emesis or Rescue
APR N260 Control N260
APR N260 Control N263
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Phase III Studies Cycle 1
Components of Primary Endpoint Overall
Protocol 052
Protocol 054
plt0.01
plt0.01
plt0.01
plt0.01
82
81
78
73
71
66
55
45
N
260
260
260
263
260
260
260
263
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Phase III Studies Cycle 1
No Nausea and No Significant Nausea Overall
Protocols 052 and 054 Combined
72
65
48
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N
517
523
522
517
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Phase III Studies Cycle 1
Other Prespecified Endpoints

• 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

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Phase III Studies Cycle 1
Concomitant Emetogenic Chemotherapy
(Cyclophosphamide and/or Doxorubicin)
Protocols 052 and 054 Combined Overall(Post-hoc
Analysis)
plt0.001
Aprepitant (N70)
Control (N72)
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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 (plt0.001)
• 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

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Phase III Studies Multiple Cycles
Protocols 052 and 054

• 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?

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Phase III Studies Multiple Cycles
Observed Proportion of Patients without Emesis
and without Significant Nausea
Protocols 052 and 054 Combined
N 349 270 184 117 83N 393 278 180 111 72
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Phase III Studies Multiple Cycles
Proportion of Patients Symptom Free by Cycle
Protocols 052 and 054 Combined
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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
  

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Clinical Development Program
Number of Patients Receiving Aprepitant
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Clinical Adverse Experience Summary
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Most Common Serious Clinical AEs
(Incidence ?0.7)
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Many Patients Still Experience Nausea
andVomiting After Highly Emetogenic Chemotherapy
Time to First Emesis or Use of Rescue
Patients treated with best therapy available today
Control
Control
N260
N263
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More Patients Benefit with Aprepitant
Time to First Emesis or Use of Rescue Therapy
Protocol 052
Protocol 054
APR 125/80 Regimen
APR 125/80 Regimen
Control
Control
Hours
Hours
APR N260 Control N260
APR N260 Control N263