aprepitantaprepitant division of gastrointestinal and coagulation drug products division of...
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AprepitantAprepitantAprepitantAprepitant
Division of Gastrointestinal and CoagulationDivision of Gastrointestinal and CoagulationDrug ProductsDrug ProductsDivision of Gastrointestinal and CoagulationDivision of Gastrointestinal and CoagulationDrug ProductsDrug Products
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
2Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Gary Della’Zanna, D.O. M.Sc.Division of Gastrointestinal and CoagulationDivision of Gastrointestinal and CoagulationDrug ProductsDrug Products
Wen-Jen Chen, Ph.D.Division of Biometrics II
Venkat Jarugula, Ph.D.Division of Pharmaceutical Evaluation II
Gary Della’Zanna, D.O. M.Sc.Division of Gastrointestinal and CoagulationDivision of Gastrointestinal and CoagulationDrug ProductsDrug Products
Wen-Jen Chen, Ph.D.Division of Biometrics II
Venkat Jarugula, Ph.D.Division of Pharmaceutical Evaluation II
3Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
OverviewOverviewOverviewOverview
• Background
• Indication
• Efficacy
• Highly emetogenic chemotherapy
• Safety- 5-HT3 antagonists- Chemotherapy
• Background
• Indication
• Efficacy
• Highly emetogenic chemotherapy
• Safety- 5-HT3 antagonists- Chemotherapy
4Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
BackgroundBackgroundBackgroundBackground
• New Drug Application- September 27, 2002
• New molecular entity
• First in a new therapeutic class- NK1 - receptor antagonist
• Priority review
• New Drug Application- September 27, 2002
• New molecular entity
• First in a new therapeutic class- NK1 - receptor antagonist
• Priority review
5Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Proposed IndicationProposed IndicationProposed IndicationProposed Indication
• In combination with other antiemetics
• Prevention of acute and delayed nausea and vomiting
• Highly emetogenic chemotherapy
• In combination with other antiemetics
• Prevention of acute and delayed nausea and vomiting
• Highly emetogenic chemotherapy
6Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Efficacy ResultsEfficacy ResultsPhase IIIPhase III
Efficacy ResultsEfficacy ResultsPhase IIIPhase III
• Primary endpoint: Complete Response- overall phase (0 - 120 hours)
• Secondary endpoints:- Complete Response
–acute (0 - 24 hours)–delayed phase (25 - 120 hours)
- Nausea- Vomiting
• Primary endpoint: Complete Response- overall phase (0 - 120 hours)
• Secondary endpoints:- Complete Response
–acute (0 - 24 hours)–delayed phase (25 - 120 hours)
- Nausea- Vomiting
7Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Successful EndpointsSuccessful EndpointsSuccessful EndpointsSuccessful Endpoints
• Primary endpoint: Complete Response- overall phase
• Secondary endpoints:- Complete Response
- acute, delayed phases
- Vomiting- overall, acute, delayed phases
• Primary endpoint: Complete Response- overall phase
• Secondary endpoints:- Complete Response
- acute, delayed phases
- Vomiting- overall, acute, delayed phases
8Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
No NauseaNo Nausea(Secondary Endpoint)(Secondary Endpoint)
No NauseaNo Nausea(Secondary Endpoint)(Secondary Endpoint)
Nausea Aprepitant Regimenn/N (%)
Standard Therapyn/N (%)
No Nausea (maximum nausea VAS<5 )Study 052 Overall Phase Acute Phase Delayed Phase
122 /257 (48) (p= 0.48) 185/256 (72) (p= 0.48) 132/259 (51) (p= 0.46)
115 / 260 (44)179/ 259 (69)124 / 260 (48)
Study 054 Overall Phase Acute Phase Delayed Phase
127 / 260 (49) (p= 0.021) 176 / 260 (68) (p= 0.71) 137 / 260 (53) (p= 0.003)
102 / 263 (39)174 / 263 (66)105 / 263 (40)
No Significant Nausea (maximum nausea VAS<25 )Study 052 Overall Phase Acute Phase Delayed Phase
188 / 257 (73) (p= 0.09) 232 /256 (91) (p= 0.16) 195 / 259 (75) (p= 0.09)
171 / 259 (66)224 / 259 (87)178 /260 (69)
Study 054 Overall Phase Acute Phase Delayed Phase
185 / 260 (71) (p= 0.08) 235 / 260 (90) (p= 0.01) 189 / 260 (73) (p= 0.07)
168 / 263 (64)218 / 263 (82)172 / 263 (65)
Nausea Aprepitant Regimenn/N (%)
Standard Therapyn/N (%)
No Nausea (maximum nausea VAS<5 )Study 052 Overall Phase Acute Phase Delayed Phase
122 /257 (48) (p= 0.48) 185/256 (72) (p= 0.48) 132/259 (51) (p= 0.46)
115 / 260 (44)179/ 259 (69)124 / 260 (48)
Study 054 Overall Phase Acute Phase Delayed Phase
127 / 260 (49) (p= 0.021) 176 / 260 (68) (p= 0.71) 137 / 260 (53) (p= 0.003)
102 / 263 (39)174 / 263 (66)105 / 263 (40)
No Significant Nausea (maximum nausea VAS<25 )Study 052 Overall Phase Acute Phase Delayed Phase
188 / 257 (73) (p= 0.09) 232 /256 (91) (p= 0.16) 195 / 259 (75) (p= 0.09)
171 / 259 (66)224 / 259 (87)178 /260 (69)
Study 054 Overall Phase Acute Phase Delayed Phase
185 / 260 (71) (p= 0.08) 235 / 260 (90) (p= 0.01) 189 / 260 (73) (p= 0.07)
168 / 263 (64)218 / 263 (82)172 / 263 (65)
9Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Nausea EndpointsNausea EndpointsNausea EndpointsNausea Endpoints
• Use of rescue therapy:
- 28% standard therapy - 18% aprepitant group
• Time to analysis- first use of rescue therapy later in
aprepitant group
• Use of rescue therapy:
- 28% standard therapy - 18% aprepitant group
• Time to analysis- first use of rescue therapy later in
aprepitant group
10Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Highly Emetogenic Highly Emetogenic CisplatinCisplatin
Highly Emetogenic Highly Emetogenic CisplatinCisplatin
• Ondansetron approval- Cisplatin dose >100 mg/m2
• Protocol dose 70 mg/m2 Cisplatin- 20% of patients <70 mg/m2 Cisplatin
• >50 mg/m2 Cisplatin (high or moderate)
• Ondansetron approval- Cisplatin dose >100 mg/m2
• Protocol dose 70 mg/m2 Cisplatin- 20% of patients <70 mg/m2 Cisplatin
• >50 mg/m2 Cisplatin (high or moderate)
11Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Drug-Drug InteractionDrug-Drug InteractionDrug-Drug InteractionDrug-Drug Interaction
• Cytochrome P450 3A4 (CPY3A4)- Substrate- Moderate inhibitor- Inducer
• Cytochrome P450 2C9 (CYP2C9)- Inducer
• Cytochrome P450 3A4 (CPY3A4)- Substrate- Moderate inhibitor- Inducer
• Cytochrome P450 2C9 (CYP2C9)- Inducer
12Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Treatment RegimenTreatment Regimen
5-HT5-HT33 Antagonists Antagonists
Treatment RegimenTreatment Regimen
5-HT5-HT33 Antagonists Antagonists
• Ondansetron and granisetron- metabolized by CYP3A4- first pass metabolism effect
• Dolasetron- metabolized by carbonyl reductase- no exposure data- QTc and cardiac warnings
• Ondansetron and granisetron- metabolized by CYP3A4- first pass metabolism effect
• Dolasetron- metabolized by carbonyl reductase- no exposure data- QTc and cardiac warnings
13Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Drug-Drug InteractionDrug-Drug InteractionDrug-Drug InteractionDrug-Drug Interaction
• Chemotherapy- CYP3A4
• Docetaxel study- 5 patients- no effect on PK
• Dexamethasone-metabolized by CYP3A4- 50% dose reduction
• Chemotherapy- CYP3A4
• Docetaxel study- 5 patients- no effect on PK
• Dexamethasone-metabolized by CYP3A4- 50% dose reduction
14Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
SafetySafetyChemotherapy (CYP3A4)Chemotherapy (CYP3A4)
SafetySafetyChemotherapy (CYP3A4)Chemotherapy (CYP3A4)
ExposureExposure
ChemotherapyAprepitantRegimen(N=547)
StandardTherapy(N=552)
n (%) n (%)Any Chemotherapy 520 95% 530 96%
Chemotherapy (CYP3A4) Imatinib Irinotecan Ifosfamide Vincristine Vinblastine Docetaxel Paclitaxel Vinorelbine Etoposide
2660022
11115284
106
49%0%0%
0.4%0.4%2%2%
10%15%19%
2510110
1214588092
46%0%
0.2%0.2%0%2%3%
11%15%17%
(Ref: Modified Table E-60 ISS.pdf)
15Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Serious Adverse Serious Adverse CYP3A4 ChemotherapyCYP3A4 Chemotherapy
Serious Adverse Serious Adverse CYP3A4 ChemotherapyCYP3A4 ChemotherapyPhase III Studies (Cycle 1)Phase III Studies (Cycle 1)
AprepitantRegimen(N=266)
StandardTherapy(N=251)
Chemotherapy(CYP3A4)
n (%) n (%)Serious Adverse Events Septic shock Sepsis Upper respiratory infection
40311
15%1%
0.4%0.4%
34000
14%0%0%0%
Neutropenia 8 3% 2 1%
(Ref: Modified Table E-113 ISS.pdf)
16Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Serious Adverse ExperiencesSerious Adverse ExperiencesCYP3A4 CYP3A4
Serious Adverse ExperiencesSerious Adverse ExperiencesCYP3A4 CYP3A4
AprepitantRegimen(N=106)
StandardTherapy(N=91)
EtoposideCycle 1
n (%) n (%)Serious Adverse Events 16 15% 14 15%Serious Hematologic Adverse Events Neutropenia Febrile neutropenia Thrombocytopenia Anemia
94411
9%4%4%1%1%
30200
3%0%2%0%0%
Any Infection Adverse Events 19 18% 8 9%Serious Infection Adverse Events Fever Septic shock Upper respiratory infection Pneumonia
1111
1%1%1%1%
0000
0%0%0%0%
(Ref: Modified Table E-127 ISS.pdf)The same patient may appear in different categories.
17Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Serious Adverse ExperiencesSerious Adverse ExperiencesCYP3A4 CYP3A4
Serious Adverse ExperiencesSerious Adverse ExperiencesCYP3A4 CYP3A4
AprepitantRegimen(N=82)
StandardTherapy(N=76)
VinorelbineCycle 1
n (%) n (%)Serious Adverse Events Septic shock Sepsis Pneumonia Infection
132110
16%2%1%1%0%
80011
11%0%0%1%1%
Serious Respiratory Adverse Events 6 7% 1 1%
(Ref: Modified Table E-133 ISS.pdf)The same patient may appear in different categories.
18Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
VinorelbineVinorelbineDeathsDeaths
VinorelbineVinorelbineDeathsDeaths
• Aprepitant: 7 deaths (9%)
- 4 respiratory insufficiency- 2 septic shock- 1 cardiopulmonary arrest
• Standard Therapy: 2 deaths (3%)
- 1 pulmonary emboli- 1 unknown
• Aprepitant: 7 deaths (9%)
- 4 respiratory insufficiency- 2 septic shock- 1 cardiopulmonary arrest
• Standard Therapy: 2 deaths (3%)
- 1 pulmonary emboli- 1 unknown
19Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Serious Adverse ExperiencesSerious Adverse ExperiencesCYP3A4 CYP3A4
Serious Adverse ExperiencesSerious Adverse ExperiencesCYP3A4 CYP3A4
AprepitantRegimen(N=52)
StandardTherapy(N=58)
PaclitaxelCycle 1
n (%) n (%)Serious Adverse Events Febrile neutropenia Pneumonia
711
14%2%2%
611
10%2%2%
(Ref: Modified Table E-135 ISS.pdf)The same patient may appear in different categories.
20Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
SafetySafetyChemotherapy (CYP3A4)Chemotherapy (CYP3A4)
SafetySafetyChemotherapy (CYP3A4)Chemotherapy (CYP3A4)
(limited or no exposure)(limited or no exposure)
Chemotherapy(CYP3A4)
AprepitantRegimen(N=547)
StandardTherapy(N=552)
n (%) n (%)ImatinibIrinotecanIfosfamideVincristineVinblastineDocetaxel
0022
1111
0%0%
0.4%0.4%2%2%
0110
1214
0%0.2%0.2%0%2%3%
21Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Precaution SectionPrecaution SectionPrecaution SectionPrecaution Section
“EMEND should be used with caution in patients receiving concomitant medicinal products that are primarily metabolized through CYP3A4; some chemotherapy agents are metabolized by CYP3A4.”
“EMEND should be used with caution in patients receiving concomitant medicinal products that are primarily metabolized through CYP3A4; some chemotherapy agents are metabolized by CYP3A4.”