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Efficacy and Safety ofEfficacy and Safety of3 Different IV Doses of Palonosetron for 3 Different IV Doses of Palonosetron for the Prevention of PONV in the Outpatient the Prevention of PONV in the Outpatient (Study 1) and Inpatient (Study 2) Settings(Study 1) and Inpatient (Study 2) Settings

Study 1 (Outpatients—US): Candiotti KA, et al. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo for preventing postoperative nausea and vomiting. Anesth Analg. 2008;107:445-451. Study 2 (Inpatients—Europe): Kovac A, et al. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesth Analg. 2008;107:439-444.

Keith Candiotti, MDKeith Candiotti, MDDepartments of Anesthesiology, Perioperative Medicine and Pain ManagementDepartments of Anesthesiology, Perioperative Medicine and Pain Management

University of MiamiUniversity of MiamiMiami, FloridaMiami, Florida

American Society of Anesthesiologists Annual MeetingAmerican Society of Anesthesiologists Annual MeetingOctober 20, 2008October 20, 2008

Palonosetron PONV Trials

• Study funded by MGI/Eisai • Study presented on behalf of all investigators involved in both

trials.

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Phase 3 Study Designs

Study 1: Outpatients (US)

Study 2: Inpatients (Europe)

Patients

Randomization

Stratification

Placebo vs PALO dosage

Interactive voice response system

PlaceboPALO PALO

0.025 mg/kg IV0.025 mg/kg IVPALO PALO

0.050 mg/kg IV0.050 mg/kg IVPALO PALO

0.075 mg/kg IV0.075 mg/kg IV

(1) n = 135(2) n = 136

(1) n = 136(1) n = 136(2) n = 136(2) n = 136

(1) n = 137(1) n = 137(2) n = 137(2) n = 137

(1) n = 138(1) n = 138(2) n = 135(2) n = 135

M/F pts undergoing elective laparoscopic abdominal or

gynecological surgery

Female pts undergoing elective gynecological or

breast surgery

Hx of PONV/motion sickness Non-smoking status Gender

Hx of PONV/motion sickness Non-smoking status Type of surgery

Two Randomized, Stratified, Double-blind, Parallel-group, Balanced, Placebo-controlled Multicenter Studies

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Study 1: Outpatients (US) Study 2: Inpatients (Europe)

Palonosetron (IV) Palonosetron (IV)

Placebo 0.025 mg/kg 0.050 mg/kg

0.075 mg/kg Placebo 0.025 mg/kg

0.050 mg/kg

0.075 mg/kg

(n=135) (n=136) (n=137) (n=138) (n=136) (n=136) (n=137) (n=135)

Gender (female) 96 96 96 96 100 100 100 100

Mean age (years) 37 39 37 38 50 48 48 50

Hx of PONV/motion sickness

64 63 66 66 46 47 47 47

Smoking status (non-smoker)

86 85 85 85 85 86 85 84

Alcohol consumption (no)

50 54 58 57 38 33 35 33

Gynecologic laparoscopy

78 75 77 69 -- -- -- --

Abdominal laparoscopy

22 25 23 31 -- -- -- --

Gynecologic surgery -- -- -- -- 84 81 84 84

Breast surgery -- -- -- -- 16 19 16 16

ASA status I 42 52 50 52 36 48 45 50

ASA status II 53 43 45 45 61 49 52 48

ASA status III 5 5 4 3 3 3 3 2

Patient Demographics

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(% of Patients) Placebo

PALO0.025 mg IV PALO

0.050 mg IVPALO

0.075 mg IV

Study 1: Outpatients (US)

Male + hx PONV + non-smoker 4 4 4 4

Female + hx PONV + non-smoker 47 44 47 46

Female + hx PONV + smoker 13 15 15 15

Female + no hx PONV + non-smoker 36 37 34 34

Study 2: Inpatients (Europe)

Hx no PONV/motion sickness + non-smoker 54 53 53 53

Hx PONV/motion sickness + non-smoker 32 33 33 31

Hx PONV/motion sickness + smoker 15 14 15 16

Stratification: PONV Risk Factors

There were no statistically significant differences in PONV risk factors in patients across all treatment groups.There were no statistically significant differences in PONV risk factors in patients across all treatment groups.

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Anesthesia

• Premeds– Midazolam 1-2 mg IV or fentanyl 50-100 g IV as needed

• Induction – Propofol 2.0-2.5 mg/kg IV or thiopental 2.5-5.0 mg/kg IV; methohexital 1.5-3.0 mg/kg

IV– Succinylcholine 1-1.5 mg/kg IV; rocuronium 0.4-0.6 mg/kg IV, cisatracuronium 0.15-0.3

mg/kg IV, vecuronium 0.05-0.1 mg/kg IV, or mivacurium 0.015-0.25 mg/kg• Maintenance

– N2O 50-70% end tidal concentration, O2 30-50% end tidal concentration– Rocuronium, cisatracuronium or vecuronium titrated as needed for muscle relaxation

• Inhalation agent– Isoflurane 0.4-3%, desflurane 2-6% or sevoflurane 1-3% end tidal concentration,

titrated as needed• Intraoperative opioid

– Fentanyl 2-10 g/kg IV or sufentanil 0.2-0.6 g/kg, titrated as needed• Muscle relaxant reversal

– Neostigmine <or= 2.5 mg IV and glycopyrrolate 0.4-0.8 mg IV as per usual clinical practice

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Study Endpoints

Primary endpoint for both studies• Complete response* (CR) at 0-24 h and 24-72 h

(no emetic episodes and no rescue medication)

Secondary endpoints for both studies†

• CR at additional time intervals• Complete control (CR plus no more than mild nausea)• Percentage of pts experiencing emesis• Number of emetic episodes • Severity of nausea • Time to treatment failure • Patient functional interference (Study 1 only)

* P value adjusted for 3-dose comparison vs placebo [P=0.05/3=0.0166]† Measured at 2, 6, 24, 48, and 72 h (all tested at P<0.05)

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Complete Response(No Emesis, No Use of Rescue Medication)

41

24

36

52

3633

44

32

46

56

4439

47

37

47

61

454349

39

56

70

52

26

0

10

20

30

40

50

60

70

80

90

100

0-24 h 24-72 h 0-72 h 0-24 h 24-72 h 0-72 h

* Statistically significant at P <0.0166 (for primary analyses); analysis by logistic regression.†Statistically significant at P <0.05 (for secondary analyses); analysis by logistic regression.

*

† †

Primary endpointsPrimary endpoints

% o

f Pat

ient

s †

* *

*

Study 1 Study 2

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Percentage of Patients With No Treatment Failure

P = 0.0185 for palonosetron 0.075 mg vs placebo.

Time to treatment failure: time to first emetic episode and/or to first use of rescue meds.Patients who did not have treatment failure were censored at 72 hours.

% o

f Pat

ient

s W

ith N

o Tr

eatm

ent F

ailu

re

P = 0.0035 for palonosetron 0.075 mg vs placebo.

Study 1: Outpatients (US) Study 2: Inpatients (Europe)

0 20 40 60 80

Hours

0

20

40

60

80

100

PALO 0.075 mg

Placebo

20

40

60

80

100

0 20 40 60 80

Hours

0

PALO 0.075 mg

Placebo

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Nausea Severity

* Statistically significant vs placebo at P<0.05 (Cochran-Mantel-Haenszel).

0-24 h 0-72 h

0

20

40

60

80

100

Placebo PALO0.075 mg

Placebo PALO0.075 mg

% o

f Pat

ient

s Ev

alua

ble

for N

ause

a

SevereModerateMildNone

* *

Placebo PALO0.075 mg

0-24 h

Placebo PALO0.075 mg

0-72 h

Study 1 Study 2

**

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Percentage of Patients Without Functional Interference* (Study 1 Only)

* Functional interference due to nausea and vomiting was measured utilizing a Modified Osoba Nausea and Emesis Module. Measurements were based on a 4-point Likert scale: 1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much. The percentages provided above represent those patients with a score of 1 on any individual subscale.† P<0.05 (Mann-Whitney test for pair-wise comparisons of palonosetron vs placebo).

6459 62

5757

7365

7366

44

0

20

40

60

80

100

Appetite Sleep Physical activities Social life Enjoyment of life

% o

f Pat

ient

s W

ithou

t Int

erfe

renc

e

0-24 h

Placebo PALO 0.075 mg

††

†

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Study 1: Outpatients (US)Adverse Events: n, %

Placebo(n=137)

PALO0.025 mg IV

(n=136)

PALO0.050 mg IV

(n=138)

PALO0.075 mg IV

(n=136)

Total treatment-related AEs 13 (10%) 12 (9%) 15 (11%) 9 (7%)

Headache 6 (4%) 5 (4%) 9 (7%) 4 (3%)

Constipation 4 (3%) 2 (2%) 6 (4%) 4 (3%)

Study 2: Inpatients (Europe)Adverse Events: n, % (n=136) (n=136) (n=137) (n=135)

Total treatment-related AEs 45 (27%) 48 (29%) 49 (29%) 48 (29%)

Bradycardia 15 (9%) 16 (10%) 14 (8%) 13 (8%)

ECG QTc prolonged 11 (7%) 10 (6%) 14 (8%) 15 (9%)

Most Frequent Treatment-related Adverse Events

There were no statistically significant differences among treatment groups.There were no statistically significant differences among treatment groups.

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Changes in QTc

Study 1: Outpatients (US)

Mean change from baseline in QTc by Fridericia, msec

Placebo

(n=137)

PALO

0.025 mg IV

(n=136)

PALO

0.050 mg IV

(n=138)

PALO

0.075 mg IV

(n=136)

15 minutes 18 15 13 16

6 hours 9 10 11 11

Study 2: Inpatients (Europe)

Mean change from baseline in QTc by Fridericia, msec (n=168) (n=168) (n=169) (n=168)

15 minutes 20 24 22 21

6 hours 10 11 13 11

ECGs: In triplicate at baseline (screening) and as a single recording at 15 minutes and at 3-6 hours (Study 1) and 6 hours (Study 2) post-study drug administration. Independent blinded cardiologist reading with manual QT interval measurement.

Results: At 15 minutes post-dose, QT prolongation was consistent across all treatment groups. At 3 to 6 hours post-dose (Study 1) and at 6 hours post-dose (Study 2), QTc intervals remained slightly increased from baseline values; however, they tended to normalize compared with the 15-minute results.

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Overall Summary

• Dose-response trend observed with increasing doses of PALO• A single IV dose of PALO (0.075 mg) :

• was effective in reducing PONV in both the inpatient and outpatient settings

• was superior to placebo (0-24 hours) for the primary endpoint (CR)• reduced the severity of nausea compared with placebo

• Adverse events: no dose relationship, no differences vs placebo, consistent with those expected for the 5-HT3 receptor antagonist class

• These benefits may:• distinguish PALO as unique among the 5-HT3 receptor antagonists• address important unmet needs, including nausea control