Effect of Alvimopan on Gastrointestinal Recovery, Length of Hospital Stay, and

Postoperative Ileus-Related Morbidity in Patients Undergoing Bowel Resection for

Colon or Rectal Cancer

James L. Weese, MD1; Wei Du, PhD2; Lee Techner, DPM2

1School of Osteopathic Medicine, University of Medicine and Dentistry

of New Jersey, Stratford, NJ; 2Adolor Corporation, Exton, PA

June 1 - 5, 2007Chicago, IL

Bowel Resection (BR)

More than 250,000 patients undergo BR in the US annually1

Colorectal cancer (CRC) is a common reason for BR2

Surgical treatment plays a critical role in the management of progressive and aggressive forms of colorectal disease and is a primary means of curing CRC

Recovery from BR can be impeded by postoperative ileus (POI)

1HCUPnet. 2004. http://hcup.ahrq.gov/HCUPnet.jsp. Accessed April 6, 2007; 2Rao KV, Goodin S. J Am Pharm Assoc (Wash). 2001;41:585-595.

POI

Temporary cessation of gastrointestinal (GI) functionOccurs to some degree after all BRs1

Characterized by2,3

Inability to tolerate solid food Delayed passage of flatus or stool Abdominal pain and distension Nausea and vomiting

Exacerbated by opioid analgesics after BR4

Associated with increased morbidity, prolonged hospital stay/readmission, and hospital costs5,6

1Delaney CP. Neurogastroenterol Motil. 2004;16(suppl 2):61-66; 2Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493; 3Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:121-132; 4Kehlet H, Holte K. Am J Surg. 2001;182:3S-10S; 5Bauer AJ, et al. Neurogastroenterol Motil. 2004;16(suppl 2):54-60; 6Kariv Y, et al. Am J Surg. 2006;191:364-371.

Alvimopan

Investigational, peripherally acting mu-opioid receptor (PAM-OR) antagonistDemonstrated efficacy in randomized, double-blind, placebo-controlled phase III trials1-6 Accelerated GI recovery Reduced POI-related morbidity (POM), time to hospital

discharge order (DCO) written, and length of hospital stay (LOS)

Dose not compromise centrally mediated opioid-based analgesia1-6

1Wolff BG, et al. Ann Surg. 2004;240:728-734; 2Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125; 3Viscusi ER, et al. Surg Endosc. 2006;20:64-70; 4Ludwig K, et al. Presented at: 92nd Annual Clinical Congress of the American College of Surgeons; Oct. 8-12, 2006; Chicago, IL. Poster SE120; 5Wolff BG, et al. J Am Coll Surg. 2007;204:609-616. 6Delaney CP, et al. Ann Surg. 2007;245:355-363.

Objective

To examine the efficacy and safety of alvimopan in patients who underwent BR for CRC in alvimopan phase III North American trials in a post hoc analysis1-4

1Wolff BG, et al. Ann Surg. 2004;240:728-734; 2Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125; 3Viscusi ER, et al Surg Endosc. 2006;20:64-70; 4Ludwig K, et al. Presented at: 92nd Annual Clinical Congress of the American College of Surgeons; Oct. 8-12, 2006; Chicago, IL. Poster SE120.

Overall Study Design

IV-PCA = Intravenous patient-controlled analgesia.*Administered orally 0.5 to 5 hours before surgery, then twice daily until hospital discharge or for a maximum of 7 days while hospitalized; †Patients who underwent BR for any reason; ‡Patients who underwent BR for CRC.

PatientsPatientsundergoing undergoing

BR, BR, scheduled for scheduled for

pain pain management management with opioid-with opioid-

based IV-PCAbased IV-PCA

4 pooled, double-blind, multicenter, placebo-controlled, phase III trials

Alvimopan 12 mg* (n = 714†, 374‡)

Placebo* (n = 695†, 349‡)

Dosing*Dosing* Hospital Hospital dischargedischarge

Standardized Accelerated Postoperative Care Pathway

Patients in both the alvimopan 12 mg and placebo groups were managed with a standardized accelerated postoperative care pathway to facilitate GI recovery Nasogastric (NGT) tube, if used, was removed

by noon on postoperative day (POD) 1 Patients were offered liquids and encouraged to

ambulate on POD 1 Solid food was offered on POD 2

Time to GI Recovery Endpoint

GI-2 recovery

Upper: tolerance of solid food

and

Lower: first bowel movement

Methods and Assessments

Assessments Upper and lower GI recovery (GI-2) DCO written Postoperative LOS POM (postoperative NGT insertion or complications

of POI)Safety was assessed by adverse event (AE) monitoring (≤ 14 days after the last dose of study medication) Treatment-emergent adverse events (TEAEs) were

defined as any AEs occurring after the first dose of and ≤ 7 days of the last dose of study medication

Statistical Analysis

Pooled subset analysis of all patients who underwent BR for CRC in 4 phase III trials 1-4

Time-to-event data presented using hazard ratios (HRs) and Kaplan-Meier means Wald chi-square test (calculate nominal P values)

Postoperative LOS endpoints and TEAEs Fisher’s exact test (calculate P values)

All statistical analyses were performed using SAS® software version 9.1 (SAS Institute, Cary, NC)

1Wolff BG, et al. Ann Surg. 2004;240:728-734; 2Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125; 3Viscusi ER, et al. Surg Endosc. 2006;20:64-70; 4Ludwig K, et al. Presented at: 92nd Annual Clinical Congress of the American College of Surgeons; Oct. 8-12, 2006; Chicago, IL. Poster SE120.

Baseline Demographics and Surgery Characteristics

Placebo (n = 349)

Alvimopan 12 mg(n = 374)

Age, yearsMean ± SD≥ 65 years, n (%)

64.8 ± 12.2188 (53.9)

65.2 ± 12.2201 (53.7)

Race, n (%)White 287 (82.2) 298 (79.7)

Female, n (%) 162 (46.4) 197 (52.7)

BMIMean ± SD, kg/m2 28.6 ± 6.2 27.9 ± 6.2

Surgery type, n (%)Large BRSmall BR

347 (99.4) 2 (0.6)

373 (99.7) 1 (0.3)

Based on modified intent-to-treat population.SD = Standard deviation; BMI = Body mass index; BR = Bowel resection.

120.8

124.5

102.0

105.2

0 20 40 60 80 100 120 140

BR for anyreason

BR for CRC

Time to GI-2 recovery, mean hours

Alvimopan 12 mg

Placebo

Efficacy Results: GI-Recovery

BR for CRC (HR = 1.4, P < 0.001); BR for any reason (HR = 1.5, P < 0.001).

142.9

147.7

124.9

128.4

0 20 40 60 80 100 120 140 160

BR for anyreason

BR for CRC

Time to GI-2 recovery, mean hours

Alvimopan 12 mg

Placebo

Efficacy Results: DCO Written

BR for CRC (HR = 1.5, P < 0.001); BR for any reason (HR = 1.4, P < 0.001).

0

10

20

30

40

50

60

70

80

90

100

2 3 4 5 6 7 8 9 10 11 12 13 14 15

Postoperative day

Pati

ents

wit

h D

CO

wri

tten

, %

Placebo

Alvimopan 12 mg

Efficacy Results: DCO Written

*

** *

* * * *† † †

BR for CRC (*P < 0.001; †P < 0.05).

7.1

6.6

5.65.7

0

1

2

3

4

5

6

7

8

BR for CRC BR for any reason

Len

gth

of h

osp

ital st

ay, days

Placebo

Alvimopan 12 mg

Efficacy Results: LOS

BR for CRC (*P < 0.001); BR for any reason (*P < 0.001).

* *

18.9

13.2

10.3

8.0

2.3

7.8 7.5

2.9 2.40.8

02468

101214161820

Overallpostoperative

morbidity

PostoperativeNGT insertion

Complicationsof POI

POI resultingin prolonged

stay

POI resultingin readmission

Pati

en

ts, %

Placebo

Alvimopan 12 mg

POI-Related Morbidity

BR for CRC (*P ≤ 0.001; †P ≤ 0.05).

* †

* *

TEAEs Reported in > 10% of Patients Undergoing BR for CRC

Placebo (n = 349)

Alvimopan 12 mg(n =374)

Nausea 228 (65.3) 205 (54.8)*

Vomiting 95 (27.2) 71 (19.0)*

Hypertension 60 (17.2) 63 (16.8)

Abdominal distension 63 (18.1) 61 (16.3)

Hypokalemia 40 (11.5) 46 (12.3)

Hypotension 47 (13.5) 42 (11.2)

Headache 18 (5.2) 39 (10.4)

Pyrexia 64 (18.3) 38 (10.2)*

Insomnia 37 (10.6) 35 (9.4)

Tachycardia 46 (13.2) 33 (8.8)

Pruritus 40 (11.5) 33 (8.8)

Postoperative ileus 53 (15.2) 32 (8.6)*

Diarrhea 48 (13.8) 29 (7.8)*

Based on safety population.*P < 0.05.

20.6

10.9

9.2

7.7

3.72.3

0.6 1.1 0.6 1.1

6.4

0.3 0.3

19.6

9.8

2.21.0

0.3 0.2

3.7

0

5

10

15

20

25

1 2 3 4 5 6 7 8 9 10

Postoperative day

Inci

den

ce o

f nau

sea,

% Placebo

Alvimopan 12 mg

Incidence of Nausea

BR for CRC, overall nausea (P < 0.05); nausea on POD 4 (†P ≤ 0.05).

†

4.0

6.0

7.2

6.3

3.4

0.9 0.9 0.9

0.30.6

4.2

0.3 0.2

2.5

0.20.5

0.3

1.2

5.25.2

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7 8 9 10

Postoperative day

Inci

den

ce o

f vo

mit

ing,

% Placebo

Alvimopan 12 mg

Incidence of Vomiting

†

†

BR for CRC, overall vomiting (P < 0.05); vomiting on PODs 4 and 5 (†P ≤ 0.05).

Conclusions

In patients who underwent BR for CRC compared with placebo, alvimopan 12 mg Significantly accelerated GI-2 recovery Significantly reduced time to DCO written,

postoperative LOS, and the proportion of patients with POI-related morbidity

Was well toleratedThis subset analysis is consistent with results from the larger population of patients undergoing BR for any reason in alvimopan phase III trials1-4

This supports the efficacy and safety of alvimopan in patients undergoing BR for CRC

1Wolff BG, et al. Ann Surg. 2004;240:728-734; 2Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125; 3Viscusi ER, et al. Surg Endosc. 2006;20:64-70; 4Ludwig K, et al. Presented at: 92nd Annual Clinical Congress of the American College of Surgeons; Oct. 8-12, 2006; Chicago, IL. Poster SE120.