1. 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, MD 1 ; Wei Du, PhD 2 ; Lee Techner, DPM 2 1 School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, NJ; 2 Adolor Corporation, Exton, PA June 1 - 5, 2007 Chicago, IL

2. Bowel Resection (BR) More than 250,000 patients undergo BR in the US annually 1 Colorectal cancer (CRC) is a common reason for BR 2  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) 1 HCUPnet. 2004. http://hcup.ahrq.gov/HCUPnet.jsp. Accessed April 6, 2007; 2 Rao KV, Goodin S. J Am Pharm Assoc (Wash). 2001;41:585-595.

3. POI Temporary cessation of gastrointestinal (GI) function Occurs to some degree after all BRs 1 Characterized by 2,3  Inability to tolerate solid food  Delayed passage of flatus or stool  Abdominal pain and distension  Nausea and vomiting Exacerbated by opioid analgesics after BR 4 Associated with increased morbidity, prolonged hospital stay/readmission, and hospital costs 5,6 1 Delaney CP. Neurogastroenterol Motil. 2004;16(suppl 2):61-66; 2 Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493; 3 Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:121-132; 4 Kehlet H, Holte K. Am J Surg. 2001;182:3S-10S; 5 Bauer AJ, et al. Neurogastroenterol Motil. 2004;16(suppl 2):54-60; 6 Kariv Y, et al. Am J Surg. 2006;191:364-371.

4. Alvimopan Investigational, peripherally acting mu-opioid receptor (PAM-OR) antagonist Demonstrated efficacy in randomized, double-blind, placebo-controlled phase III trials 1-6  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 analgesia 1-6 1 Wolff BG, et al. Ann Surg. 2004;240:728-734; 2 Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125; 3 Viscusi ER, et al. Surg Endosc. 2006;20:64-70; 4 Ludwig K, et al. Presented at: 92nd Annual Clinical Congress of the American College of Surgeons; Oct. 8-12, 2006; Chicago, IL. Poster SE120; 5 Wolff BG, et al. J Am Coll Surg. 2007;204:609-616. 6 Delaney CP, et al. Ann Surg. 2007;245:355-363.

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

6. 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. Patients undergoing BR, scheduled for pain management with opioid- based IV-PCA 4 pooled, double-blind, multicenter, placebo-controlled, phase III trials Alvimopan 12 mg* (n = 714†, 374‡) Placebo* (n = 695†, 349‡) Dosing* Hospital discharge

7. 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

8. Time to GI Recovery Endpoint GI-2 recovery Upper: tolerance of solid food and Lower: first bowel movement

9. 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

10. 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) 1 Wolff BG, et al. Ann Surg. 2004;240:728-734; 2 Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125; 3 Viscusi ER, et al. Surg Endosc. 2006;20:64-70; 4 Ludwig K, et al. Presented at: 92nd Annual Clinical Congress of the American College of Surgeons; Oct. 8-12, 2006; Chicago, IL. Poster SE120.

11. Baseline Demographics and Surgery Characteristics Placebo (n = 349) Alvimopan 12 mg (n = 374) Age, years Mean ± SD ≥ 65 years, n (%) 64.8 ± 12.2 188 (53.9) 65.2 ± 12.2 201 (53.7) Race, n (%) White287 (82.2)298 (79.7) Female, n (%)162 (46.4)197 (52.7) BMI Mean ± SD, kg/m 2 28.6 ± 6.227.9 ± 6.2 Surgery type, n (%) Large BR Small 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.

12. Efficacy Results: GI-Recovery BR for CRC (HR = 1.4, P < 0.001); BR for any reason (HR = 1.5, P < 0.001).

13. Efficacy Results: DCO Written BR for CRC (HR = 1.5, P < 0.001); BR for any reason (HR = 1.4, P < 0.001).

14. Efficacy Results: DCO Written * * * * ** ** † † † BR for CRC (*P < 0.001; † P < 0.05).

15. Efficacy Results: LOS BR for CRC (*P < 0.001); BR for any reason (*P < 0.001). * *

16. POI-Related Morbidity BR for CRC ( *P ≤ 0.001; † P ≤ 0.05). * † * *

17. TEAEs Reported in > 10% of Patients Undergoing BR for CRC Placebo (n = 349) Alvimopan 12 mg (n =374) Nausea228 (65.3)205 (54.8)* Vomiting95 (27.2)71 (19.0)* Hypertension60 (17.2)63 (16.8) Abdominal distension63 (18.1)61 (16.3) Hypokalemia40 (11.5)46 (12.3) Hypotension47 (13.5)42 (11.2) Headache18 (5.2)39 (10.4) Pyrexia64 (18.3)38 (10.2)* Insomnia37 (10.6)35 (9.4) Tachycardia46 (13.2)33 (8.8) Pruritus40 (11.5)33 (8.8) Postoperative ileus53 (15.2)32 (8.6)* Diarrhea48 (13.8)29 (7.8)* Based on safety population. *P < 0.05.

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

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

20. 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 tolerated This subset analysis is consistent with results from the larger population of patients undergoing BR for any reason in alvimopan phase III trials 1-4  This supports the efficacy and safety of alvimopan in patients undergoing BR for CRC 1 Wolff BG, et al. Ann Surg. 2004;240:728-734; 2 Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125; 3 Viscusi ER, et al. Surg Endosc. 2006;20:64-70; 4 Ludwig K, et al. Presented at: 92nd Annual Clinical Congress of the American College of Surgeons; Oct. 8-12, 2006; Chicago, IL. Poster SE120.