1 ENTEREG ® (Alvimopan) Part 1: Efficacy and General Safety Evaluation Clinical Evaluation of NDA ENTEREG ® (Alvimopan) Part 1: Efficacy and General Safety Evaluation Ruyi He, MD Medical Team Leader Division of Gastroenterology Products Office of Drug Evaluation III CDER, FDA The Gastrointestinal Drugs Advisory Committee (GIDAC) Meeting January 23, 2008

2 Overview of Presentation  Part 1: Efficacy and General Safety  Alvimopan and POI  Regulatory History  POI Clinical Program  POI Efficacy Results  POI General Safety Results  OBD Clinical Program  Part 2: Special Safety Issues  Part 3: Non-Clinical Evaluation  Part 4: Risk Management

3 Alvimopan  New Molecular Entity  Peripherally-acting opioid-receptor antagonist  Low systemic oral bioavailability (about 6%)  T max about 2 h. Half Life ranged from 4 to 17 h  One active metabolite (ADL ).

4 Sponsor’s Proposed Indication Acceleration of time to upper and lower gastrointestinal (GI) recovery following partial large and small bowel resection surgery with primary anastomosis

5 Postoperative ileus (POI)  Transient impairment of GI function after surgery  Characterized by inability to tolerate liquids and solid food, nausea, vomiting, and/or abdominal pain/bloating  Complications include prolonged hospitalization, delayed nutrition, et al.  No product is currently approved for POI in the U.S.  Off-label therapies include metoclopramide and erythromycin

6 Main Regulatory History DateEvent Aug. 1998Initial IND submitted Feb. 2004Fast Track Designation granted for POI June 2004 Original NDA submitted July 2005 Approvable action, insufficient evidence for efficacy May 2006 Complete response submitted, serious CV events noted in an ongoing OBD study Nov nd approvable action, requested final 12m safety findings and risk management plan April 2007 Full clinical hold; CV events, neoplasms and bone fractures were identified in OBD studies Aug Complete response submitted. PDUFA due day: 2/10/08

7 POI Clinical Program Six Phase 3 Clinical Studies (302, 306, 308, 313, 001 and 314): Randomized, double-blind, placebo-controlled, multi centered trials in patients undergoing partial large or small BR or total abdominal hysterectomy (TAH) surgery. Study 001 was conducted in Europe and Australia. All other studies were conducted in the US and Canada. Patients on chronic opioids were excluded from the studies.

8 POI Clinical Program Since efficacy was not demonstrated in the TAH surgery subgroup in the original NDA submission, the sponsor decided to narrow proposed indication to the BR surgery population only Study 306 is not included in the efficacy evaluation, because no BR patient was enrolled in this study (TAH only)

9 Treatment  Initial Dose given 0.5 to 2 h prior to surgery, Subsequent Doses: 12 mg PO, BID from POD 1 until hospital discharge or POD 7  Maximum number of doses is 15 (maximum of 8 days of therapy)  Study drugs only administered in hospital

10 Key Endpoints  GI-3: time from end of surgery to time of recovery of both upper and lower GI tract function  Toleration of solid food;  First BM or flatus;  It was the primary EP for Study 302, 308, 313 and 001.  GI-2 (solid food, first BM).  GI-2 was the primary EP for Study 314.  GI-2 maybe a more objective EP than GI-3.  Ready: time from end of surgery to time ready for hospital discharge based solely on recovery of GI function as defined by the surgeon.  DOW: time from end of surgery to time discharge order is written.

11 GI-3 Recovery: Difference from Placebo (Hours)* in BR Patients Study th percentile Median th percentile HR (95% CI) (0.96, 1.74) (1.03, 1.69) (1.17, 1.91) (0.94, 1.37) 1.45 (1.23, 1.71) P-value <0.001 *Using Cox Proportional Hazards Models

12 GI-2 Recovery: Difference from Placebo (Hours)* in BR Patients Study th percentile Median th percentile HR (95% CI) 1.40 (1.04, 1.89) 1.37 (1.06, 1.76) 1.63 (1.26, 2.10) 1.30 (1.07, 1.58) 1.53 (1.29, 1.82) P-value < <0.001 *Using Cox Proportional Hazards Models

13 Ready: Difference from Placebo (Hours)* in BR Patients Study th percentile Median th percentile HR (95% CI) 1.52 (1.11, 2.09) 1.40 (1.09, 1.78) 1.54 (1.20, 1.96) 1.11 (0.92, 1.35) 1.38 (1.17, 1.63) P-value < <0.001 *Using Cox Proportional Hazards Models

14 Time to DOW (Days)* in BR Patients StudyTxMedianΔ 75 th Percentile Δ HR (95% CI) p-value 302 PL Alv (0.98, 1.7) PL Alv (1.2, 2.0) < PL Alv (1.1, 1.8) PL Alv (0.9, 1.3) PL Alv (1.2, 1.7) <0.001 *Using Cox Proportional Hazards Models

15 Mean Length of Hospital Stay (Days) Study Placebo 6.4 (n=99) 6.6 (n=142) 7.4 (n=142) 9.2 (n=229) 6.2 (n=312) Alvimopan 12 mg 6.1 (n=98) 5.7 (n=139) 6.1 (n=160) 8.9 (n=238) 5.2 (n=317) Difference

16 Efficacy Summary in POI Efficacy data demonstrated: there was acceleration of recovery of upper and lower GI tract function by roughly 20 hours measured by GI2 and reduced length of hospital stay by roughly 1 day in the US.

17 Questions What is the minimum acceptable efficacy difference for recovery of GI function measured by GI2 or GI3 for alvimopan relative to placebo? 12h? 24h? 36h? other? Do you consider the efficacy results from the POI studies to be clinically meaningful?

18 General Safety Evaluation in the POI Population A total of 3975 patients are included in the POI safety database –1365 patients received placebo –2610 patients received alvimopan at doses of 1, 3, 6, or 12 mg

19 Demographics-Overall POI Population CharacteristicPla. N=1365 n (%) Alv. N=2610 n (%) Age, Mean5857 Age > 65 yr491 (36)898 (34.4) Race: White1156 (84.7)2207 (84.6) Other209 (15.3)403 (15.4) Female850 (62.3)1680 (64.4)

20 POI Safety: Deaths and SAEs n (%) Placebo (N=1365) Alv 6 mg (N=898) Alv 12 mg (N=1650) Total Deaths 9 (0.7)5 (0. 6)8 (0.5) All Nonfatal SAEs250 (18)110 (12)192 (12) POI/SBO 86 (6)18 (2)32 (2) Infection 19 (1)10 (1)18 (1) Anastomotic leak 15 (1)12 (1)11 (1) Pulmonary emboli 13 (1)9 (1)11 (1)

21 POI: AEs Leading to Discontinuations n (%) Placebo (N=1365) Alv. 6 mg (N=898) Alv. 12 mg (N=1650) Total162 (12)74 (8)125 (8) Nausea42 (3)19 (2)39 (2) Vomiting43 (3)17 (2)24 (2) POI45 (3)11 (1)20 (1) Abd. distension11 (1)6 (1)8 (1) Diarrhea4 (0.3)08 (0.5) Dyspepsia01 (0.1)8 (0.5)

22 Treatment-Emergent Events n (%) Placebo N=986 Alv. 6 mg N=663 Alv. 12 mg N=999 Nausea491 (49.8)246 (37.1)433 (43.3) Vomiting209 (21.2)111 (16.7)141 (14.1) Abd. distension137 (13.9)59 (8.9)120 (12) Pruritus97 (9.8)46 (6.9)85 (8.5) POI113 (11.5)33 (5)60 (6) Urinary retention21 (2.1)17 (2.6)32 (3.2) Pain18 (1.8)18 (2.7)12 (1.2) SBO18 (1.8)5 (0.8)9 (0.9) Anastomotic leak11 (1.1)8 (1.2)8 (0.8)

23 General Safety Summary in POI Similar or lower incidences of death, nonfatal SAEs, discontinuations due to AEs and treatment-emergent events were identified in the alvimopan groups in comparison with the placebo group in POI population

24 Chronic Opioid-Induced Bowel Dysfunction (OBD)  OBD is chronic condition characterized by decreased frequency of bowel movements and associated symptoms  Patients in OBD studies were treated for chronic pain with opioids for months, years; instead of days in POI  Although current submission is only for POI indication, imbalances in CV events, neoplasms and bone fractures were identified in OBD clinical studies

25 Regimen in POI & OBD Dose Regimen in POI & OBD POIOBD RouteOral Dose Regimen 12 mg BID (up to 7 days postop) mg QD or BID (up to one year) Maximum Daily Dose 24 mg/day1-2 mg/day DurationUp to 8 daysUp to 1 year LocationHospital onlyMostly Outpatient

26 Thank You  Eric Brodsky (Medical Reviewer)  Sonia Castillo (Statistician)  Joyce Korvick (Deputy Division Director)  Julie Beitz (Office Director)  Daniel Shames (Deputy Office Director)  Matthew Scherer (Projector Manager)  Sue Chih Lee (Biopharmaceutics)  Tamal Chakraborti (Pharmacologist)  Marie Kowblansky (Chemist)  And everyone in the review team