1 ENTEREG ® (Alvimopan) Special Safety Section Marjorie Dannis, M.D. Division of Gastroenterology Products Office of Drug Evaluation III CDER, FDA The Gastrointestinal Drugs Advisory Committee (GIDAC) Meeting January 23, 2008

2 Overview Cardiovascular Neoplasms Fractures

3 Cardiovascular Safety Post-operative Ileus (POI)

4 CV Risk Factors in Worldwide POI Population CV Risk Factor Alvimopan % (N=2610) Placebo % (N=1365) Mean age57 years58 years BMI ≥ Diabetes1210 Hypertension3943 Smoking810

5 Patients Experiencing Death or Serious Cardiovascular Events Total POI Population Alvimopan N=2610 n (%) Placebo N=1365 n (%) Relative Risk (95% CI) All Cause Death (Total) - Death from CV events 13 (0.5) 4 (0.2) 9 (0.7) 2 (0.2) 0.8 (0.3,1.7) 1.0 (0.2,4.9) Patients with CV events (Total) 51 (2.0)39 (2.9)0.7 (0.4,1.0)

6 Cardiovascular Events Worldwide POI Population Alvimopan N=2610 n (%) Placebo N=1365 n (%) Relative Risk (95%CI) Ischemic events - Fatal 17 (0.7) 2 (0.1) 14 (1.0) 0 (0.0) 0.6 (0.3, 1.3) -- (0.3,--) Other serious CV events - Fatal 39 (1.5) 2 (0.1) 29 (2.1) 2 (0.2) 0.7 (0.4, 1.1 ) 0.5 (0.1, 3.0)

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8 Post Discharge Surveillance Worldwide POI Population Time after last dose (days) Alvimopan N=2610 Placebo N=1365 Had follow-up phone call n (%) Anytime1874 (72)1052 (77) (13)164 (12) (56)835 (61) ≥ 1589 (3)53 (4) Had investigator follow-up visit n (%) Anytime416 (16)110 (8) (<1)11 (<1) (14)94 (7) ≥ 1519 (<1)5 (<1)

9 Limitations of POI Study Design Follow-up by phone call only (except 1/9 studies) Important safety endpoints such as 30 day and 60 day morbidity/mortality not collected CV events not prospectively defined nor consistently assessed post exposure Missing data does not imply no CV events

10 Conclusion POI studies were not designed to adequately establish CV risk estimate in this population

11 Cardiovascular Safety Opioid-induced Bowel Dysfunction (OBD) Non-cancer pain studies Cancer pain studies

12 OBD Safety Population (at least 1 dose) Study (Time)PlaceboAlvimopanTotal 011 (6 wks) (12 wks) (12 wks) (12 mos) C217 (phase 2) C304 (phase 2) (3-6wks) 684 (< 2 yrs) Total

13 Patients Experiencing Death or Serious Cardiovascular Events Non-Cancer OBD Population* Alvimopan N=1728 n (%) Placebo N=790 n (%) Relative Risk (95% CI) All Cause Death (Total) - Death from CV events 4 (0.2) 2 (0.1) 2 (0.3) 0 (0.0) 0.9 (0.2, 5.0) -- (0.2, --) Patients with CV events (Total) 21 (1.2)4 (0.5)2.4 (0.9, 6.7) *Studies 011,012,013, 014, 13C217, 13C304

14 Cardiovascular Events Non-Cancer OBD Population* Alvimopan N=1728 n (%) Placebo N=790 n (%) Relative Risk (95%CI) Ischemic events - Fatal 14 (0.8) 1 (0.1) 3 (0.4) 0 (0.0) 2.1 (0.7, 6.9) -- (0.1, --) Other serious CV events - Fatal 8 (0.5) 1 (0.1) 2 (0.3) 0 (0.0) 1.8 (0.4, 7.6 ) -- (0.1, --) *Studies 011, 012, 013, 014, 13C217, 13C301

15 Patients Experiencing Death or Serious Cardiovascular Events Study 014 Alvimopan N=538 n (%) Placebo N=267 n (%) Relative Risk (95% CI) All Cause Death (Total) - Death from CV events 2 (0.4) 1(0.2) 2 (0.8) 0 (0.0) 0.5 (0.1, 2.8) -- (0.1, --) Patients with CV events (Total) 14 (2.6)0 (0.0)-- (1.8, --)

16 Cardiovascular Events Study 014 Alvimopan N-538 n (%) Placebo N=267 n (%) Relative Risk (95%CI) Ischemic events - Fatal 11 (2.1) 1 (0.2) 0 (0.0) -- (1.4, --) -- (0.1, --) Other serious CV events 3 (0.6)0 (0.0)-- (0.4, --)

17 Patients Experiencing Death or Serious Cardiovascular Events Total OBD Population Non-Cancer and Cancer Studies* Alvimopan N=1888 n (%) Placebo N=860 n (%) Relative Risk (95% CI) All Cause Death (Total) - Death from CV events 24 (1.3) 5 (0.3) 5 (0.6) 1 (0.1) 2.2 (0.9, 5.5) 2.3 (0.4, 14.7) Patients with CV events (Total) 26 (1.4)6(0.7)2.0 (0.8, 4.7) *Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684

18 Cardiovascular Events Total OBD Population Non-Cancer and Cancer Studies* Alvimopan N-1888 n (%) Placebo N=860 n (%) Relative Risk (95%CI) Ischemic events - Fatal 14 (0.8) 1 (0.1) 4 (0.5) 0 (0.0) 1.6 (0.6, 4.6) -- (0.1, --) Other serious CV events - Fatal 14 (0.8) 4 (0.2) 3 (0.4) 1 (0.1) 2.1 (0.7, 6.9) 1.8 (0.3, 11.1) *Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684

19 Time to All Cardiovascular Events Total OBD Population All Studies ≥ 14 Days Days Alvimopan (n=26) Placebo (n=6) 14 or less53 15 to to to or more21

20 Time to All Ischemic Events Only (MI, Angina, CVA) Total OBD Population All Studies ≥ 14 Days Days Alvimopan (n=13) Placebo (n=4) 14 or less11 15 to to to or more11

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22 Additional Observations No differences in patient demographics or underlying CV risk factors: –Between study 014 and other OBD trials –Within study 014 Study duration of most other OBD studies was 3-12 weeks ; duration of study 014 was 12 months

23 Summary and Conclusions Numerical imbalance of serious CV events in: –Pooled analyses of OBD studies –Study 014 alone – Finding not explained by pre-clinical findings May suggest that chronic alvimopan use can increase risk of serious CV events in OBD population –Implications for short-term use in POI unclear

24 Neoplasms POI Population

25 Neoplasia Events POI Studies Alvimopan N=2610 Placebo N=1365 Burkitt’s lymphoma01 Bladder neoplasm01 Carcinoma01 Chronic myelogenous leukemia 10 Colon cancer metastatic10 Hepatic neoplasm10 Lymphoma10 Thyroid neoplasm10 TOTAL5 (0.2%)3 (0.2%)

26 Summary POI Population Number of neoplasms reported in each treatment group appears to be balanced Study design does not allow for significant conclusions to be drawn Long term effects unclear

27 Neoplasms OBD Population Non-cancer pain studies Cancer pain studies

28 All Neoplasms Non-Cancer OBD Population* Alvimopan N=1598 n (%) Placebo N=732 n (%) Relative Risk (95% C.I.) All Neoplasms 22 (1.4)4 (0.5)2.5 (0.9, 7.0) Malignant Neoplasms 13 (0.8)3 (0.4)2.0 (0.6, 6.5) Benign Neoplasms 9 (0.6)1 (0.1)4.12 (0.7, 25.2)

29 Neoplasms Study 014 Alvimopan N=538 n (%) Placebo N=267 n (%) Relative Risk (95% C.I.) All Neoplasms 15 (2.8)3 (1.1)2.5 (0.8, 8.0) Malignant Neoplasms 7 (1.3)2 (0.7)1.7 (0.4, 7.3) Benign Neoplasms 8 (1.5)1 (0.4)4.0 (0.7, 24.4)

30 Time to Malignant Neoplasm Non-Cancer OBD Population Alvimopan

31 Time to Malignant Neoplasm Non-Cancer OBD Population Placebo

32 Time to Neoplasm Non-Cancer OBD Population Time to Neoplasm Non-Cancer OBD Population

33 Most Common Malignancies Non-Cancer OBD Population Neoplasm Type Alvimopan N=1598 Placebo N=732 Squamous cell carcinoma 40 Breast cancer 30 Lung cancer31

34 OBD Studies Cancer Pain Study 008 Extension Study 684

35 Deaths Reported During OBD Studies in Cancer Pain (Studies 008 and 684) Deaths Reported During OBD Studies in Cancer Pain (Studies 008 and 684) Study 008Study 684 (extension study) Studies 008 and 684 combined Placebo N=70 n (%) Alvimopan N=160 n (%) Placebo N=15 n (%) Alvimopan N=50 n (%) Placebo N=70 n (%) Alvimopan N=160 n (%) Deaths1 (1.4)9 (5.6)2 (13.0)11 (22.0)3 (4.0)20 (13.0)

36 Time to All Cause Death Studies 008 and 684 Time to All Cause Death Studies 008 and 684

37 Imbalances in Index Cancer Diagnosis –In study 008, more subjects with head and neck cancers received alvimopan (N=14, 9%) than placebo (N=1, 1%), however Deaths were almost entirely in Gyn, GU, breast cancers (balanced between treatment groups) –In study 684, more subjects with non-small cell lung cancer received alvimopan (N=16, 31%) than placebo (N=1, 7%), and Most deaths occurred in non-small cell lung CA patients

38 Imbalances in Baseline Karnofsky Performance Scores In study 008, Karnofsky Performance Scores appeared balanced between treatment groups. In study 684, there was a higher percentage of patients with lower Karnofsky Performance scores in the alvimopan group as compared to the placebo group, 42% vs. 13% respectively.

39 Other Factors Demographic Characteristics (age, race, gender): –Similar between study 008 and study 684 populations –Balanced between treatment groups within each study Extent of Metastatic Disease: –Similar between study 008 and study 684 populations –Balanced between treatment groups within each study

40 Summary Non-Cancer OBD Population Alvimopan-treated patients had a higher incidence of neoplasia events as compared to placebo Possibly driven by the imbalance in neoplasia events in the only long term safety study for OBD in patients without cancer, study 014 – No obvious reason for the observed imbalance between treatment groups in this placebo controlled study

41 Summary Cancer OBD Population Large discrepancy seen in the death rates between treatment groups in studies 008 and 684 –Some differences in index cancer etiology and patient performance status were noted

42 Fractures POI Population

43 Fractures POI Population One patient with a fracture identified: –Multiple rib fractures secondary to syncope and subsequent fall after BR surgery With only one fracture event reported, no conclusions can be drawn L imited follow-up may not adequately assess fracture risk

44 Fractures OBD Population

45 Fracture Incidence All OBD Non-Cancer and Cancer Population Alvimopan: 1.4% (25/1758) Placebo: 1.2% (10/802) Relative Risk: 1.14 (95% CI: 0.6 to 2.3)

46 Fracture Incidence Study 014 Alvimopan: 3.7% (20/538) Placebo: 1.1% (3/267) Relative Risk: 3.30 (95% CI: 1.1 to 10.4)

47 Fracture Location: All OBD Studies Placebo N= 802 n (%) Alvimopan N=1758 n (%) Vertebra1 (0.1)2 (0.1) Rib2 (0.2)4 (0.2) Humerus0 (0.0)4 (0.2) Wrist1 (0.1) Femur1 (0.1) Patella/fibula/tibia2 (0.2)4 (0.2) Ankle1 (0.1)4 (0.2) Foot2 (0.2)5 (0.3) Total10 (1.2)25 (1.4)

48 Time to Fracture All OBD Studies Time to Fracture (weeks) Placebo N=802 n (%) Alvimopan N=1758 n (%) 1-54 (0.5)2 (0.1) (0.4)5 (0.3) (0.0)5 (0.3) (0.3)6 (0.3) (0.0)6 (0.3) > 451 (0.1) TOTAL10 (1.2)25 (1.4)

49 Time to Bone Fracture Study 014 Time to Bone Fracture Study 014

50 Specific Clinical Findings Majority of fractures were secondary to falls –Etiologies for increased fall risk (dizziness, hypotension, syncope, gait instability, etc) were not apparent Of subjects reporting fractures, the alvimopan group had a higher percentage of women, more individuals ≥ 65 years of age, and a higher average BMI

51 Specific Clinical Findings Baseline demographics well balanced between treatment groups in study 014* as well as total OBD population The mean opioid daily dose was similar between treatment groups * (except higher percentage of patients > 65 years in the alvimopan group),

52 Summary OBD Population –Fractures were not typical osteoporotic fractures, such as hip and vertebrae –Unclear etiology for imbalance in fracture rates between treatment groups in study 014 (alvimopan > placebo)

53 Overall Summary A large, long-term safety study of alvimopan for OBD indication showed potential safety signals in 3 specific areas: –serious cardiovascular events, neoplasms and fractures The POI studies did not show evidence of these safety signals; however, the follow-up of patients was extremely limited