1. 1 Alvimopan Entereg TM On May 20th 2008, FDA Approves Entereg to Help Restore Bowel Function Following Surgery, after a third review cycle. Entereg has been in development for seven years. Why did it take so long? Regulation: insights into the risk evaluation and mitigation strategy (REMs): FDA’s decision on the NDA for alvimopan (Entereg®) could be a good indicator of the agency’s use of newly mandated risk management plans, as its advisory committee supported the short term benefits of the drug in postoperative ileus, but also worried about CV risk signals in longer term use.

2. 2 Gershell and Goater Nature Reviews Drug Discovery 5, 889–890 (November 2006) | doi:10.1038/nrd2179 Pain submarkets The total market for pain drugs is an estimated US$7.25 billion. Cancer Post-Op Cancer Opioid-treated pain + PAR, …

3. 3 Evolution of Consumption of Morphine 1980-2006 (mg/capita) USAFRANCE 1. Pain & Policy Studies Group ; Univ. Madison Wisconsin http://www.painpolicy.wisc.edu/ Mg/capita

4. 4 1. The medical need treatment of OBD/POI :market and pharmacoeconomics OBD: Opioid Bowel Dysfunction POI : Post-Operative Ileus

5. 5 Inhibitory Effects of Opioids on Bowel Function 1. Senagore; Supplement to Contemporary Surgery August 2007 S3

6. 6 OBD : Opioid-Induced Bowel Dysfunction Common AE associated with opioid therapy Add to patient discomfort Limits therapy or prompts discontinuation. Major limit to effective pain management 2. Gershell and Goater Nature Reviews Drug Discovery 5, 889–890 (November 2006) | doi:10.1038/nrd2179 Problems associated with chronic opioid use. % of surveyed physicians who rated the different symptoms in order of importance. 1. Pappagallo M 2001 Nov;182(5A Suppl):11S-18S

7. 7 Transient impairment of GI function after surgery May last > 5 days Incidence rates reported 6-20% Physiopathology: POI : Post Operative Ileus

8. 8 Restoring GI function after surgery : an unmet medical need 1. Andrew Luckey, Arch Surg (2003).

9. 9 Restoring GI function after surgery : an unmet medical need 1.Peter J. S. Koo, Balancing Postoperative Analgesia and Management of Side Effects, Medscape 2.Expert Opin. Investig. Drugs 2008 17(9) 1365 3.Person & Werxner, Supplement to Contemporary Surgery n August 2007 S9 Opioid-sparing regimens (NSAIDS in Europe) Prokinetic agents

10. 10 Incidence of POI after select procedures 1.National Center For Health Statistics 2.Goldstein Pharm.&Therapeut. February 2007 Vol. 32 No. 2; 82 3.Saunders ASHSP, 2004, Abstract 30346 Patients

11. 11 Projected Incidence of POI with common Abdominal-related Procedures 42.5 million inpatient surgical procedures in 2002 (45 million in 2007) 30% on digestive tract 713,628 intestinal resections 142,026 cases of POI 1.National Center For Health Statistics 2.Goldstein Pharm.&Therapeut. February 2007 Vol. 32 No. 2; 82 3.Saunders ASHSP, 2004, Abstract 30346

12. 12 POI effects 1. Senagore; Supplement to Contemporary Surgery n August 2007 S3 Direct effects –Increase nausea and vomiting –Increased post-operative pain –Accumulation of gas & fluids –Delayed passage of flatus & defecation –Prolonged time to regulatory diet Complications –Increased risk for malnutrition/catabolism –Prolonged time to mobilization –Increased pulmonary complications Prolonged hospitalisation and increased costs

13. 13 Associated costs The total direct cost of coded POI : $1.26 billion including: –nasogastric intubation. –intravenous (IV) hydration. –laboratory tests. –nursing care. –increased hospital length of stay (LOS). The rate of readmission within 30 days 3.6% for recurrent POI, vs 0.02% for non coded POI. 1.Senagore; Supplement to Contemporary Surgery n August 2007 S3 2.Goldstein P&T® February 2007 Vol. 32 No. 2; 82 3.Liu & Carpenter & Mackey

14. 14 1. Senagore; Supplement to Contemporary Surgery n August 2007 S3 Economic Burden of POI

15. 15 Potential annual savings 1. The Surgical Team and Outcomes Management Journal of PeriAnesthesia Nursing, Vol 21, No 2A (April), 2006: pp S2-S6

16. 16 1. The medical need treatment of OBD/POI :market and pharmacoeconomics 2. The drug –A « long » pre-NDA history –Pharmacological mode of action

17. 17 A « long » story… 1984: Discovery 1988 : Eli Lilly then Roberts Pharmaceutical 1998 : Exclusive worldwide license to 03/2001 : 1st Phase III trial 04/2002 : Collaboration with 08/2002 : Acquisition of IP rights 2004 : NDA filing.

18. 18 Strategies for antagonizing opioid induced adverse GI effects 1. Peter J. S. Koo, Balancing Postoperative Analgesia and Management of Side Effects, Medscape

19. 19 Strategies for antagonizing opioid induced adverse GI effects 1. Peter J. S. Koo, Balancing Postoperative Analgesia and Management of Side Effects, Medscape Limit systemic absorption –Naloxone (oral : 1st pass metabolism) Limit BBB penetration –Methylnaltrexone Both –Alvimopan

20. 20 Limit BBB penetration Quaternary amines: N-Methylnaltrexone bromine MNTX Zwitterions : Alvimopan

21. 21

22. 22 Alvimopan : the 1st PAM-OR a Peripherally Acting Mu- Opioid Receptor antagonist ED50 1mpk Duration of action 8hrs Induces Diarrhea in morphine dependent mice 1. ChemMedChem 2007, 2, 1552 – 1570 2. J. Med. Chem. 1994,37, 2262-2265

23. 23 1. The medical need treatment of OBD/POI :market and pharmacoeconomics 2. The drug –A « long » pre-NDA history –Pharmacological mode of action 3. Key Clinical results & Regulation Timeline –The timeline –Clinical trials

24. 24 Entereg regulatory timeline 1999 : beginning of clinical development Mar 2001 : 1st Phase III trial Fev 2004 : Pre NDA meeting May 2005 : FDA wants results from GSK001 Phase III study (failed) Jul 2005 : FDA requires additional efficacy data Sept 2005 : Concern about optimal dosing May 2006 : Complete response to FDA. PDFUA sets to Nov 2006 Prescription Drug User Fee Act (PDFUA) 1. Biocentury 2008, VOL16, 5

25. 25 Clinical Programs patients undergoing partial large or small bowel resection (BR) or total abdominal hysterectomy (TAH) surgery 6 or 12 mg, BID only in hospital R andomized, double-blind, placebo-controlled, multicentered trials POI patients on chronic opioids < 0,5 mg, BID outpatient OBD

26. 26 Endpoints in POI GI Recovery –GI-3 = toleration of solid food + first bowel movement or flatus –GI-2 Length of hospital stay Post Operative Morbidity = readmission, NG tube,... 1. Advisory Panel Briefing Document, Adolor Corp.

27. 27 1. Supplement To Contemporary Surgery 08/2007

28. 28 First results 12 mg = better consistency in benefit/response without ↑ risk of AEs not significant in TAH treatment only in BR : –1 dose prior to surgery –then BID –until hospital discharge or POD 7 5 studies to prove efficacy

29. 29 Time to Upper and Lower GI Recovery Standard of Care Evaluation and Treatment of Post-Operative Ileus Widmann, CUMC: Department of Surgery; October 11th, 2007

30. 30 Patients Remaining in Hosp. POD ≥7 1. Advisory Panel Briefing Document, Adolor Corp.

31. 31 Patients with Post-Op Morbidity May 2006 : Complete response to FDA Dec 06.

32. 32 CV-Risk in OBD May 2006 : imbalance in MIs May 06

33. 33 Entereg regulatory timeline Nov 2006 : FDA requires OBD results, safety (Study GSK014) Prescription Drug User Fee Act (PDFUA) 1. Biocentury 2008, VOL16, 5 Nov 06

34. 34 Safety nausea and vomiting ↓ other adverse events = mortality = POI imbalance in MIs imbalance in neoplasms bone fractures↑ OBD CLINICAL HOLD in Jun. 2007

35. 35 CV-Risk GSK014 isolated observation preexisting CV risk 5/7 MIs were enrolled at 2/230 sites no numerical imbalances in the Worldwide POI Safety Database timeframe 5/7 MIs occurred within 90 days and no MIs beyond 111 days not relevant in POI 1. Advisory Panel Briefing Document, Adolor Corp. Unexpected No causal relationship to alvimopan

36. 36 Entereg regulatory timeline Aug 2007 : FDA sets PDFUA for POI to Fev 2008 Fev 2008 : Approval but need of a REMS for POI May 2008 : Response with REMS, Approved for POI Aug 2008 : End of clinical hold 1. Biocentury 2008, VOL16, 5

37. 37 1. The medical need treatment of OBD/POI :market and pharmacoeconomics 2. The drug –A « long » pre-NDA history –Pharmacological mode of action 3. Key Clinical results & Regulation Timeline –The timeline –Clinical trials 4. RiskMAP & REMS –First propositions –Final REMS

38. 38 14th Dec. 2007 « A risk management plan has been proposed that will communicate the possible CV risk of longer-term alvimopan exposure as well as minimize off-label use » Dec 07

39. 39 Scientific Communication & Promotion Professional labeling : –MI (GSK014) –Contraindications (7-day consecutive Opioid treatment) –Hospital use only –Approved dosing regimen (15 max) Patient Counseling Info. via healthcare professionals Limited Promotion No samples

40. 40 Distribution/pharmacists Wholesale Distribution Agreement. An electronic notice in retail pharmacy drug information systems.

41. 41 DRG payment Cost for Entereg 12 mg covered under the DRG payment for BR surgery. Not for outpatient DRG :diagnosis related group

42. 42 Entereg regulatory timeline Sept 2007: FDAAA FDA Amendments Act Sep.07

43. 43 RiskMAP vs REMS Under the FDAAA* a Risk Evaluation and Mitigation Strategy (REMS) is the new legal framework for risk management plans, specifying timelines and procedures for submission and review. RiskMAP is a tool of REMS. (safety studies, targeted education and outreach, reminder systems and performance-linked access systems) 1. 2009 Pharmaceutical Product Development, Inc.

44. 44 Entereg regulatory timeline Feb 2008: « If alvimopan is approved for the POI indication, do you believe Adolor’s proposed risk management plan is adequate to adress the potential risks? » 15/15 Experts answered NO !!! 1. Biocentury 2008, VOL16, 5 Feb 08.

45. 45 20th May. 2008 In approving Entereg, FDA determined that a REMS is necessary to ensure that the benefits of Entereg outweigh its risks. The REMS will include restricting Entereg to inpatient use only, requiring that hospitals be specially certified, distribution of educational materials to health care professionals, and regular assessments of the effectiveness of the REMS. May 08.

46. 46 Risk Evaluation and Mitigation Strategy

47. 47 Drug Dispensed in Specially Certified Hospitals Direct control over who purchases Entereg

48. 48 REMS assessment Survey Program (phone, mail, email) Questions and Quizz Response to surgeon with the right message if errors were done

49. 49 REMS assessment

50. 50 1.Nature Reviews Drug Discovery 7, 963 (December 2008); FDA website

51. 51 Different levels of REMS

52. 52 1. The medical need treatment of OBD/POI :market and pharmacoeconomics 2. The drug –A « long » pre-NDA history –Pharmacological mode of action 3. Key Clinical results & Regulation Timeline –The timeline –Clinical trials 4. RiskMAP & REMS –First propositions –Final REMS 5. Consequences of delay and perspective IP matter Competition

53. 53 Data exclusivity/Patent protection Patent term extension filed 1.FDA orange book october 2008 2.Drugs R D. 2006 ;7 (4):245-53 16784249 Fda Orange Book 64518062020 combinations of alvimopan, methylnaltrexone with a variety of opioid analgesics for the treatment of pain.

54. 54 Competition 2004 : Big winners from this delay with Entereg are Progenics Pharmaceuticals and Wyeth Mar 2008 : RELISTOR (MTNX) subcutaneous injection was approved in Canada in April 2008 for the treatment of opioid-induced constipation in patients with advanced illness, receiving palliative care

55. 55 Key elements for Alvimopan 900 hospitals registered Net shipments of Entereg were $0.6 million (09/30/08) Adolor begins a Phase 4 study of Entereg in patients undergoing radical cystectomy

56. 56 19th December 2008 In September, GSK returned to Adolor worldwide rights to alvimopan for OBD. GSK retains rights for postoperative ileus (POI). Adolor announces it will discontinue development of Entereg to treat OBD Adolor (NASDAQ:ADLR) fell $0.73 (33%) to $1.47 on the12/19/08 1. Adolor Press release Dec 08.

57. 57 Gershell and Goater Nature Reviews Drug Discovery 5, 889–890 (November 2006) | doi:10.1038/nrd2179 Pain submarkets vs potential market for alvimopan Cancer Post-Op Cancer Opioid-treated pain

58. 58

59. 59 Why did it take so long? Complex project management –2 industrial actors –complex IP situation –2 pathologies targeted Clinical Facts : –Efficacy/Dosing concerns initially –Lethal MIs during OBD clinical trial Change in the legal environment during clinical development : –RiskMAP → REMS

60. 60 Safety in POI 1. Advisory Panel Briefing Document, Adolor Corp.