Gastrointestinal Drugs Advisory Committee June 25, 2003

1. Gastrointestinal DrugsAdvisory CommitteeJune 25, 2003 NDA #21-597 Pamela Williamson Joyce, RAC Vice President, Regulatory Affairs& Quality Assurance – US Serono, Inc.

2. Proposed Indication Serostim® [somatropin (rDNA origin) for injection] is indicated for the treatment of Short Bowel Syndrome in patients receiving specialized nutritional support. Serostim therapy should be used in conjunction with optimal management of Short Bowel Syndrome.

3. Agenda

4. Serostim®[somatropin (rDNA origin) for injection] • Growth hormone produced by recombinant DNA technology • Lyophilized in 4 mg, 5 mg, 6 mg and 8.8 mg vials administered by subcutaneous injection

5. Recombinant Human Growth Hormone Other Currently Approved Indications • Pediatric growth hormone deficiency • Adult growth hormone deficiency • Turner syndrome • Prader-Willi syndrome • Pediatric chronic renal insufficiency • Small for Gestational Age (SGA) • AIDS wasting or cachexia

6. Orphan Drug Designation for Serostim® *Annals of Surgery 1995; 222: 243

7. Regulatory History – Serostim® in SBSClinical Development Program

8. August 1995 Correspondence from FDA • We suggest that a study with the following design be incorporated to help answer the necessary questions required for approval: • 3-arm randomized double-blind • 5 patients GH only, 5 patients GLN only,15 patients combination • 2 week in-house control period • Treatment of at least 3 weeks • With patients followed for at least 3 months to establish database on safety • Adequate statistical power to meet objectives Source: FDA Letter to previous Sponsor’s CRO (Cato); 8/3/95

9. Regulatory History – Serostim® in SBS Clinical Development Program

10. October 1997 Correspondence from FDA “The Division DID agree with Cato that one study (the May 30, 1997 protocol submission from Cato with our medical officers comments incorporated) will suffice as THE pivotal study for the SBS treatment with somatropin and glutamine indication.” Source: FDA e-mail to current Sponsor (Serono); October 29, 1997

11. Regulatory History – Serostim® in SBS Clinical Development Program

12. Regulatory History – Serostim® in SBS Clinical Development Program

13. External Consultant Experts • Kareem Abu-Elmagd, MD, PhD • Professor of Surgery; Director of Intestinal Transplant ServicesThomas E. Starzl Transplantation Institute (Pittsburgh, PA) • Theresa A. Byrne, DSc • Director of Research and Clinical ServicesNutritional Restart Center • Instructor in the Department of SurgeryHarvard Medical School (Boston, MA) • Gary Koch, PhD • Statistical ConsultantChapel Hill, NC

14. External Consultant Experts • Donald P. Kotler, MD • Professor of MedicineColumbia University (New York, NY) • Chief of GISt. Luke's-Roosevelt Hospital Center (New York, NY) • Bert Spilker, MD, PhD • Co-founder and former PresidentOrphan Medical • Adjunct Professor of Medicine; Clinical Professor of PharmacyUniversity of North Carolina (Chapel Hill, NC) • Douglas W. Wilmore, MD, FACS • Frank Sawyer Professor of SurgeryBrigham and Women’s Hospital • Harvard Medical School (Boston, MA)

15. Short Bowel Syndrome:Unmet Medical Need Douglas W. Wilmore, M.D., FACS Frank Sawyer Professor of Surgery Brigham & Women’s HospitalHarvard Medical School

16. What is Short Bowel Syndrome? • Healthy small intestine is about 600-650 cmin length • Short bowel syndrome is loss of approximately 2/3 of this amount

17. Causes of Short Bowel Syndrome in Adults • Impaired blood flow • Thrombosis, trauma, malrotation, volvulus • Inflammatory bowel diseases • Primarily Crohn’s disease • Others • Radiation enteritis  10,000-20,000 patients in US dependenton parenteral nutrition

18. Characteristics of Short Bowel Syndrome • Results in impaired absorption of nutrients • Diarrhea, dehydration, macro and micro nutrient deficiency resulting in weight loss • A life-threatening condition which shortens life expectancy • Life expectancy is about 75% at 5 years in the total population • In those with 0-49 cm small bowel, survival at 5 years is 50% Source: Messing et al, Gastroenterology 1999, Howard, JPEN 2002

19. Evolution of Care of Patientswith Short Bowel Syndrome • Before 1960’s – no major therapies • >1970 – total parenteral nutrition • >1985 – bowel rehabilitation • >Late 1980’s – intestinal transplantation

20. Problems with Current Approaches • Parenteral nutrition does not enhance bowel function • Long term parenteral nutrition is associated with serious complications prompting 1-2 hospitalizations annually • Catheter sepsis, hepatic dysfunction (42% of home PN patients had complex liver disease at 17 mos.), micro nutrient deficiency (70% abnormal) • Intestinal transplantation remains an evolving therapy with limited application • Cost of caring for patients receiving parenteral nutrition is > $100,000/yr Howard et al Gastroenterology 1995, Tokars et al Ann Int Med 1999, Cavicchi et al Ann Int Med 2000

21. Limitations of the Current Standard of Care Parenteral nutrition: • Diminishes quality of life • Restricts patient’s life style • Depletes patient’s economic resources Howard, JPEN 2002

22. Attributes of New Therapy • Reduce or eliminate the need for parenteral infusion in terms of volume, calories, and frequency • Allow patients to maintain a near-normal nutritional state primarily by an accepted oral diet • Have an appropriate benefit/risk profile • Tolerated and accepted by patients without undue burden • Cost-effective

23. What is Intestinal Rehabilitation? • Following intestinal resection, adaptation or increased absorptive function of the residual intestine occurs • A program to optimize diet, and to provide appropriate nutrient and growth factors to allow increase in the adaptive response

24. Starting in the 1980s Laboratory and Clinical Investigations Examined the Effects of Available Substances to Enhance Function of the Residual Bowel Mechanism of action of GH • Increased mucosal mass and villi proliferation in animals • Enhanced transport of water, electrolytes and nutrients • Increase insulin-like growth factor-l generation in the intestinal mucosa

25. Role of Glutamine • Important nutrient for the enterocyte and colon • Necessary for cell proliferation • Enhances adaptive responses in animal models • Co-factor in regulating enterocyte responses to growth factors

26. Pilot Studies With Growth Hormone • Experimental and clinical data on the effect ofGH in enhancing function of residual bowel • 15 years of experience at Brigham & Women’s Hospital with GH in treatment of short bowel syndrome • Several publications detailing results of this therapeutic approach

27. Experience at Brigham and Women’s Hospital with rhGH in SBS • Byrne T, Cox S, Karimbakas M, Veglia L, Bennett H, Lautz D, Robinson M, Wilmore DBowel Rehabilitation: An alternative to long-term parenteral nutrition and intestinal transplantation forsome patients with short bowel syndrome.Transplantation Proceedings 2002; 34:887-890. • Byrne T, Nonpleggi D, Wilmore DAdvances in the management of patients with intestinal failure. Transplantation Proceedings1996; 28(5):2683-2690. • Byrne T, Persinger R, Young L, Ziegler T, Wilmore DA new treatment for patients with short bowel syndrome – Growth hormone, glutamine and a modified diet.Ann Surg 1995;222(3):243-255.

28. Treatment Rationale and Conclusions • SBS – a life-threatening condition in a limited and difficult-to-study patient population • Parenteral nutrition is the standard of care – does not enhance intestinal function • rhGH and optimized nutrition support the concept that bowel rehabilitation is possible • A well-controlled double-blind study was needed to confirm preliminary findings

29. Emerging Treatment Hypothesis for Confirmation • From the evidence in the prior work and other publications, treatment with growth hormone and an optimal oral diet supplemented with glutamine may allow patients with short bowel syndrome to be nutritionally maintained on oral feedings

30. SBS Clinical Trial IMP 20317 Joseph Gertner, M.B., M.R.C.P. Vice President,Metabolic EndocrinologyClinical Development Unit Serono, Inc.

31. SBS Clinical Trial IMP 20317 “Randomized, double-blind, controlled, parallel-group evaluation of the relative efficacy and safety of recombinant human growth hormone and glutamine, singly andas co-therapy, in the improvement of residual gut absorptive function in patients with short bowel syndrome”

32. Antecedent Publications Byrne TA, et al. Growth hormone glutamine and a modified diet enhance nutrient absorption in patients with the severe short bowel syndrome. J Parenter Enteral Nutr 1995; 19:296-302. Protropin, Genentech 0.14 mg/kg/d; increased energy, protein, CHO absorption, decreased stool output; n = 10 Byrne TA, et al. A New Treatment for Patients with Short Bowel Syndrome. Ann. Surg. 1995; 222:243-255. Protropin, Genentech 0.14 mg/kg/d; 40% off TPN at average 1 yr. followup; n = 45 Byrne TA, et al. Bowel rehabilitation. An alternative to long-term parenteral nutrition and intestinal transplantation for some patients with short bowel syndrome. Transplant Proc 2002; 34(3):887-890. Humatrope, Eli Lilly and rhGH, Serono 0.1 mg/kg/d; prospective case series, 49 dependent on PN. Provided further evidence of improved intestinal function. 20 of 49 were weaned completely from PN and remained off for up to 1 year.

33. Review of Relevant Publications * “+ve” indicates p- < 0.05 for authors’ chosen endpoint DBPC: double-blind placebo control

34. Considerations for Clinical Trial • Serious and rare condition with limited patient population • Need for an adequately-powered double-blind trial of GH in a representative group of adults with SBS • Residential for clinical trial purposes: ensures rigorous control and clinical observation of response • Practical and ethical considerations in choice of trial endpoint

35. SBS Pivotal TrialIMP 20317

36. Trial Design Left Clinic SOD (GLN) Randomization Screening Period rhGH + SOD Stabilization SOD SOD (GLN) rhGH + SOD (GLN) Signed ICF + Entered Clinic 2-Week Baseline 4-Week Treatment 12-Week Follow-up by Referring Specialist rhGH = recombinant human growth hormone; SOD = specialized oral diet; GLN = glutamine 30 g/d po

37. Dosing • Antecedent experience showed good efficacy and tolerability for 0.1 mg/kg/d • Sponsor proposed doses from 0.03 - 0.14 mg/kg/d • Concern from FDA (March 1997): range of doses would be difficult to interpret • Sponsor proposed 0.1 mg/kg/d and 50% decrease if signs of toxicity occur (April 1997) • Proposal of Serostim (rhGH) 0.1 mg/kg/d agreed • Same as recommended dosing in other indications

38. Study Diet • Objective: to ensure each patient is able to maintain, through oral feeding, adequate nutritional status • Readily available foods • Complex carbohydrates: 50% to 55% of calories • Protein: 20% of calories • Fat: 25% to 30% of calories • Rehydration fluids and dietary supplements • Multivitamins and minerals

39. Endpoints – Rationale • Need for intravenous nutrition chosen as quantitative endpoint • Reduction in IPN volume represents a direct clinical benefit to the patient • Alternate endpoints considered: • Intestinal function measurement: inappropriate for a therapeutic trial of this scope • Nutritional status: could not serve as endpoint since all patients must remain optimally nourished

40. Eligibility • Male or female, ages 18 to 75 years • Body mass index: 17-28 kg/m2 • SBS with  200 cm small bowel • Regularly eat some solid food but require  3,000 calories/wk IPN for nutritional support • Bowel resection surgery at  6 months pre-trial, intact stomach and duodenum and 1 or more of the following: •  30% of colon functional and  15 cm jejunum and/or ileum remaining intact •  30% of colon functional and  90 cm jejunum and/or ileum intact • Stool output  3 L/day

41. Patient Disposition n=47 Subjects Enrolled n=6 Discontinued Intercurrent illness (5) Withdrew consent (1) n=41 Subjects Randomized n=9 SOD (GLN) n=16 rhGH + SOD n=16 rhGH + SOD (GLN) n=1 Discontinued (SAE) n=9 Completed Treatment Period n=15 Completed Treatment Period n=16 Completed Treatment Period n=9 Completed Follow-up Period n=15 Completed Follow-up Period n=16 Completed Follow-up Period

42. Demographics

43. Geographical Distribution of Study Patients for IMP20317* Shown in Orange * 2 patients outside United States(India and Israel)

44. SBS Etiology

45. Additional SBS Related Factors

46. Etiology of SBS in the General SBS Population IMP 20317 • SBS etiologies(Buchman et al, 2003) • Crohn’s • Vascular • Volvulus • Trauma(incl surgical accident) • Cancer

47. Generalizability of the Clinical Trial • Underlying causes cover spectrum of recognized etiologies for SBS • Professionally diverse group of referring physicians responsible for referral and management after Week 6 • Wide geographical referral base • Components of optimal nutritional therapy widely available • Standard of care comparable to usual practice

48. Clinical Trial Endpoints Assess need for parenteral support while applying uniform weaning criteria: • Reduction in total IPN volume – primary endpoint • Reduction in total IPN calories • Reduction in frequency of administration of PN or Supplemental Lipid Emulsion (SLE)

49. Definition of Endpoints Total IPN = sum of: • Parenteral nutrition (PN) • IV hydration • Supplemental lipid emulsion(in patients with essential fatty acid deficiency)

50. Weaning Criteria Reduce IPN prescription when patient shows the ability to: • Hydrate • Maintain serum electrolytes • Sustain appropriate body weight