Serostim ® Treatment of Short Bowel Syndrome NDA Division of Gastrointestinal and Coagulation Drug Products Hugo E. Gallo-Torres, M.D., Ph.D, PNS Medical Team Leader Treatment of Short Bowel Syndrome NDA Division of Gastrointestinal and Coagulation Drug Products Hugo E. Gallo-Torres, M.D., Ph.D, PNS Medical Team Leader

Gastrointestinal Drugs Advisory Committee Meeting June 25, OutlineOutline Introduction Medical Literature Study IMP20317 Outstanding Issues –replicability –generalizability –validity of endpoints –exploration of dosing Introduction Medical Literature Study IMP20317 Outstanding Issues –replicability –generalizability –validity of endpoints –exploration of dosing

Gastrointestinal Drugs Advisory Committee Meeting June 25, Proposed Indication Serostim ® –Treatment of Short Bowel Syndrome (SBS) in patients receiving specialized nutritional support –In conjunction with optimal management of SBS Serostim ® –Treatment of Short Bowel Syndrome (SBS) in patients receiving specialized nutritional support –In conjunction with optimal management of SBS

Gastrointestinal Drugs Advisory Committee Meeting June 25, Short Bowel Syndrome Treatment Nutritional management and replacement of fluid and electrolyte losses IPN requirements vary depending on the presence or absence of: ileocecal valve, jejunum, functional colon and length of residual bowel Patients with residual small bowel 100 cm or less frequently require chronic administration of IPN Nutritional management and replacement of fluid and electrolyte losses IPN requirements vary depending on the presence or absence of: ileocecal valve, jejunum, functional colon and length of residual bowel Patients with residual small bowel 100 cm or less frequently require chronic administration of IPN

Gastrointestinal Drugs Advisory Committee Meeting June 25, Complications of Long-Term Parental Nutrition Cholelithiasis Catheter Sepsis Hepatic Dysfunction Nutrient Deficiencies Bone Demineralization Central Vein Thrombosis Glucose Metabolism Disorders Progressive Renal Insufficiency Cholelithiasis Catheter Sepsis Hepatic Dysfunction Nutrient Deficiencies Bone Demineralization Central Vein Thrombosis Glucose Metabolism Disorders Progressive Renal Insufficiency

Gastrointestinal Drugs Advisory Committee Meeting June 25, Known Complications of Growth Hormone Edema Arthralgia Headache Hypothyroidism Antibody Formation Glucose Metabolism Disorders Possible Association with Leukemia Intracranial Hypertension with Papilledema Edema Arthralgia Headache Hypothyroidism Antibody Formation Glucose Metabolism Disorders Possible Association with Leukemia Intracranial Hypertension with Papilledema

Gastrointestinal Drugs Advisory Committee Meeting June 25, Controversy in Medical Literature Clinical Outcome Measure rh-GH Dose High 1 Low 2 Low 3 Body WeightNC++ Lean Body MassNC++ Fat MassNC Absorption of Fat+ Absorption of Fatty AcidsNC 24-hour Creatinine ExcretionNC IGF-1 or IGF Binding Protein++ References 1 (Novo-Nordisk AS, Bagsvaerd, Denmark) rh-GH (0.14 mg/kg/d) plus glutamine Jeppessen PB. Scand J Gastroenterology 36:48-54 (2001) 2 (Genotropin, Pharmacia & Upjohn AB, Stockholm, Sweden) ) rh-GH (0.05 mg/kg/d) Seguy et al. Gastroenterology 124: (2003) 3 (Genotropin Kabi Pharmacia, Stockholm, Sweden) rh-GH (0.024 mg/kg/d) Ellegard L Gastroenterology 113: (1997)

Gastrointestinal Drugs Advisory Committee Meeting June 25, Study IMP20317 Design Study IMP20317 Design Evaluation of Recombinant Human Growth Hormone (rh-GH) and Glutamine, Singly and as Co-therapy, in the Improvement of Residual Gut Absorptive Function in Patients with Short Bowel Syndrome –phase III –dose: (0.1 mg/kg) subcutaneous daily –randomized –double-blind –controlled –parallel-group (3-arm) Evaluation of Recombinant Human Growth Hormone (rh-GH) and Glutamine, Singly and as Co-therapy, in the Improvement of Residual Gut Absorptive Function in Patients with Short Bowel Syndrome –phase III –dose: (0.1 mg/kg) subcutaneous daily –randomized –double-blind –controlled –parallel-group (3-arm)

Gastrointestinal Drugs Advisory Committee Meeting June 25, Treatment Arms GROUP A: –rh-GH + (GLN Placebo) GROUP B: –rh-GH + GLN GROUP C: (control group) –(rh-GH placebo) + GLN Specialized Oral Diet, received by all patients: Components: fluid, oral cal., protein, carbohydrates, fat GROUP A: –rh-GH + (GLN Placebo) GROUP B: –rh-GH + GLN GROUP C: (control group) –(rh-GH placebo) + GLN Specialized Oral Diet, received by all patients: Components: fluid, oral cal., protein, carbohydrates, fat

Gastrointestinal Drugs Advisory Committee Meeting June 25, Primary Endpoint Change in total IPN volume: –IPN volume plus –supplemental lipid emulsion (lipids) plus –intravenous hydration fluid Total IPN volume requirements were captured on a daily basis Change in total IPN volume: –IPN volume plus –supplemental lipid emulsion (lipids) plus –intravenous hydration fluid Total IPN volume requirements were captured on a daily basis

Gastrointestinal Drugs Advisory Committee Meeting June 25, Secondary Endpoints Mean change in total IPN calories –carbohydrate –protein –fat Mean change in IPN or lipid frequency –number of days per week of IPN or –lipids if greater than 200 kcal –intravenous hydration Mean change in total IPN calories –carbohydrate –protein –fat Mean change in IPN or lipid frequency –number of days per week of IPN or –lipids if greater than 200 kcal –intravenous hydration

Gastrointestinal Drugs Advisory Committee Meeting June 25, Sponsor’s Exploratory Analysis Subjects who demonstrated a “complete response” at Week 6 –complete wean from IPN, lipids and wean from intravenous hydration –complete wean from IPN, and lipids intravenous hydration allowed Results in these study populations summarized descriptively Subjects who demonstrated a “complete response” at Week 6 –complete wean from IPN, lipids and wean from intravenous hydration –complete wean from IPN, and lipids intravenous hydration allowed Results in these study populations summarized descriptively

Gastrointestinal Drugs Advisory Committee Meeting June 25, Randomized Patients Site Group A rhGH Group B rhGH + GLN Group C GLN Total Subtotal16 941

Gastrointestinal Drugs Advisory Committee Meeting June 25, Study Population 41 randomized patients –age 20 to 75 years < 65 years (n = 33) >= 65 years (n = 8) –Caucasian (n = 32), non-Caucasian (n = 9) –females (n = 29), males (n = 12) baseline characteristics were similar between treatment groups: i.e. length of residual bowel, IPN requirements, duration of therapy 41 randomized patients –age 20 to 75 years < 65 years (n = 33) >= 65 years (n = 8) –Caucasian (n = 32), non-Caucasian (n = 9) –females (n = 29), males (n = 12) baseline characteristics were similar between treatment groups: i.e. length of residual bowel, IPN requirements, duration of therapy

Gastrointestinal Drugs Advisory Committee Meeting June 25, Primary Efficacy Analysis Mean Change in Total IPN Vol. Difference in Total IPN Volume [L/wk] (p-value) Group A rhGH (n=16) Group B rhGH + GLN (n=16) Group C GLN (n=9) Group B vs C Group A vs C (<0.001)-2.1 (0.043) Changes in Total IPN Volume* *ITT Population Base Line IPN Requirements: Group A: 10.3 L/wk Group B: 10.5 L/wk Group C: 13.5 L/wk

Gastrointestinal Drugs Advisory Committee Meeting June 25, Secondary Efficacy Analysis Secondary Efficacy Analysis Treatment Groups * Group A rhGH (n=16) Group B rhGH + GLN (n=16) Group C GLN (n=9) Group B vs C Group A vs C Change in Total IPN Calories [kcal/wk] / (p-value) (<0.001) (0.005) Change in IPN or Lipid frequency [d/wk] (p-value) (<0.001)-1.0 (0.025) *ITT Population

Gastrointestinal Drugs Advisory Committee Meeting June 25, Effects of Covariates on Primary Endpoint Total IPN volume was significantly influenced by: –patients' weight the higher the body weight the greater the reductions in IPN volume – length of residual bowel the longer the residual bowel the greater the reduction in IPN volume – IPN volume history the higher the IPN volume requirements the greater the decrease in IPN volume during the treatment period – race Caucasians responded to treatment better than non-Caucasians Total IPN volume was significantly influenced by: –patients' weight the higher the body weight the greater the reductions in IPN volume – length of residual bowel the longer the residual bowel the greater the reduction in IPN volume – IPN volume history the higher the IPN volume requirements the greater the decrease in IPN volume during the treatment period – race Caucasians responded to treatment better than non-Caucasians

Gastrointestinal Drugs Advisory Committee Meeting June 25, Significance of Treatment Effect After Adjusting for Covariates Pairwise Comparison of Group B to C –Maintained significant difference in total IPN volume after adjusting for covariates Pairwise Comparison of Group A to C –Only reached a significant difference in total IPN volume when weight was used as a covariate Pairwise Comparison of Group B to C –Maintained significant difference in total IPN volume after adjusting for covariates Pairwise Comparison of Group A to C –Only reached a significant difference in total IPN volume when weight was used as a covariate

Gastrointestinal Drugs Advisory Committee Meeting June 25, Effects of Covariates on Secondary Endpoints Total IPN calories for the ITT population were not influenced by any of the covariates Only weight influenced the treatment results for frequency of administration of IPN or lipids Covariate analyses for the Evaluable for Efficacy population yielded similar results to the ITT population Total IPN calories for the ITT population were not influenced by any of the covariates Only weight influenced the treatment results for frequency of administration of IPN or lipids Covariate analyses for the Evaluable for Efficacy population yielded similar results to the ITT population

Gastrointestinal Drugs Advisory Committee Meeting June 25, Changes in Specialized Oral Diet The greater the reduction in total IPN the greater the increase in oral diet –with exception of oral fluids, a larger increase in oral intake occurred in Groups A & B compared to Group C (control group) As nutritional status improved subjects appetite increased The greater the reduction in total IPN the greater the increase in oral diet –with exception of oral fluids, a larger increase in oral intake occurred in Groups A & B compared to Group C (control group) As nutritional status improved subjects appetite increased

Gastrointestinal Drugs Advisory Committee Meeting June 25, Exploratory Analysis Complete Responders Group A rhGH (n=16) Group B rhGH + GLN (n=16) Group C GLN (n=9) Complete Wean from IPN, Lipids and IV Hydration 441 Complete Wean from IPN and Lipids (IV Hydration Acceptable) 571

Gastrointestinal Drugs Advisory Committee Meeting June 25, Adverse Events Adverse Events One or more AE groups A&B: 100% control group: 89% Most Common AEs tissue edema fatigue gastrointestinal disorders No Deaths One or more AE groups A&B: 100% control group: 89% Most Common AEs tissue edema fatigue gastrointestinal disorders No Deaths

Gastrointestinal Drugs Advisory Committee Meeting June 25, Adverse Events No SAE were considered drug related Safety profile in SBS population similar to rates reported in Serostim ® package insert No clinically significant difference in laboratory values for the 3 treatment groups No SAE were considered drug related Safety profile in SBS population similar to rates reported in Serostim ® package insert No clinically significant difference in laboratory values for the 3 treatment groups

Gastrointestinal Drugs Advisory Committee Meeting June 25, ConclusionsConclusions Study IMP20317: A single center, 41- patient study demonstrated subcutaneous rh-GH (0.1 mg/kg) in co- therapy with GLN and SOD reduces the total IPN volume requirement in patients with SBS Clinical relevance of the primary endpoint (reduction in Total IPN requirement per week) is uncertain Study IMP20317: A single center, 41- patient study demonstrated subcutaneous rh-GH (0.1 mg/kg) in co- therapy with GLN and SOD reduces the total IPN volume requirement in patients with SBS Clinical relevance of the primary endpoint (reduction in Total IPN requirement per week) is uncertain

Gastrointestinal Drugs Advisory Committee Meeting June 25, Outstanding Issues Replicability –Essentially a one center, single study trial enrolling 41-patients Generalizability –Can one center be representative of the US SBS population? Validity of Primary Endpoint of Efficacy –reduction in Total IPN Volume requirements –should primary endpoint be complete wean from IPN and lipid? –durability of response Further exploration of Dosing –Is low-dose rh-GH more effective? Replicability –Essentially a one center, single study trial enrolling 41-patients Generalizability –Can one center be representative of the US SBS population? Validity of Primary Endpoint of Efficacy –reduction in Total IPN Volume requirements –should primary endpoint be complete wean from IPN and lipid? –durability of response Further exploration of Dosing –Is low-dose rh-GH more effective?