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SerostimSerostim®®SerostimSerostim®®
Treatment of Short Bowel Syndrome
NDA 21-597
Division of Gastrointestinal and Coagulation Drug ProductsDivision of Gastrointestinal and Coagulation Drug Products
Hugo E. Gallo-Torres, M.D., Ph.D, PNSMedical Team Leader
Treatment of Short Bowel Syndrome
NDA 21-597
Division of Gastrointestinal and Coagulation Drug ProductsDivision of Gastrointestinal and Coagulation Drug Products
Hugo E. Gallo-Torres, M.D., Ph.D, PNSMedical Team Leader
2Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
OutlineOutlineOutlineOutline
• 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
3Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Proposed IndicationProposed IndicationProposed IndicationProposed 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
4Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Short Bowel SyndromeShort Bowel SyndromeTreatmentTreatment
Short Bowel SyndromeShort Bowel SyndromeTreatmentTreatment
• 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
5Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Complications of Long-Term Complications of Long-Term Parental Nutrition Parental Nutrition
Complications of Long-Term Complications of Long-Term Parental Nutrition 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
6Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Known Complications of Known Complications of Growth Hormone Growth Hormone
Known Complications of Known Complications of Growth Hormone 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
7Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Controversy in Medical LiteratureControversy in Medical LiteratureControversy in Medical LiteratureControversy in Medical Literature
Clinical Outcome Measurerh-GH Dose
High1 Low2 Low3
Body Weight NC + +
Lean Body Mass NC + +
Fat Mass NC
Absorption of Fat +
Absorption of Fatty Acids NC
24-hour Creatinine Excretion NC
IGF-1 or IGF Binding Protein + +References
1(Novo-Nordisk AS, Bagsvaerd, Denmark) rh-GH (0.14 mg/kg/d) plus glutamineJeppessen 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 124:293-302 (2003)
3(Genotropin Kabi Pharmacia, Stockholm, Sweden) rh-GH (0.024 mg/kg/d)Ellegard L Gastroenterology 113:1402-1405 (1997)
8Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Study IMP20317Study IMP20317DesignDesign
Study IMP20317Study IMP20317DesignDesign
• 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)
9Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Treatment ArmsTreatment ArmsTreatment ArmsTreatment 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
10Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Primary EndpointPrimary EndpointPrimary EndpointPrimary 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
11Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Secondary EndpointsSecondary EndpointsSecondary EndpointsSecondary 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
12Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Sponsor’sSponsor’sExploratory AnalysisExploratory Analysis
Sponsor’sSponsor’sExploratory AnalysisExploratory 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
13Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Randomized PatientsRandomized PatientsRandomized PatientsRandomized Patients
SiteGroup A
rhGHGroup B
rhGH + GLNGroup C
GLN Total
01 15 15 8 38
02 1 1 1 3
Subtotal 16 16 9 41
14Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Study PopulationStudy PopulationStudy PopulationStudy 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
15Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Primary Efficacy AnalysisPrimary Efficacy AnalysisPrimary Efficacy AnalysisPrimary Efficacy Analysis
Mean Change in Total IPN Vol.Difference in Total IPN Volume
[L/wk] (p-value)
Group ArhGH(n=16)
Group BrhGH + GLN
(n=16)
Group CGLN(n=9)
GroupB vs C
GroupA vs C
-5.9 -7.7 -3.8 -3.9 (<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
16Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Secondary Efficacy AnalysisSecondary Efficacy Analysis Secondary Efficacy AnalysisSecondary Efficacy Analysis
Treatment Groups*
Group ArhGH(n=16)
Group BrhGH + GLN
(n=16)
Group CGLN(n=9)
GroupB vs C
GroupA vs C
Change in Total IPN Calories [kcal/wk] / (p-value)
-4338.3 -5751.2 -2633.3-3117.9 (<0.001)
-1705.0 (0.005)
Change in IPN or Lipid frequency [d/wk] (p-value)
-3.0 -4.2 -2.0 -2.2 (<0.001) -1.0 (0.025)
*ITT Population
17Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Effects of CovariatesEffects of Covariateson Primary Endpointon Primary EndpointEffects of CovariatesEffects of Covariateson Primary Endpointon 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
18Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Significance of Treatment Effect Significance of Treatment Effect After Adjusting for CovariatesAfter Adjusting for Covariates
Significance of Treatment Effect Significance of Treatment Effect After Adjusting for CovariatesAfter 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
19Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Effects of CovariatesEffects of Covariateson Secondary Endpointson Secondary Endpoints
Effects of CovariatesEffects of Covariateson Secondary Endpointson 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
20Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Changes in Specialized Changes in Specialized Oral DietOral Diet
Changes in Specialized Changes in Specialized Oral DietOral 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
21Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Exploratory AnalysisExploratory AnalysisExploratory AnalysisExploratory Analysis
Complete RespondersGroup A
rhGH(n=16)
Group BrhGH + GLN
(n=16)
Group CGLN(n=9)
Complete Wean from IPN, Lipids and IV Hydration
4 4 1
Complete Wean from IPN and Lipids(IV Hydration Acceptable)
5 7 1
22Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Adverse EventsAdverse Events Adverse EventsAdverse 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
23Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Adverse EventsAdverse EventsAdverse EventsAdverse 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
24Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
ConclusionsConclusionsConclusionsConclusions
• 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
25Gastrointestinal Drugs Advisory Committee MeetingJune 25, 2003
Outstanding IssuesOutstanding IssuesOutstanding IssuesOutstanding 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?
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