serostim ® treatment of short bowel syndrome nda 21-597 division of gastrointestinal and...

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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


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


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


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


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


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)


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)


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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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