# Presentation: 747553

## Serostim®

**Treatment of Short Bowel Syndrome**
**NDA 21-597**
**Division of Gastrointestinal and Coagulation Drug Products**
**Hugo E. Gallo-Torres, M.D., Ph.D, PNS**
**Medical Team Leader**

## Outline

**  **

** ****Introduction**
** ****Medical Literature **
** ****Study IMP20317**
** ****Outstanding Issues**
**replicability**
**generalizability **
**validity of endpoints**
**exploration of dosing**

## Proposed Indication

**Serostim****®**** **
**Treatment of Short Bowel Syndrome (SBS) in patients receiving specialized nutritional support **
**In conjunction with optimal management of SBS**

## 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**

## Complications of Long-Term Parental Nutrition 

**Cholelithiasis**
**Catheter Sepsis**
**Hepatic Dysfunction**
**Nutrient Deficiencies**
**Bone Demineralization**
**Central Vein Thrombosis**
**Glucose Metabolism Disorders**
**Progressive Renal Insufficiency**

## Known Complications of  Growth Hormone 

**Edema**
**Arthralgia**
**Headache**
**Hypothyroidism**
**Antibody Formation**
**Glucose Metabolism Disorders**
**Possible Association with Leukemia**
**Intracranial Hypertension with Papilledema**** **

## Controversy in Medical Literature

| Clinical Outcome Measure | rh-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 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 124:293-302 (2003) |  |  |  |
| 3(Genotropin Kabi Pharmacia, Stockholm, Sweden) rh-GH (0.024 mg/kg/d)
Ellegard L  Gastroenterology 113:1402-1405 (1997) |  |  |  |

##  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)**

## 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**

## 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**

## 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**

## 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 **

## Randomized Patients

| Site | Group A
rhGH | Group B
rhGH + GLN | Group C
GLN | Total |
| --- | --- | --- | --- | --- |
| 01 | 15 | 15 | 8 | 38 |
| 02 | 1 | 1 | 1 | 3 |
| Subtotal | 16 | 16 | 9 | 41 |

## 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**

## 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 |
| -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 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) |  |  |  |  |
| -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 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 **

## 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**

## 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**

## 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**

## 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 |  |  |
| 4 | 4 | 1 |
| Complete Wean from IPN and Lipids
(IV Hydration Acceptable) |  |  |
| 5 | 7 | 1 |

##  Adverse Events

**One or more AE**
**groups A&B: ****	****100%**
**control group:****	**** 89%**
**Most Common AEs**
**tissue edema**
**fatigue**
**gastrointestinal disorders**
** ****No Deaths**

## 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**

## Conclusions

_**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 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?**