# Presentation: 660448

## Gastrointestinal DrugsAdvisory CommitteeJune 25, 2003 

**Pamela Williamson Joyce, RAC**
**Vice President, Regulatory Affairs****& Quality Assurance – US**
**Serono, Inc.**

**NDA #21-597**

## 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.**

## Agenda

| Introduction and Regulatory History | Pamela Williamson Joyce, RAC
Vice President, Regulatory Affairs & Quality Assurance – U.S.
Serono, Inc. |
| --- | --- |
| Short BowelSyndrome (SBS):Unmet Medical Need | Douglas W. Wilmore, M.D., FACS Brigham & Women’s HospitalHarvard Medical School |
| SBS Phase III Clinical Study IMP 20317
Efficacy and Safety | Joseph Gertner, M.B., M.R.C.P.Vice President, Head – Metabolic and Endocrine Clinical Development Unit
Serono, Inc. |
| Conclusions | Pamela Williamson Joyce, RACSerono, Inc. |

## 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**

## 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**

## Orphan Drug Designation for Serostim®

| For use alone or in combination with glutamine in the treatment of patients with short bowel syndrome |  |
| --- | --- |
| Orphan Drug Regulation | Provides incentive for the development of drugs to treat rare diseases and conditions |
| Rare Disease orCondition | Prevalence < 200,000 patients with the disease in the US |
| Prevalence | 10,000 to 20,000 US adults dependent on parenteral nutrition due to SBS* |

***Annals of Surgery 1995; 222: 243**

## Regulatory History – Serostim® in SBSClinical Development Program

| October 1994 | Pre-IND meeting with DMEDP to discuss options for approval |
| --- | --- |
| August 1995 | FDA provided guidance for study design required for approval |

## 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**

## Regulatory History – Serostim® in SBS Clinical Development Program

| June 1997 | FDA agreement on protocol design including dose and primary endpoint |
| --- | --- |
| October 1997 | FDA confirmation that this one study will suffice as the pivotal study |
|  |  |

## 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**

## Regulatory History – Serostim® in SBS Clinical Development Program

| July 1998 | IND 48,750 transferred from original sponsor to Serono |
| --- | --- |
| August 2000  | Meeting/teleconference with FDA:
•	Difficulty in identifying a secondresidential clinical site
•	FDA recommends additional clinical site
•	No statistical requirement for minimum number of patients per center
•	Second residential clinical site identified     (July 2001)
Single study, single center can be filed – hurdles high for approvability |

## Regulatory History – Serostim® in SBS Clinical Development Program

| September 2002 | Pre-NDA meeting with FDA DMEDP
•	FDA agrees safety and efficacy adequate to support filing of NDA
•	Additional information needed (quantify the intake in diet to determine whether there is an imbalance between treatment groups) |
| --- | --- |
| October 2002 | SBS file submitted to FDA DMEDP |
| November 2002
 | Transferred to Gastrointestinal Drug Products Division
 |

## 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

## 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)

## Short Bowel Syndrome:Unmet Medical Need

**Douglas W. Wilmore, M.D., FACS**
**Frank Sawyer Professor of Surgery**
**Brigham & Women’s Hospital****Harvard Medical School**

## What is Short Bowel Syndrome?

**Healthy small intestine is about 600-650 cm****in length**
**Short bowel syndrome is loss of ****approximately 2/3 of this amount**

## 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 dependent****on parenteral nutrition**

## 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**

## Evolution of Care of Patientswith Short Bowel Syndrome

**Before 1960’s – no major therapies**
**>1970 – total parenteral nutrition**
**>1985 – bowel rehabilitation**
**>Late 1980’s – intestinal transplantation**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## Pilot Studies With Growth Hormone

**Experimental and clinical data on the effect of****GH 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**

## 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 D****Bowel Rehabilitation:  An alternative to long-term parenteral nutrition and intestinal transplantation for****some patients with short bowel syndrome.*****Transplantation Proceedings***** 2002; 34:887-890.**
**Byrne T, Nonpleggi D, Wilmore D****Advances in the management of patients with intestinal failure. *****Transplantation Proceedings***** ****1996; 28(5):2683-2690.**
**Byrne T, Persinger R, Young L, Ziegler T, Wilmore D****A new treatment for patients with short bowel syndrome – Growth hormone, glutamine and a modified diet.*****Ann Surg***** 1995;222(3):243-255.**

## 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**

## 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**

## SBS Clinical Trial IMP 20317

**Joseph Gertner, M.B., M.R.C.P.**
**Vice President,****Metabolic Endocrinology****Clinical Development Unit**
**Serono, Inc.**

## 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 and****as co-therapy, in the improvement of residual gut absorptive function in patients with short bowel syndrome”**

## 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.

## Review of Relevant Publications

| First AuthorDate | GHRx  | Major Endpoints* | n | DBPC | Comments |
| --- | --- | --- | --- | --- | --- |
| Ellegard1997 | Genotropin,Pharmacia0.024 mg/kg/d | LBM gain; +ve
Water, protein, energy absorption; -ve | 10 | Y | low dose |
| Scolapio1997 & 1999 | Humatrope, Eli Lilly 0.14 mg/kg/d | Fat, N balance; -ve d-xylose -ve
electrolyte bal. +ve Morphology -ve | 8 | Y | No colon 6/8
Crohn’s 7/8
Mean post surgery 12.9 y |
| Szkudlarek2000 | Norditropin,Novo0.14 mg/kg/d | Energy, CHO, fat, electrolyte balance; -ve | 8 | Y | Non-optimal nutrition
Crohn’s 6/8 |
| Zhu2002 | Serono rhGH, 0.053 mg/kg/d | Stool freq, stool N, d-xylose; all +ve | 27 | N | 8 followed >2 y, 4/8 off TPN |
| Seguy2003 | Genotropin,Pharmacia0.05 mg/kg/d | Energy, N,CHO, fat, electrolyte balance; +ve | 12 | Y | No glutamine |

**Review of Relevant Publications**

*** “+ve” indicates p- < 0.05 for authors’ chosen endpoint ****DBPC: double-blind placebo control**

## 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**

## SBS Pivotal TrialIMP 20317

## Trial Design

**Trial Design**

**rhGH = recombinant human growth hormone;**
**SOD = specialized oral diet;**
**GLN = glutamine 30 g/d po**

**Signed ICF +**
**Entered Clinic**

**Left**
**Clinic**

**Screening**
**Period**

**Randomization**

**Stabilization**

**SOD (GLN)**

**SOD**

**rhGH + SOD**

**rhGH **
**+**
**SOD (GLN)**

**4-Week**
**Treatment**

**2-Week**
**Baseline**

**12-Week**
**Follow-up by ****Referring Specialist**

**SOD (GLN)**

## 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**

## 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

## 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

## Eligibility

**Male or female, ages 18 to 75 years**
**Body mass index: 17-28 kg/m****2**
**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

## Patient Disposition

**n=16**
**rhGH + SOD (GLN)**

**n=15**
**Completed**
**Treatment Period**

**n=1**
**Discontinued**
**(SAE)**

**n=15**
**Completed**
**Follow-up Period**

**n=16**
**Completed**
**Follow-up Period**

**n=16**
**Completed**
**Treatment Period**

**n=9**
**Completed**
**Follow-up Period**

**n=9**
**Completed**
**Treatment Period**

**n=41**
**Subjects Randomized**

**n=47**
**Subjects Enrolled**

**n=6**
**Discontinued**
**Intercurrent illness (5)**
**Withdrew consent (1)**

**n=9**
**SOD (GLN)**

**n=16**
**rhGH + SOD**

## Demographics

|  | SOD (GLN)
(n=9) | rhGH + SOD 
(n=16) | rhGH +SOD (GLN)
(n=16) |
| --- | --- | --- | --- |
| Age (y)
Mean ± SD | 45 ± 15.5 | 50.5 ± 17.1 | 52.5 ± 14.4 |
| Male
Female | 33%
67% | 25%
75% | 31%
69% |
| Body weight (kg)
Mean ± SD | 61.3 ± 8.5 | 61.4 ± 10.4 | 62.1 ± 11.4 |

## Geographical Distribution of Study Patients for IMP20317* Shown in Orange 

**Geographical Distribution of Study Patients for IMP20317***** ****Shown in Orange **

*******	****2 patients outside United States****(India and Israel)**

## SBS Etiology

|  | SOD (GLN)
(n=9) | rhGH + SOD 
(n=16) | rhGH +SOD (GLN)
(n=16) |
| --- | --- | --- | --- |
| Intestinal Obstruction
Crohn’s Disease
Vascular Insufficiency
Volvulus
Acute Trauma
Toxic Megacolon
Antiphospholipid Syndrome | 2
1
1
3
2
–
– | 3
1
6
1
3
1
1 | 3
5
5
2
1
–
– |

## Additional SBS Related Factors

|  | SOD (GLN)
(n=9) | rhGH + SOD 
(n=16) | rhGH +SOD (GLN)
(n=16) |
| --- | --- | --- | --- |
| Time since resection (y)Mean ± SD | 3.9 ± 3.9 | 5.1 ± 5.9 | 4.6 ± 4.6 |
| No colon | 1 | 1 | 3 |

## 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**

## 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**

## 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)**

## Definition of Endpoints

**Total IPN = sum of:**
**Parenteral nutrition (PN)**
**IV hydration**
**Supplemental lipid emulsion****(in patients with essential fatty acid deficiency)**

## Weaning Criteria

**Reduce IPN prescription when patient shows**
**the ability to:**
**Hydrate**
**Maintain serum electrolytes**
**Sustain appropriate body weight**

## Efficacy DataSBS Pivotal TrialIMP 20317

## Change in Total IPN Volume:2-6 Weeks (liters/week)

## Change in Total IPN Calories:2-6 Weeks (kcal/week)

## PN or SLE Frequency:2-6 Week (infusions/week)

**0.025**

**<0.001**

**p-value vs. SOD (GLN):**

## Changes in Total IPN Volume

| 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) |

- Baseline 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) |

## Definition of Endpoints

**Total IPN = sum of:**
- Parenteral nutrition (PN)
- IV hydration
- Supplemental lipid emulsion

## Change in PN:  Week 2 vs. Week 6

*** p-value vs. SOD (GLN):**

**0.001**

**<0.001 for all 3***

**0.002**

**0.006***

**SOD (GLN)****(n=9)**

**rhGH + SOD****(n=16)**

**rhGH + SOD (GLN)****(n=16)**

**(L/wk)**

**(kcal/wk)**

**(f/wk)**

**(L/wk)**

**(kcal/wk)**

**(f/wk)**

**(L/wk)**

**(kcal/wk)**

**(f/wk)**

## PN:  Week 2 vs. Week 18

**Volume**

**Kcal**

**Frequency**

**P=not significant for rhGH + SOD vs. SOD (GLN)**
**P<0.05 for rhGH + SOD (GLN) vs. SOD (GLN)**

## Dietary Factors at Baseline

## Dietary Factors at Week 6

## Nutritional Changes to Week 18 Mean (±SD)

|  | WEEK 2 |  |  | WEEK 18 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | SOD (GLN) | rhGH + SOD | rhGH + SOD (GLN) | SOD (GLN) | rhGH + SOD | rhGH + SOD (GLN) |
| Sodium  (mEq/L) | 139.1
(1.9) | 139.9 
(2.6) | 141.0 
(1.9) | 140.8 
(2.6) | 139.4 
(3.6) | 141.8 
(3.0) |
| BUN  (mg/dL) | 19.0 
(8.4) | 19.6 
(7.0) | 21.0
(7.0) | 21.2 
(10.7) | 18.8 
(7.5) | 22.2 
(7.2) |
| Creatinine (mg/dL) | 0.8 
(0.4) | 0.7 
(0.3) | 0.7 
(0.2) | 0.7 
(0.3) | 0.7 
(0.2) | 0.8 
(0.3) |
| BUN:Creatinine (ratio) | 28.3
(18.5) | 29.2 
(14.3) | 29.2 
(9.8) | 29.0 
(13.1) | 26.4 
(9.8) | 29.5 
(10.4) |
| Magnesium (mEq/L) | 1.6 
(0.3) | 1.6 
(0.3) | 1.6 
(0.3) | 1.5 
(0.3) | 1.7 
(0.3) | 1.6 
(0.2) |
| Albumin  (g/dL) | 3.9 
(0.3) | 3.7 
(0.3) | 3.9 
(0.3) | 4.2 
(0.2) | 3.9 
(0.4) | 4.2 
(0.3) |
| Weight  (kg) | 62.5 
(8.4) | 62.9 
(10.2) | 63.9 
(11.6) | 60.0 
(9.1) | 58.9 
(10.5) | 58.7 
(9.4) |

## Follow-up of Patients Totally off IPN at 18 Weeks

| Pt. # | Treatment Group | Discharge Date | 1 Year | Current Status | Comments |
| --- | --- | --- | --- | --- | --- |
| 101 | rhGH + SOD (GLN) | 10/12/98 | On | On | Resumed PN daily in April, 1999. Currently requires 1 day of PN, 4 days of hydration. |
| 103 | rhGH + SOD | 10/12/98 | On |  | Resumed PN in January 1999, Tube feedings were stopped |
| 109 | SOD (GLN) | 12/21/98 | Off | Off |  |
| 110 | rhGH + SOD (GLN) | 2/22/99 | Off | Off | Received PN for 3 months 6/02 to 9/02 |
| 116 | rhGH + SOD | 4/19/99 | Off | Off |  |
| 126 | rhGH + SOD | 9/20/99 | Off | Off |  |
| 133 | rhGH + SOD | 3/24/00 | Off | Off |  |

**Follow-up of Patients Totally off IPN at 18 Weeks**

## Clinical Relevance of the Primary Endpoint

**Permanent intestinal failure in 94% after 2 yrs of PN**
**Reduction of PN**
- Reduces line sepsis and catheter occlusion
- Reduces liver disease proportional to reduction in PN (ESLD >15% in chronic PN)
- Permits oral feeding, which reduces biliary disease
- Enhances patient well-being and autonomy
**Additional benefits**
- Reduces costs of intravenous line maintenance and PN

## Safety DataSBS Pivotal TrialIMP 20317

## Adverse Events

|  | Patients n (%) |  |  |
| --- | --- | --- | --- |
|  | SOD (GLN)
(n=9) | rhGH + SOD
(n=16) | rhGH + SOD (GLN)
(n=16) |
| Patients 1 AE | 8 (89) | 16 (100) | 16 (100) |
| Body as a whole: general | 4 (44) | 15 (94) | 15 (94) |
| Peripheral edema | 1 (11) | 11 (69) | 13 (81) |
| Facial edema | 0 (0) | 8 (50) | 7 (44) |
| Gastrointestinal  | 6 (67) | 12 (75) | 12 (75) |
| Flatulence | 2 (22) | 4 (25) | 4 (25) |
| Abdominal pain | 1 (11) | 4 (25) | 2 (13) |
| Nausea | 0 (0) | 2 (13) | 5 (31) |
| Tenesmus | 3 (33) | 1 (6) | 3 (19) |
| Musculoskeletal system | 1 (11) | 7 (44) | 7 (44) |
| Arthralgia | 0 (0) | 7 (44) | 5 (31) |
| Myalgia | 1 (11) | 2 (13) | 0 (0) |

## Serious Adverse Events:  Weeks 2-6

|  | Related to rhGH | SOD (GLN)
n (%) | rhGH + SOD 
n (%) | rhGH + SOD (GLN)
n (%) |
| --- | --- | --- | --- | --- |
| Total number of patients with at least 1 SAE |  | 1 (11) | 4 (25) | 0 (0) |
| Chest pain | unlikely | 0 (0) | 2 (13) | 0 (0) |
| Hemorrhoids | unlikely | 1 (11) | 0 (0) | 0 (0) |
| Purpura | unlikely | 0 (0) | 1 (6) | 0 (0) |
| Fungal infection | unlikely | 0 (0) | 1 (6) | 0 (0) |
| Pharyngitis | unlikely | 0 (0) | 1 (6) | 0 (0) |

## Serious Adverse Events:  Weeks 6-18

| Patient | Adverse Event | Rx Group | Relatedness |
| --- | --- | --- | --- |
| 102 | Crohn’s & complications | SOD(GLN) | Unlikely |
| 105 | Acute pancreatitis | GH+SOD(GLN) | Unlikely |
| 113 | Line sepsis | GH+SOD | Unlikely |
| 116 | Dehydration, hypokalemia | GH+SOD | Unlikely |
| 117 | Line sepsis | SOD(GLN) | Unlikely |
| 122 | Line sepsis, septicemia | GH+SOD | Unlikely |
| 123 | Line sepsis | GH+SOD(GLN) | Unlikely |
| 131 | Wound infection | GH+SOD(GLN) | Unlikely |
| 134 | Line sepsis | GH+SOD | Unlikely |
| 301 | Pancreatitis | GH+SOD(GLN) | Unlikely |
| 302 | Fever, thrombosis | GH+SOD | Unlikely |

## Clinical Trial Summary

**Four week double-blind randomized clinical trial of rhGH in patients receiving a specialized diet with or without glutamine supplementation**
- 41 IPN-dependent adults with short bowel syndrome
- Patients receiving specialized diet with glutamine supplementation served as the control group
**Patients were re-evaluated by their referring physician 12 weeks after discharge**

## Summary of Efficacy

**rhGH achieved significantly greater reduction ****in PN than with glutamine-supplemented ****diet alone**
**Response was maintained 12 weeks after the ****end of rhGH therapy**
**Reduction in volume and frequency of infusions constitutes a major clinical benefit to this ****PN-dependent patient population**

## Summary of Safety

**rhGH was generally well-tolerated **
**rhGH-related adverse events were expected, ****well-characterized, and transient**
**Only one patient withdrew during the trial**
**No serious adverse events were considered related to growth hormone**

## Pamela Williamson Joyce, RAC
Vice President, Regulatory Affairs& Quality Assurance – US
Serono, Inc.

**Vice President, Regulatory Affairs****& Quality Assurance – US**
**Serono, Inc.**

**Conclusions**

## Medical Therapy of Short Bowel Syndrome

**“****The goal of medical therapy is for the patient to resume work and a normal lifestyle, or as normal of one as possible.  This is undertaken via the use of specific measures to gradually decrease the requirements for TPN, and at best, to eliminate its need.”**

**AGA Technical Review on Short Bowel Syndrome and Intestinal Transplant  *****Gastroenterology***** 2003;124:1111-1134**

## Conclusions

**Largest double-blind controlled clinical trial conducted in patients with this rare and ****life-threatening condition**
**rhGH reduces the needed quantity, calories, and frequency of IPN**
**Dose of 0.1 mg/kg/d safe and effective**
**Generalizable and accessible to SBS patients**
**Enhanced patient well-being and autonomy**
**Considerable reduction in cost**
**No other currently approved drug treatment**
**Positive benefit/risk profile**