Transcript Gastrointestinal Drugs Advisory Committee NDA #21-597 Pamela Williamson Joyce, RAC

Gastrointestinal Drugs
Advisory Committee
June 25, 2003
NDA #21-597
Pamela Williamson Joyce, RAC
Vice President, Regulatory Affairs
& Quality Assurance – US
Serono, Inc.
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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.
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Agenda
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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.
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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
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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
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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
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Regulatory History – Serostim® in SBS
Clinical Development Program
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October 1994
Pre-IND meeting with DMEDP to discuss
options for approval
August 1995
FDA provided guidance for study design
required for approval
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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
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Regulatory History – Serostim® in SBS
Clinical Development Program
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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
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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
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Regulatory History – Serostim® in SBS
Clinical Development Program
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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
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Regulatory History – Serostim® in SBS
Clinical Development Program
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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
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External Consultant Experts
• Kareem Abu-Elmagd, MD, PhD
– Professor of Surgery; Director of Intestinal Transplant Services
Thomas E. Starzl Transplantation Institute (Pittsburgh, PA)
• Theresa A. Byrne, DSc
– Director of Research and Clinical Services
Nutritional Restart Center
– Instructor in the Department of Surgery
Harvard Medical School (Boston, MA)
• Gary Koch, PhD
– Statistical Consultant
Chapel Hill, NC
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External Consultant Experts
• Donald P. Kotler, MD
– Professor of Medicine
Columbia University (New York, NY)
– Chief of GI
St. Luke's-Roosevelt Hospital Center (New York, NY)
• Bert Spilker, MD, PhD
– Co-founder and former President
Orphan Medical
– Adjunct Professor of Medicine; Clinical Professor of Pharmacy
University of North Carolina (Chapel Hill, NC)
• Douglas W. Wilmore, MD, FACS
– Frank Sawyer Professor of Surgery
Brigham and Women’s Hospital
– Harvard Medical School (Boston, MA)
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Short Bowel Syndrome:
Unmet Medical Need
Douglas W. Wilmore, M.D., FACS
Frank Sawyer Professor of Surgery
Brigham & Women’s Hospital
Harvard Medical School
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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SBS Clinical Trial IMP 20317
Joseph Gertner, M.B., M.R.C.P.
Vice President,
Metabolic Endocrinology
Clinical Development Unit
Serono, Inc.
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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”
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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.
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Review of Relevant Publications
First Author
Date
GH
Rx
Ellegard
1997
Scolapio
1997 & 1999
Szkudlarek
2000
Major Endpoints*
n
DBPC
Genotropin,
Pharmacia
0.024 mg/kg/d
LBM gain; +ve
10
Y
low dose
Humatrope,
Eli Lilly
0.14 mg/kg/d
Fat, N balance; -ve
d-xylose -ve
8
Y
No colon 6/8
Water, protein, energy
absorption; -ve
Crohn’s 7/8
electrolyte bal. +ve
Morphology -ve
Mean post
surgery 12.9 y
Norditropin,
Novo
0.14 mg/kg/d
Energy, CHO, fat,
electrolyte balance; -ve
Zhu
2002
Serono rhGH,
0.053 mg/kg/d
Stool freq, stool N,
d-xylose; all +ve
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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
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8
Y
Non-optimal
nutrition
Crohn’s 6/8
* “+ve” indicates p- < 0.05 for authors’ chosen endpoint
DBPC: double-blind placebo control
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Comments
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
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SBS Pivotal Trial
IMP 20317
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Trial Design
Left
Clinic
SOD (GLN)
Screening
Period
Stabilization
rhGH + SOD
Randomization
Signed ICF +
Entered Clinic
2-Week
Baseline
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SOD
(GLN)
rhGH
+
SOD (GLN)
4-Week
Treatment
rhGH = recombinant human growth hormone;
SOD = specialized oral diet;
GLN = glutamine 30 g/d po
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SOD
12-Week
Follow-up by
Referring Specialist
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
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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
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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
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Eligibility
• Male or female, ages 18 to 75 years
• Body mass index: 17-28 kg/m2
• 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:
a)  30% of colon functional and  15 cm jejunum and/or ileum
remaining intact
b)  30% of colon functional and  90 cm jejunum and/or ileum
intact
c) Stool output  3 L/day
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Patient Disposition
n=47
Subjects Enrolled
n=6
Discontinued
Intercurrent illness (5)
Withdrew consent (1)
n=41
Subjects Randomized
n=9
SOD (GLN)
41
n=16
rhGH + SOD
n=9
Completed
Treatment Period
n=15
Completed
Treatment Period
n=9
Completed
Follow-up Period
n=15
Completed
Follow-up Period
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n=1
Discontinued
(SAE)
n=16
rhGH + SOD (GLN)
n=16
Completed
Treatment Period
n=16
Completed
Follow-up Period
Demographics
Age (y)
Mean ± SD
Male
Female
Body weight (kg)
Mean ± SD
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SOD (GLN)
(n=9)
rhGH + SOD
(n=16)
rhGH +
SOD (GLN)
(n=16)
45 ± 15.5
50.5 ± 17.1
52.5 ± 14.4
33%
67%
25%
75%
31%
69%
61.3 ± 8.5
61.4 ± 10.4
62.1 ± 11.4
Geographical Distribution of Study Patients
for IMP20317* Shown in Orange
* 2 patients outside United States
(India and Israel)
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SBS Etiology
SOD (GLN)
(n=9)
2
rhGH + SOD
(n=16)
3
rhGH +
SOD (GLN)
(n=16)
3
Crohn’s Disease
1
1
5
Vascular Insufficiency
1
6
5
Volvulus
3
1
2
Acute Trauma
2
3
1
Toxic Megacolon
–
1
–
Antiphospholipid Syndrome
–
1
–
Intestinal Obstruction
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Additional SBS Related Factors
Time since resection (y)
Mean ± SD
No colon
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SOD (GLN)
(n=9)
rhGH + SOD
(n=16)
rhGH +
SOD (GLN)
(n=16)
3.9 ± 3.9
5.1 ± 5.9
4.6 ± 4.6
1
1
3
Etiology of SBS in the General SBS Population
IMP 20317
17%
20%
SBS etiologies
(Buchman et al, 2003)
• Crohn’s
• Vascular
12%
• Volvulus
• Trauma
(incl surgical accident)
26%
10%
15%
• Cancer
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Crohn's
Vascular insufficiency
Volvulus
Trauma
Other
Intestinal obstruction
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
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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)
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Definition of Endpoints
Total IPN = sum of:
• Parenteral nutrition (PN)
• IV hydration
• Supplemental lipid emulsion
(in patients with essential fatty acid deficiency)
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Weaning Criteria
Reduce IPN prescription when patient shows
the ability to:
1. Hydrate
2. Maintain serum electrolytes
3. Sustain appropriate body weight
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Efficacy Data
SBS Pivotal Trial
IMP 20317
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Change in Total IPN Volume:
2-6 Weeks (liters/week)
SOD (GLN)
rhGH + SOD
rhGH + SOD (GLN)
0
-2
-3.84
-4
-5.85
-6
-7.74
-8
-10
-12
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p-value vs. SOD (GLN):
0.043
<0.001
Change in Total IPN Calories:
2-6 Weeks (kcal/week)
SOD (GLN)
rhGH + SOD
rhGH + SOD (GLN)
0
-2000
-2633.3
-4338.3
-4000
-5751.2
-6000
-8000
-10000
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p-value vs. SOD (GLN):
0.005
<0.001
PN or SLE Frequency:
2-6 Week (infusions/week)
p-value vs. SOD (GLN):
0.025
<0.001
6
5.89
5.44
5
5.06
4
3.89
3
2
2.11
1
1.25
0
SOD (GLN)
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rhGH + SOD
rhGH + SOD (GLN)
Changes in Total IPN Volume
Mean Change in Total IPN Vol.
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
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Difference in Total IPN Volume [L/wk]
(p-value)
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Secondary Efficacy Analysis
Treatment Groups
Group A
rhGH
(n=16)
Group B
rhGH + GLN
(n=16)
Group C
GLN
(n=9)
Change in Total IPN Calories
-4338.3
-5751.2
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-4.2
Group
A vs C
[kcal/wk] / (p-value)
-2633.3
Change in IPN or Lipid frequency
-3.0
Group
B vs C
-3117.9 (<0.001) -1705.0 (0.005)
[d/wk] / (p-value)
-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
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Change in PN: Week 2 vs. Week 6
SOD (GLN)
(n=9)
0
(L/wk)
(kcal/wk)
(f/wk)
rhGH + SOD
(n=16)
(L/wk)
(kcal/wk)
(f/wk)
rhGH + SOD (GLN)
(n=16)
(L/wk)
(kcal/wk)
(f/wk)
-3
-6
-9
-12
* p-value vs. SOD (GLN):
-15
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0.001
0.002 0.006*
<0.001 for all 3*
PN: Week 2 vs. Week 18
14
Volume
Kcal
Frequency
12
10
8
6
4
2
0
SOD(GLN)
GH+SOD
GH+SOD(GLN)
SOD(GLN)
GH+SOD
GH+SOD(GLN)
P=not significant for rhGH + SOD vs. SOD (GLN)
P<0.05 for rhGH + SOD (GLN) vs. SOD (GLN)
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SOD(GLN)
GH+SOD
GH+SOD(GLN)
Dietary Factors at Baseline
2,500
2,000
1,500
1,000
500
0
Fluid (L/w*100)
Kcal/w/10
SOD (GLN)
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Protein (g/w)
rhGH+SOD
CHO (g/w)
Fat (g/w)
rhGH+SOD (GLN)
Dietary Factors at Week 6
2,500
2,000
1,500
1,000
500
0
Fluid (L/w*100)
Kcal/w/10
SOD (GLN)
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Protein (g/w)
rhGH+SOD
CHO (g/w)
Fat (g/w)
rhGH+SOD (GLN)
Nutritional Changes to Week 18 Mean (±SD)
WEEK 2
Sodium (mEq/L)
BUN (mg/dL)
Creatinine
(mg/dL)
BUN:Creatinine
(ratio)
Magnesium
(mEq/L)
Albumin (g/dL)
Weight (kg)
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WEEK 18
SOD
(GLN)
rhGH +
SOD
rhGH +
SOD (GLN)
SOD
(GLN)
rhGH +
SOD
rhGH +
SOD (GLN)
139.1
139.9
141.0
140.8
139.4
141.8
(1.9)
(2.6)
(1.9)
(2.6)
(3.6)
(3.0)
19.0
19.6
21.0
21.2
18.8
22.2
(8.4)
(7.0)
(7.0)
(10.7)
(7.5)
(7.2)
0.8
0.7
0.7
0.7
0.7
0.8
(0.4)
(0.3)
(0.2)
(0.3)
(0.2)
(0.3)
28.3
29.2
29.2
29.0
26.4
29.5
(18.5)
(14.3)
(9.8)
(13.1)
(9.8)
(10.4)
1.6
1.6
1.6
1.5
1.7
1.6
(0.3)
(0.3)
(0.3)
(0.3)
(0.3)
(0.2)
3.9
3.7
3.9
4.2
3.9
4.2
(0.3)
(0.3)
(0.3)
(0.2)
(0.4)
(0.3)
62.5
62.9
63.9
60.0
58.9
58.7
(8.4)
(10.2)
(11.6)
(9.1)
(10.5)
(9.4)
Follow-up of Patients Totally off IPN at 18 Weeks
Pt. #
Discharge
Date
1 Year
Current
Status
101
rhGH +
SOD
(GLN)
10/12/98
On
103
rhGH +
SOD
10/12/98
On
12/21/98
Off
Off
2/22/99
Off
Off
109
110
63
Treatment
Group
SOD
(GLN)
rhGH +
SOD
(GLN)
On
Resumed PN daily in April, 1999.
Currently requires 1 day of PN,
4 days of hydration.
Resumed PN in January 1999,
Tube feedings were stopped
116
rhGH +
SOD
4/19/99
Off
Off
126
rhGH +
SOD
9/20/99
Off
Off
133
rhGH +
SOD
3/24/00
Off
Off
5/20/2016 10:45 AM
Comments
Received PN for 3 months
6/02 to 9/02
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
64
5/20/2016 10:45 AM
Safety Data
SBS Pivotal Trial
IMP 20317
65
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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)
1 (11)
7 (44)
7 (44)
Arthralgia
0 (0)
7 (44)
5 (31)
Myalgia
1 (11)
2 (13)
0 (0)
Musculoskeletal system
66
5/20/2016 10:45 AM
Serious Adverse Events: Weeks 2-6
Related
to rhGH
Total number of
patients with at
least 1 SAE
67
SOD (GLN)
n (%)
rhGH + SOD
n (%)
rhGH +
SOD (GLN)
n (%)
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)
5/20/2016 10:45 AM
Serious Adverse Events: Weeks 6-18
68
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
5/20/2016 10:45 AM
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
69
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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
70
5/20/2016 10:45 AM
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
71
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Conclusions
Pamela Williamson Joyce, RAC
Vice President, Regulatory Affairs
& Quality Assurance – US
Serono, Inc.
72
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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
73
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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
74
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