Management of Short Bowel Syndrome in the Era of Teduglutide

Charlene Compher, PhD, RD

University of Pennsylvania

compherc@nursing.upenn.edu

Disclosures

• Research funding for clinical trials by NPS Pharmaceuticals 2003-2012

• Investigator-initiated protocol funding by NPS Pharmaceuticals 2009-2011

• No current conflicts to report

Overview

• Review of short bowel syndrome

• Home parenteral nutrition risks

• Gut adaptation

• Established dietary strategies

• Human growth hormone

• Teduglutide

What is Short Bowel Syndrome (SBS)?

• SBS exists when a patient’s remaining intestinal function cannot meet nutrient needs for survival, growth (children), hydration, electrolyte balance

What Causes SBS in Adults?

• Surgical response to

– Blood clots in the artery or vein that feeds the bowel

– Malrotation (volvulus)

– Crohn’s disease resections

– Abdominal trauma

– Adhesions that cause bowel obstruction

What Causes SBS in Children?

• Surgical response to – Congenital anomalies

• Atresias (20%) – Narrowing or absence of a segment of bowel

• Gastroschisis (12.5%) – Bowel outside the abdominal wall at birth

• Aganglionosis (6%) – Nerves that control the bowel do not develop in utero

– Necrotizing enterocolitis in very low birth weight neonates (35%)

– Malrotation (10%)

Short Bowel Syndrome Anatomy

www.shortbowelsupport.com

Jejunocolic Anastomosis Jejunoileal Anastomosis

End Jejunostomy

SBS and HPN

• HPN is needed – When the bowel is very short

• <100 cm or 40 inches in adults • <40cm in children

– When much ileum is gone – When remaining bowel is diseased

• Active Crohn’s disease • Radiation damage • When bowel just doesn’t work

– Early after the bowel resection • Some patients don’t need HPN for a long time • Others do

Patient-identified Risks of HPN

• These factors are most important to patients

– Line infections

– Survival

– Quality of life

• Education about HPN

• Rapport with HPN team

• Psychological support

• Maximal HPN-free days – Dreesen, JPEN June 10 2014

Clinician-identified HPN Risks

• Catheter-related bloodstream infections – 61% of PN complications

• Van Gossum, Clin Nutr 2001; 20:205

– 50% of PN-associated deaths • Jeppesen, Scand J Gastro

1998; 338:839 • Am Gastro Assoc Position,

Gastro 2003; 124:1107

– Correlated with liver disease risk

• Kaufman, Pediatr Transpl 2002; 6:37

• Bouza, Clin Micro Infect 2002; 8:265

• PN-associated liver disease – 15% to 50%, depending on

definitions • Chan, 1999 • Cavicchi, Ann Intern Med

2000; 132:525

• Metabolic bone disease – 41% osteoporosis

• Pironi, Clin Nutr 2002; 21:289

Management Goals of PN-dependent SBS

• In adults

– Wean HPN as gut adaptation proceeds

– Push oral diet as key approach

• In children

– Achieve enteral autonomy

– Push enteral tube feedings and diet as approach to reduce PN dependence

Gut Adaptation

• Normal process by which the intestine steps up to do the work (absorbing nutrition from food) of bowel that’s gone

– Intestine tissue grows in number of cells

– Takes 1-2 years at least in adults, may be shorter in children

– Eating food is important

Gut Adaptation

• Spontaneous adaptation (SA)

• Hyper adaptation (HA) > SA

• Accelerated adaptation (AA), faster than SA

• Accelerated hyperadaptation (AHA)

• Goal of growth factors is to enhance adaptation

Jeppesen, Gastroenterol 2006; 130:S127-S131

Diet to Support Adaptation

• Grazing eating style

• Good quality protein foods, simply prepared

• Complex carbohydrates

• Salty foods

• Sip salty fluids

Somatropin

• Growth hormone (Zorbtive®)

• Approved by FDA for use in adult SBS

• Course is 4 weeks, dose 0.14 mg/kg/d

• Intestinotrophic

• Not advised for patients with history of cancer

• Common adverse drug effects are musculoskeletal pain, peripheral edema

Somatropin

• 41 adult HPN patients with SBS

• 4 wk treatment arms – 0.1 mg/kg/d GH vs – 0.1 mg/kg/d GH+ 30 g/d

oral glutamine vs – 30 g/d oral glutamine

• Byrne, Ann Surg 2005; 242:655

• Somatropin permitted significantly more HPN weaning than oral glutamine

• Only somatropin + glutamine + diet maintained reduction for 12 weeks

• AE – 94% w peripheral edema,

44% musculoskeletal complaints

Somatropin

HPN Volume (Liters/week) Infusions (Days/week)

* * *

Weight Change

• No significant change in weight during study

• Weight change after study end attributed to fluid shifts

– Byrne, Ann Surg 2005; 242:655

-4

-3

-2

-1

0

1

2

3

4

End Follow-up

Ch

an

ge f

rom

Baseli

ne (

kg

)

Weeks

Gln GH Gln + GH

Human Growth Hormone in Children

• N=14 children – Age 8-10 years – HPN dependent 8 years – 33 cm small bowel

• 0.14 mg/kg/day growth hormone for 4 months (N=7) vs no treatment (N=7)

• No difference in weaning from HPN

• No effect at 6 months off drug – Peretti JPEN 2011; 35:723

• N=8 children – Age 3-12 years – HPN dependent 4-12 years – 5-38 cm small bowel

• Gave 0.12 mg/kg/day for 3 months

• 6 of 8 children weaned off HPN

• At 12 months only 2 of 8 still off HPN – Goulet JPEN 2010; 34:513

Summary Somatropin

• In adults, usually 1 month treatment

• In children, 3-4 months

• Most studies show reduced benefit when drug stopped

• Side-effects improve with lower doses

Glucagon Like Peptide 2 (GLP2)

• Intestinotrophic

• Antisecretory

• ↑ blood flow to the bowel

– Brenholm, Scand J Gastro 2008

• Increases absorption of fluid, energy, nutrients

– Jeppesen JPEN J Parenter Enteral Nutr 2014 38: 45S

Teduglutide Clinical Trials

Inclusion

• Adults • 1 year HPN dependent

SBS • HPN 3 infusions/week • Urinary output > 1 L/d • Urine sodium >20 mmol/d • Serum Cr, BUN <1.5 ULN • LFTs < 2 ULN

Exclusion

• Pregnancy, lactation

• Cancer

• Clinical trial within 30 d

• GLP2 in past 3 m

Primary Outcome

• ≥20% reduction in HPN Volume

Teduglutide RCT Flow Chart

O’Keefe, Clin Gastroenterol Hepatol 2013; 11:815-823

HPN Reduction after 12 months, N=52

O’Keefe, Clin Gastroenterol Hepatol 2013; 11:815-823

Adverse Events

AE 0.05 mg/kg/d (N=25) 0.10 mg/kg/d (N=27)

Cardiac 3(12%) 2 (7%)

GI 17 (68%) 17 (63%)

• Abd distension 4 (16%) 4 (15%)

• Abd pain 7 (28%) 6 (22%)

• Nausea 5(20%) 11 (41%)

Musculoskeletal 9(36%) 11 (41%)

Headache 7 (29%) 11 (41%)

Stoma complication 3 (12%) 3 (11%)

Catheter sepsis 5 (20%) 4 (15%)

Injection site disorders 13 (52%) 19 (70%)

O’Keefe, Clin Gastroenterol Hepatol 2013; 11:815-823

SBS-QOL in Teduglutide Patients

Significantly improved • Diarrhea/ostomy output • GI s/s • Sleep • Daily activities • Skeletal muscle s/s • Social life • Physical health • Fatigue

• But not significantly better

than placebo (N=35 each group)

• >20% HPN volume reductions associated with improved QOL scores

• Patients with > 100 cm SB had more GI s/s • Jeppesen, Clinical Nutrition 32

(2013) 713e721

What happens to adults after stopping teduglutide?

• Subjects had received the drug ≥ 28 wk (N=37)

• Subset of drug responders, defined as ≥ 20% reduction in PN volume in response to drug (N=25)

Hypothesis:

• Most subjects would require increase in PN back to baseline levels

– Compher, JPEN J Parenter Enteral Nutr published online 8 August 2011

Intestinal Anatomy

30

60 67

59

91 91

Small Bowel(cm)

Colon(cm)

Colon inContinuity

(%)

INCREASE PN (n=15)

NO CHANGE/DECREASE PN (n=22)

* *

• No difference – Age

– Gender

– Time since GI surgery

– Pre-drug citrulline

– Drug dose

– Drug duration

– Change in citrulline on-drug

• 3 patients came off, stayed off PN – JPEN J Parenter Enteral Nutr

published online 8 August 2011

INC NEUT/DEC-6-4

-20

2

kg

/m2

0 1

Entire Sample

BMI Change After Stopping Teduglutide

BMI_Chg_3M BMI_Chg_6M

BMI_Chg_12M

Median, IQR error bars. BMI ↓in INC, p<0.001; no change in NEUT/DEC subjects

BMI Change and Complications

Complication Incidence

Increase PN

Decrease/ No Change PN

All, N=25 14 in 3/15 subjects

11 in 7/22 subjects

Drug responders, N=18

13 in 3/12 subjects; 1.5/person year*

5 in 3/13 subjects 0.38/ person year*

Regression Models Predict Change in BMI off-drug

Entire Sample adj R2=0.71

Variable Beta P

Colon(cm) 0.010 <0.001

SB (cm) 0.010 0.002

BMI off-drug (kg/m2)

-0.155 0.001

On-drug Reduction in PN vol (L/wk)

0.150 0.001

Drug Responders, adj R2=0.74

Beta P

0.012 <0.001

0.010 0.007

-0.120

0.037

0.198

0.012

Summary Teduglutide

• Teduglutide (Gattex®) – Safe for at least 12 months

• Adverse events not > placebo

– Effective • > 65% patients had > 20% ↓ in HPN volume over 12 months • 5/82 patients came off HPN

• Drug approved by FDA in December 2012 • Not if history of intestinal cancer • Require colonoscopy within 6 months of drug start • Insurance coverage • Not approved for children

• Outcomes after stopping drug less clear • No data on reduced doses

Pediatric Teduglutide Study

• Safety study

– Measure adverse effects after 3 months drug therapy

• 3 doses of Teduglutide, 1 placebo

– 36 children age 1-17 years

– Excluded if

• STEP in past 3 months

• Bowel obstruction

• Major intestinal surgery in past 3 months

• Untreated intestinal disease

– www.clinicaltrials.gov

Neonatal Piglets Treated with GLP2 5 days after SBS

Vegge A et al. Am J Physiol Gastrointest Liver Physiol

2013;305:G277-G285

©2013 by American Physiological Society

Neonatal Piglet Jejunostomy Model, Teduglutide + PN for 7 days

Enhanced early trophicity No early effect on function

Twymann, JPGN 2014; 58: 694

Neonatal Piglets with HPN +/- Teduglutide 17 days

Improved Liver Histology Improved Bile Flow

HPN w saline, cholestasis

HPN w Teduglutide, less cholestasis

Non-HPN oral diet control, normal

Turner, JPEN epub 2014; Oct 3.

Summary

• At present, we use best available approaches to improve the quality of life and reduce HPN dependence for patients with SBS – Diet strategies – Teduglutide in some adults

• Data not yet available in – Early adaptation window – Children – Dose reduction or alternate day dosing – Long-term outcomes – Data on outcomes after stopping drug