Management of Short Bowel Syndrome in the Era of Teduglutide. Charlene Compher, PhD, RD University of Pennsylvania

Transcription

1 Management of Short Bowel Syndrome in the Era of Teduglutide Charlene Compher, PhD, RD University of Pennsylvania

2 Disclosures Research funding for clinical trials by NPS Pharmaceuticals Investigator-initiated protocol funding by NPS Pharmaceuticals No current conflicts to report

3 Overview Review of short bowel syndrome Home parenteral nutrition risks Gut adaptation Established dietary strategies Human growth hormone Teduglutide

4 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

5 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

6 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%)

7 Short Bowel Syndrome Anatomy Jejunoileal Anastomosis Jejunocolic Anastomosis End Jejunostomy

8 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

9 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 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

11 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

12 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

13 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

14 Diet to Support Adaptation Grazing eating style Good quality protein foods, simply prepared Complex carbohydrates Salty foods Sip salty fluids

15 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

16 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

17 Somatropin HPN Volume (Liters/week) Infusions (Days/week) * * *

18 Change from Baseline (kg) Weight Change No significant change in weight during study 4 3 Weight change after study end attributed to fluid shifts End Follow-up Byrne, Ann Surg 2005; 242: Weeks Gln GH Gln + GH

19 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

20 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

21 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 : 45S

22 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

23 Teduglutide RCT Flow Chart O Keefe, Clin Gastroenterol Hepatol 2013; 11:

24 HPN Reduction after 12 months, N=52 O Keefe, Clin Gastroenterol Hepatol 2013; 11:

25 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:

26 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 >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 But not significantly better than placebo (N=35 each group)

27 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

28 Intestinal Anatomy 30 INCREASE PN (n=15) NO CHANGE/DECREASE PN (n=22) 59 Small Bowel (cm) 60 Colon (cm) * * 67 Colon in Continuity (%) 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

29 BMI Change and Complications BMI Change After Stopping Teduglutide Entire Sample Complication Incidence Increase PN Decrease/ No Change PN All, N=25 14 in 3/15 subjects 11 in 7/22 subjects INC NEUT/DEC 0 1 BMI_Chg_3M BMI_Chg_6M BMI_Chg_12M Drug responders, N=18 13 in 3/12 subjects; 1.5/perso n year* 5 in 3/13 subjects 0.38/ person year* Median, IQR error bars. BMI in INC, p<0.001; no change in NEUT/DEC subjects

30 Regression Models Predict Change in BMI off-drug Entire Sample adj R 2 =0.71 Variable Beta P Drug Responders, adj R 2 =0.74 Beta P Colon(cm) <0.001 SB (cm) < BMI off-drug (kg/m 2 ) On-drug Reduction in PN vol (L/wk)

31 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

32 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

33 Neonatal Piglets Treated with GLP2 5 days after SBS Vegge A et al. Am J Physiol Gastrointest Liver Physiol 2013;305:G277-G by American Physiological Society

34 Neonatal Piglet Jejunostomy Model, Teduglutide + PN for 7 days Enhanced early trophicity No early effect on function Twymann, JPGN 2014; 58: 694

35 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.

36 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

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