Andrew Ukleja, MD., AGAF., CNSP. Lecturer in Medicine, Harvard Medical School Division of Gastroenterology Beth Israel Deaconess Medical Center/BILH Boston, MA Speaker Disclosure n Medical Advisor for Coram 2 n Goals of management of SBS n Teduglutide (GATTEX®) n Indications/Mode of action n Efficacy/Benefits n Safety n Complications/Adverse effects n Limitations n Future directions n SBS has significant impact on patient’s quality of life n Management of SBS-IF is essentially supportive by parenteral nutrition (PN) n PN is associated with undesirable complications (line infections, liver disease, clotting) n Reduction in PS dependence is needed n Targeted therapy with Teduglutide (Gattex) is available for SBS patients dependent on parenteral support (PN/IV fluids) n Remnant small bowel length n < 100cm end-jejunostomy n < 65cm jejunocolic anastomosis n Time on parenteral nutrition n > 2 yrs. adults n > 4 yrs. children n Energy absorption < 84%/day n Fasting plasma citrulline level < 20μmol/L Jeppesen, Mortensen, 2003 Factors Associated with Successful Parenteral Support Weaning in Patients with Intestinal Failure • Length of remnant functional small bowel: >75 cm • Presence of colon • Presence of ileocecal valve • Absence of disease in remnant bowel • Degree of intestinal adaptation • Younger age of patient • Duration of parenteral support: <2 years • Nutritional status prior to weaning attempt • Compliance with diet, hydration and drugs • Higher plasma citrulline levels: >20 mmols/dL n Prevent dehydration and reduce diarrhea n Stabilization of electrolytes n Correct nutritional deficiencies n Maximize intestinal absorption n Weight stabilization or gain n Improve quality of life n Restore enteral autonomy n Eliminate need for PN Patient success Intestinal Long term Surgical Intestinal Rehabilitation PN Augmentation Transplant Teduglutide (Gattex) Bianchi Procedure Grading of SBS: Average Daily Need for PS Severity of SBS-IF Parenteral Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Support Volume <1000 1000-2000 2000-3000 3000- >4000 [ml/d] 4000 Energy <1000 1000-3000 3000-5000 5000- >7000 [kJ/d] 7000 Sodium <100 100-200 200-300 300SBS-400 Patient>400 [mmols/d] Potassium <25 25-50 50-75 75-100 >100 [mmols/d] Magnesium <5 5-10 10-15 15-20 >20 [mmol/d] Calcium <4 4-6 6-8 8-10 >10 [mmol/d] Jeppesen PB. Expert Opinion on Orphan Drugs 2013 Promoting Intestinal Adaptation: Enteral Nutrition Mediators of Intestinal Adaptation - Trophic Factors Non-specific Specific luminal nutrients stimulation Polymeric diet GI blood flow Pancreaticobiliary GI hormones secretions GLP-2 Tappenden KA. JPEN 2010;34:716-722 Role of Glucagon Like Peptide (GLP-2) in Intestinal Adaptation Drucker DJ, Erlich P, et al. Proc Natl Acad Sci U S A. 1996; 93:7911. National Academy of Sciences, USA Effects of Glucagon-like Peptide 2 Glucagon-like peptide-2 release by enteral nutrients and signaling effects n Promotes expansion of intestinal mucosa n Increased villi length n Reduced enterocyte apoptosis n Enhances nutrient & fluid absorption n Increased intestinal blood flow n Increases intestinal barrier function n Delays gastric emptying DL Sigalet, The assessment, and glucagon-like peptide-2 modulation, of intestinal absorption and function. Semin Pediatr Surg, 2010; 19; 44 SBS (n=7) vs. controls (n=7) Liquid meal (1.88 MJ) Solid meal (3.92MJ) Jeppesen PB, et al. Gut 1999;45:559 Intestinal Adaptation Spontaneous adaptation – SA; Arrows demonstrate: AA, accelerated adaptation; and HA, hyperadaptation; AHA, accelerated hyperadaptation Jeppesen PB. Growth factors in short-bowel syndrome patients Gastroenterol Clin N Am, 36 (2007), 109-121 n It is a recombinant analog of glucagon-like peptide (GLP-2) n Approved by FDA in December 2012 (USA) for adults n > 5 years of clinical experience n >1500 patients received Teduglutide in USA n Patients with short bowel syndrome-intestinal failure who are dependent on parenteral support (IV fluids/parenteral nutrition) n Adults n Approved for children 1 year of age and older (5/2019) IV Fluids Adults >18 year Short bowel syndrome-IF Parenteral Children >1 Nutrition year End-point: >20% PN weekly volume reduction 63% *P=0.002 N=86, >12 months from resection 30% % Response TG 0.05 mg/kg/d 27/43 13/43 SC x 24 weeks TG Placebo Jeppesen PB et al. Gastroenterology 2012;143:1473-81 TG (p=0.005) Absolute PN volume weekly reduction TG vs. Plac. 4.4 vs. 2.3 (L/wk) Jeppesen PB. et al. Gastroenterology 2012;143:1473-81 Off PS >1 day TG Jeppesen PB et al. Gastroenterology 2012;143:1473-81 PS reductions sustained with 30 months of TG therapy • 93% (28/30) achieved ≥ 20% reduction of PS volume • Mean reduction in PS volume from baseline 7.5 L/week (65.6%) Duration of Tedugutide 30 months 24 months* therapy (n=30) (n=29) Reduction of days per ≥ 1 day/week ≥ 1 day/week week on PS 70% (21/30) 48.3% (14/29) ≥ 2 days/wk ≥ 2 days/wk 60% (18/30) 24.1% (7/29) ≥ 3 days/wk ≥ 3 days/wk 60% (18/30) 17.2% (5/29) Weaned off PS 10 2 completely NPS Pharmaceuticals, Inc.; 2014. n Retrospective study; 18 pts. with SBS-IF (2009-2015) n RESULTS: n 61% complete enteral independence from PN/fluids n Wean off PS - ~10 months (3-36 months) n 10 of 11 pts. (91%) with enteral autonomy had colon n PN/IV volume reduced in all patients except 2 pts. Lam K, et al. Single-Center Experience with the Use of Teduglutide in Adult Patients with Short Bowel Syndrome. JPEN 2018;42:225 n 12-week study, 34 SBS-IF pts; age 1-17 yrs. n 3 TG groups: 0.0125 [n=8], 0.025 [n=14], 0.05 mg/kg/d [n=15] vs. standard care (n=5) n Results: n 4 patients weaned from PN n PN volume /calories (kcal/kg/d) reduced 41%/45%, (TG 0.025 mg/kg) vs. by 25%/52% (TG 0.05 mg/kg) n No serious teduglutide-related adverse events n Teduglutide was well tolerated n TG associated with reduced PN needs Carter BA, et al. J of Pediatrics 2017.P103 n 24-week, phase III trial, 59 pts., TED 0.025/0.05 mg/kg daily TED 0.025 mg/kg (n = 24); 0.05 mg/kg (n = 26), SOC: n = 9 RESULTS: n Primary end point (20% volume reduction) achieved by 13 (54.2%) vs. 18 (69.2%) pts. on teduglutide (0.025 vs. 0.05 mg/kg) n Teduglutide associated with significant reductions in PS volume, PS calories, days/week and hours/day of PS infusions, increases in enteral nutrition n 5 patients achieved enteral autonomy n Common AEs were pyrexia and vomiting Kocoshis SA, . Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study. JPEN 2019.1690 n STEPS studies combined 134 Pts. n Complete independence from PS 16 (12%) n Age 55 (50% men) n Volume 5.1 L/wk n SB length 52.5 cm n Colon in continuity 12 n Lower PS volume needs (< 7L/wk) 11 Iyer KR, Kunecki M, et al. JPEN 2017;41:946-951 n Recommended dose of GATTEX: 0.05 mg/kg x daily (adults) n Administered by subcutaneous injection only (daily) n 50% dosage reduction if moderate to severe renal impairment n How should I store Gattex? n Store in room temperature • Subcutaneous injections • Alternate sites between 1 of 4 quadrants of abdomen or thighs/arms n Potential risk of accelerated neoplastic growth n Advised colonoscopy 6 months prior to Rx and at 1 yr. of TG therapy (later q 5 years) n Intestinal obstruction n Pancreatic and biliary disease n Check amylase/lipase Before and q 6 months n Check LFTs Before and q 6 months while on TG n Fluid overload n Potential for fluid overload n Monitor for fluid overload or cardiac decompensation (pts. with cardiovascular disease) n Stoma swelling n Will Gattex affect my medications? n Increased absorption of oral medications with narrow therapeutic index (coumadin, anti-anxiety, pain medications) n Injection site reactions n 22% (125/566) of pts. experienced injection site reaction n Stoma swelling 41.9% n Abdominal pain 37.7% n Nausea/vomiting 36.4% n URI/Nasopharyngitis 26% n Injection site reaction 22% n Constipation/bloating 9.1% n Headache n ? Carcinogenesis Management of Adverse Effects of Teduglutide During Reduction of Parenteral Support Adverse effect Intervention Stoma • No intervention or dose reduction temporary swelling/enlargement • May need stoma appliance adjustment or change Abdominal • Consider teduglutide dose reduction pain/bloating • Exclude other conditions: obstruction, SIBO • If SIBO – treat with antibiotics • Consider surgical or endoscopic intervention if mechanical obstruction • Consider anti-bloat medications and probiotics Bowel obstruction • Consider teduglutide discontinuation if chronic obstruction • Stop teduglutide if mechanical obstruction identified • Temporary teduglutide discontinuation • Consider surgery if patient is a surgical candidate to correct obstruction. • If obstruction resolved --restart therapy Ukleja A. Weaning from Parenteral Nutrition. Gastroenterol Clin North Am. 2019;48:525 Management of Adverse Effects of Teduglutide During Reduction of Parenteral Support Adverse effect Intervention CHF/fluid overload • PN/IV fluid reduction • Consider diuretics • Reduce temporary teduglutide dose or temporary discontinuation until condition resolved Injection reaction • Consider dose reduction Increased absorption of • Reduce concomitant oral medication dose concomitant oral • Consider close frequent monitoring if blood medications levels for monitoring are available Colon polyps • Colonoscopy at appropriate intervals Ukleja A. Weaning from Parenteral Nutrition. Gastroenterol Clin North Am. 2019;48:525 n Active bowel stricture/mechanical obstruction n Colon cancer recent <5 years n Familial Polyposis Syndrome n Hx of duodenal adenoma n If active or prior non-GI cancer consider therapy based on risk vs.