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. benefit ratio assessment after consultation with n Intestinal failure due to dysmotility n Scleroderma n Chronic intestinal pseudoobstruction n Massive bowel distention n (Post trauma) n What to expect? – A reduction in daily PS volume +/- days on PS – Individual responses may vary

§ What NOT to expect? – Immediate or full discontinuation of PS § Compliance to the safety assessments: Colonoscopy, blood tests, follow-up

§ Adherence to parenteral support, diet/fluids, and adjunctive medications

§ Self-monitoring of daily nutrient/fluid intake, urinary output, stool characteristics How will we determine how much fluid volume I need?

>10% increase During days over the off PS, UO >1 On PS less baseline in YES YES YES L/d and no than 3 average UO sign of days/week? with stable dehydration? clinical status?

NO NO NO Wean off PS Reduce PS Reduce days volume by on PS by 1 Do NOT 10%-30% reduce PS volume Do NOT reduce days No weaning on PS off PS attempt PS Weaning Protocol with TG is based on Urine Output!

UO – Urine output Seidner D, et al. JPEN 2013;37:201-211 Algorithm for PN Weaning

PN/IV Weaning Patient characteristics* • < 1 year from surgery YES and Standard measures • Complex case with • Optimization of multiple comorbidities hydration, diet, and • Severe malabsorption medications Teduglutide Therapy • High stoma output > 2L/d not controlled with standard antidiarrhea Patient characteristics medications • Any PN/IV • High PS needs requirements • PN complications • Any time from YES surgery if patient Reduce PN days or stable volume weekly Patient characteristics • Prior PN/IV weaning failure • On PN/IV >1 year • On PN/IV >3 days x a Continue to monitor: PN/IV weaning failure week • Renal function • Dehydration • Last surgery >1 year • Electrolytes • Urine output <1L/d • No GI cancer/GI • Vitamins/Minerals • Weight loss obstruction • Weight • Lytes abnormalities Risks of Weaning from Parenteral Support

• Dehydration • Renal insufficiency • Electrolytes abnormalities • Vitamin and mineral deficiencies • Vitamin B12, fat soluble vitamins: A, D, E • Magnesium, phosphorus, zinc • Essential fatty acids deficiency • Weight loss • Feeling tired/fatigue • Kidney stones • Hypotension n Duration of therapy n Rx for life? n When to start TG in relation to onset of SBS (from time of last bowel resection)? n Optimal patient selection n How to determine failure of TG therapy? n Long-term safety and efficacy SBS-IF Case

• 71-year-old male with small bowel and partial right colon resection following complications of sigmoid colectomy • Anatomy: 90 cm of small bowel +40 cm of transverse colon + end-colostomy • Dependent on parenteral support (volume 1,6 L; 6 times/week) x 12 months • High stoma output > 1.5 L/d

• TG started in July 2013

• 1st month of TG: abdominal pain/severe bloating - resolved with doxycycline 100 mg daily x 21 days (SIBO)

SBS—IF Case

• Stoma enlargement was managed conservatively

• Small bowel obstruction at 1 +3 month of TG therapy • Subsequently, mechanical obstruction at the stoma site was identified, requiring surgical revision and temporary discontinuation of TG

• Episode of fluid overload & congestive heart failure at month 16 of TG

• Large duodenal polyp was removed

• PS was weaned off after 16 months Teduglutide Therapy in SBS-IF

TPN

PS reduction n Novel long-acting GLP-2 analogs (? once a week) n Glepaglutide (ZP1848) [Zealand Pharma] (1) n Apraglutide (Terachon) (2) n GLP-1 n Exenatide (3)

1.Naimi RM. Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial. Lancet Gastroenterol Hepatol. 2019;4:354 2.Slim GM, Novel Long-Acting GLP-2 Analogue, FE 203799 (Apraglutide), Enhances Adaptation and Linear Intestinal Growth in a Neonatal Piglet Model of Short Bowel Syndrome with Total Resection of the Ileum. JPEN 2019. 43:891 3. Kunkel D, Efficacy of the glucagon-like peptide-1 agonist exenatide in the treatment of short bowel syndrome. Neurogastroenterol Motil. 2011;23:739 n Teduglutide n Demonstrates restoration of structural and functional integrity of remaining intestine n Provides clinically meaningful benefits n Reduces needs for PN/fluids or leads to PN/fluids discontinuation n Less days on PS n Appears to be safe and well-tolerated n Patient compliance with therapy is important This is one of those new miracle drugs. If you can afford it, it’s a miracle!

Thank you