Safety and Efficacy of Teduglutide After 52 Weeks of Treatment in Patients With Short Bowel Syndrome Intestinal Failure

Transcription

1 Safety and Efficacy of Teduglutide After 52 Weeks of Treatment in Patients With Short Bowel Syndrome Intestinal Failure O keefe, S.J.D et al, Clinical Gastroenterology and Hepatology Accepted date: 21 December 2012

2 Background Loss of 50% of small intestine is well tolerated Intestinal failure occurs when >70% of small intestine and colon or >80% of small intestine has been lost Natural adaption due to peptide hormones: hypertrophy of gut and hyperplasia of mucosal surface (villous hyperplasia) Growth hormone: increases energy absorption, acromegaly Glucagon-like peptide-2 (GLP-2): villous hypertrophy, retards gastric secretion/emptying, increases mucosal blood flow/absorption Teduglutide: GLP-2 analog, longer half-life Bible class

3 Methods study design Patients who completed a 24-week randomized, double blind, placebo-controlled, parallel group, multicenter study of teduglutide (0.05mg/kg/d or 0.1mg/kg/d) Conclusion: Teduglutide was safe, well tolerated, intestinotrophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS with intestinal failure Jeppesen et al, Gut 2011;60: Bible class

4 Methods study design 32 centers in US, Canada, Denmark, France, Poland, Germany, Netherlands, UK, Belgium 28-week double-blind extension study, total treatment 52w Patients randomized to teduglutide initially continued with same dose Bible class

5 Methods exclusion criteria <18y cancer or lymphoproliferative disease Pregnancy / lactation active Crohn s disease radiation enteritis Scleroderma celiac disease alcohol/drug abuse allergy to teduglutide no use of immunomodultators, GH or GLP-2 in the last 12 weeks Bible class

6 Methods inclusion criteria >18y On parenteral nutrition SBS secondary to Crohn s disease, volvulus, injury, vascular ischaemia Remnant small bowel <150cm No suspicion of active inflammatory bowel disease or fistulas No history of radiation enteritis or sprue No alcohol/drug abuse No significant renal/hepatic/cardiac disease No glutamin/gh Bible class

7 Methods use of parenteral nutrition PN optimization and stabilization where IV fluids were adjusted until urine output 1-2L/d with >20mEq of sodium and blood creatitin normal Randomization teduglutide or placebo once daily for 24 weeks Efficacy of drug assessed by ability to reduce IV fluid requirements to maintain constant urine output PN reduced at 4-week intervalsif 48h urine output increased by 10% After 24 weeks willing patients continued for additional 28 weeks Bible class

8 Aim of the study Evaluation of long term safety, tolerability and efficacy of daily teduglutide for 52 weeks Bible class

9 Patient characteristics Bible class

10 Safety and tolerability Bible class

11 Efficacy 0.05: -4.9L/w (52%) 0.1: -3.3L/w (26%) Bible class

12 Efficacy Bible class

13 Discussion Efficacy not only maintained but increased after 52w Adverse event profile satisfactory Number of PN infusions per week could be reduced In 4 PN could be stopped Fasting plasma citrulline raised as sign of increased enterocyte mass (68% in 0.05, 86% in 0.1, significant) Animal models: GLP-2 in supraphysiologic doses may enhance rather than induce tumor growth longer studies needed Drug absorption is likely to be increased on teduglutide Reduction of PN translates to an inprovement of quality of life Bible class