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General Information

Gattex is specifically indicated for the treatment of adults with Short Bowel Syndrome who are dependent on parenteral support. Gattex was subsequently approved for pediatric patients 1 year of age and older with Short Bowel Syndrome (SBS) who need additional nutrition or fluids from intravenous (IV) feeding (parenteral support).

Gattex is supplied as a powder for reconstitution into a solution designed for subcutaneous injection. The recommended daily dose is 0.05 mg/kg body weight administered by subcutaneous injection once daily. Alternation of sites for subcutaneous injection is recommended.

Clinical Results

FDA Approval
The FDA approval of Gattex was based on four studies: Study 1 (Placebo-controlled) and Study 2 (Open-label extension of Study 1) and Study 3 (Placebo-controlled) and Study 4 (Blinded uncontrolled extension of Study 3).

Study 1 and Study 2
Study 1
This randomized, double-blind, placebo-controlled, parallel-group, multi-national, multi-center clinical trial enrolled adults with SBS who were dependent on parenteral nutrition/intravenous (PN/I.V.) support for at least 12 months and required PN at least 3 times per week. For 8 weeks (or less) prior to randomization, investigators optimized the PN/I.V. volume of all subjects. Optimization was followed by a 4-week to 8-week period of fluid stabilization. Subjects then were randomized to placebo (n=43) or Gattex 0.05 mg/kg/day (n=43). Study treatment was administered subcutaneously once daily for 24 weeks. PN/I.V. volume adjustments (up to 30% decrease) and clinical assessments were made at 2, 4, 8, 12, 20, and 24 weeks. The primary efficacy endpoint was based on a clinical response, defined as a subject achieving at least 20% reduction in weekly PN/I.V. volume from baseline to both Weeks 20 and 24. Treatment response was reached by 63% of Gattex-treated subjects versus 30% of placebo-treated subjects (p=0.002). At Week 24, the mean reduction in weekly PN/I.V. volume was 4.4 Liters for Gattex-treated subjects (from pre-treatment baseline of 12.9 Liters) versus 2.3 Liters for placebo-treated subjects (from pre-treatment baseline of 13.2 Liters/week) (p<0.001). Twenty-one subjects on Gattex (53.8%) versus 9 on placebo (23.1%) achieved at least a one-day reduction in PN/I.V. support.
Study 2
This ongoing two-year open-label extension of Study 1 has treated 88 subjects who receive Gattex 0.05 mg/kg/day. Of responders in Study 1 who entered Study 2, 100% sustained their response to Gattex after one year of continuous treatment. A 20% or greater reduction of parenteral support was achieved in 72% of subjects after an additional 28 weeks of continuous Gattex treatment. The mean reduction of weekly PN/I.V. volume was 5.2 L/week after one year of continuous Gattex treatment. Six subjects in Study 2 were weaned off their PN/I.V. support while on Gattex.
Study 3 and 4
Study 3
This randomized, double-blind, placebo-controlled, three parallel-group, multinational study enrolled adults with Short Bowel Syndrome who were dependent on parenteral nutrition/intravenous (PN/I.V.) support for at least 12 months and required PN at least 3 times per week. After a period of optimization and stabilization similar to Study 1, subjects were randomized to receive 24 weeks of one of the following treatment regimens: Gattex 0.05 mg/kg/day (n=35), Gattex 0.10 mg/kg/day dose (n=33), or placebo (n=16). The primary efficacy endpoint was a graded categorical score that did not achieve statistical significance for the high dose. Evaluation of PN/I.V. volume reduction using the endpoint of response (defined as at least 20% reduction in PN/I.V. fluid from Baseline to Weeks 20 and 24) showed that 46% of subjects on Gattex 0.05 mg/kg/day responded versus 6% on placebo. Subjects on Gattex at both dose levels experienced a 2.5 L/week reduction in parenteral support requirements versus 0.9 L/week for placebo at 24 weeks. Two subjects in the Gattex 0.05 mg/kg/day dose group were weaned off parenteral support by Week 24.
Study 4
This blinded, uncontrolled extension of Study 3, enrolled 65 subjects from Study 3 who received Gattex for up to an additional 28 weeks of treatment. Of responders in Study 3 who entered Study 4, 75% sustained response on Gattex after one year of treatment. In the Gattex 0.05 mg/kg/day dose group, a 20% or greater reduction of parenteral support was achieved in 68% (17/25) of subjects. The mean reduction of weekly PN/I.V. volume was 4.9 L/week (52% reduction from baseline) after one year of continuous Gattex treatment. The subjects who had been completely weaned off PN/I.V. support in Study 3 remained off parenteral support through Study 4. During Study 4, an additional subject from Study 3 was weaned off parenteral support.

FDA Approval in Pediatrics:

In a 24-week pediatric study 59 pediatric patients with SBS aged 1 year through 17 years chose whether to receive Gattex or standard of care (SOC). Patients who chose to receive Gattex treatment were subsequently randomized in a double-blind manner to 0.025 mg/kg/day (n=24) or 0.05 mg/kg/day (n=26), while 9 patients enrolled in the SOC arm. The recommended dosage of Gattex is 0.05 mg/kg/day. Randomization to the Gattex dose groups was stratified by age. At the end of the 24-week study, 69% of patients (18/26) who took Gattex 0.05 mg/kg each day reduced PS volume by 20% or more. Based on patient-diary data, patients who received Gattex 0.05 mg/kg/day experienced a 42% mean reduction in PS volume (mL/kg/day) from baseline (-23 mL/kg/day from baseline). At week 24, 38% of patients (10/26) were able to reduce PS infusion by at least 1 day per week. Patients reduced their PS infusion time by 3 hours per day on average compared to baseline. In addition, during this study 3 out of 26 (12%) children who received Gattex 0.05 mg/kg/day completely weaned off PS.

Side Effects

Adverse events associated with the use of Gattex may include, but are not limited to, the following:

abdominal pain
injection site reactions
nausea
headaches
abdominal distension
upper respiratory tract infection
vomiting
fluid overload

Mechanism of Action

Gattex (teduglutide) is an analog of naturally occurring human glucagon-like peptide 2 (GLP-2), a peptide secreted primarily in the distal intestine and involved in the regeneration and repair of the intestinal epithelium. GLP-2 is known to increase intestinal and portal blood flow, and inhibit gastric acid secretion.Teduglutide binds to the GLP-2 receptors located in intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Activation of these receptors results in the local release of multiple mediators including insulin-like growth factor (IGF)-1, nitric oxide and keratinocyte growth factor (KGF).

Literature References

Jeppesen PB, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O'keefe SJ, Forbes A, Heinze H, Joelsson B Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology 2012 Dec;143(6):1473-1481

Jeppesen PB, Gilroy R, Pertkiewicz M, Allard JP, Messing B, O'Keefe SJ Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome. Gut 2011 Jul;60(7):902-14.