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Gattex

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Gattex

CLINICAL PHARMACOLOGY

Mechanism Of Action

Teduglutide is an analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a peptide secreted by L-cells of the distal intestine. GLP-2 is known to increase intestinal and portal blood flow, and inhibit gastric acid secretion. Teduglutide binds to the glucagon-like peptide-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).

Pharmacodynamics

The ability of GATTEX to improve intestinal absorption was studied in 17 adult subjects with Short Bowel Syndrome using daily doses of 0.03, 0.10, 0.15 mg/kg (N=2-3 per dose group) in a 21-day, open-label, multi-center, dose-ranging study. All subcutaneous (abdomen) doses studied, except 0.03 mg/kg once daily, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750-1000 mL/day, and increased villus height and crypt depth of the intestinal mucosa.

At a dose 5 times the maximum recommended dose, teduglutide did not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetics

Absorption

In healthy subjects, GATTEX administered subcutaneously had an absolute bioavailability of 88% and reached maximum plasma teduglutide concentrations at 3-5 hours after administration. Following a 0.05 mg/kg subcutaneous dose in SBS subjects, the median peak teduglutide concentration (Cmax) was 36 ng/mL and the median area under the curve (AUC0-inf) was 0.15 μg•hr/mL. No accumulation of teduglutide was observed following repeated subcutaneous administrations.

Distribution

In healthy subjects, teduglutide has a volume of distribution (103 mL/kg) similar to blood volume.

Metabolism

The metabolic pathway of teduglutide was not investigated in humans. However, teduglutide is expected to be degraded into small peptides and amino acids via catabolic pathways, similar to the catabolism of endogenous GLP-2.

Elimination

In healthy subjects, teduglutide plasma clearance was approximately 123 mL/hr/kg which is similar to the GFR suggesting that teduglutide is primarily cleared by the kidney. Teduglutide has a mean terminal half-life (t1/2) of approximately 2 hours in healthy subjects and 1.3 hours in SBS subjects.

Dose Linearity

The Cmax and AUC of teduglutide was dose proportional over the dose range of 0.05 to 0.4 mg/kg GATTEX.

Hepatic Impairment

Subjects with moderate hepatic impairment had lower teduglutide Cmax and AUC (10 ~15%) compared to healthy matched control subjects after a single subcutaneous dose of 20 mg GATTEX. Teduglutide PK was not assessed in subjects with severe hepatic impairment.

Renal Impairment

In subjects with moderate to severe renal impairment or end stage renal disease (ESRD), teduglutide Cmax and AUC0-inf increased with the degree of renal impairment following a single subcutaneous administration of 10 mg teduglutide. Teduglutide exposure increased by a factor of 2.1 (Cmax) and 2.6 (AUC0-inf) in ESRD subjects compared to healthy subjects.

Geriatric Patients

No differences were observed between healthy subjects younger than 65 years and those older than 65 years. Experience in subjects 75 years and above is limited.

Gender

No clinically relevant gender differences were observed.

Clinical Studies

Study 1 (Placebo-controlled) And Study 2 (Open-label extension Of Study 1)

Study 1

The efficacy, safety, and tolerability of GATTEX was evaluated in a randomized, double-blind, placebo-controlled, parallel-group, multi-national, multi-center clinical trial (Study 1) in 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 (1:1) 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 (immediately before randomization) to both Weeks 20 and 24.

The mean age of subjects was 50.3 years. Mean duration of PN/I.V. dependency prior to enrollment was 6.25 years (range 1-25.8 years). The most common reasons for intestinal resection leading to SBS were vascular disease (34.1%, 29/85), Crohn's Disease (21.2%, 18/85), and “other” (21.2%, 18/85). Stoma was present in 44.7% (38/85) of subjects, and the most common type was jejunostomy/ileostomy (81.6%, 31/38). The mean length of remaining small intestine was 77.3±64.4 cm (range: 5 to 343 cm). The colon was not in continuity in 43.5% (37/85) subjects. At baseline, the mean (± SD) prescribed days per week for PN/I.V. infusion was 5.73 (±1.59) days.

The percentages of treatment group responders were compared in the intent-to-treat population of this study which was defined as all randomized patients. 63% (27/43) of GATTEX-treated subjects versus 30% (13/43) of placebo-treated subjects were considered responders (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.

The mean changes from Baseline in PN/I.V. volume by visit are shown in Figure 2.

Figure 2: Change ( ±95% CI) in PN/I.V. volume (L/week)

The mean changes from Baseline in PN/I.V. volume by visit - Illustration

Study 2. Study 2 was a 2-year open-label extension of Study 1 in which 88 subjects received GATTEX 0.05 mg/kg/day. Ninety-seven percent (76/78) of subjects who completed Study 1 elected to enroll in Study 2 (37 received GATTEX; (39 received Placebo). An additional 12 subjects entered Study 2, who had been optimized and stabilized but not randomized in Study 1 because of closed enrollment.

30 months exposure

Thirty GATTEX subjects completed a total duration of 30 months (Study 1 followed by Study 2 treatment). Of these, 28 subjects (93%) achieved a 20% or greater reduction of parenteral support. Of responders in Study 1 who had completed 2 additional years of continuous treatment with GATTEX, 96% (21/22) sustained their response to GATTEX. The mean reduction in PN/I.V. (n=30) was 7.55 L/week (a 65.6% reduction from baseline). Ten subjects were weaned off their PN/I.V. support while on GATTEX treatment for 30 months. Subjects were maintained on GATTEX even if no longer requiring PN/I.V. support. These 10 subjects had required PN/I.V. support for 1.2 to 15.5 years, and prior to GATTEX had required between 3.5 L/week and 13.4 L/week of PN/I.V. support. At the end of study, 21 (70%), 18 (60%) and 18 (60%) of the 30 completers achieved a reduction of 1, 2, or 3 days per week in PN/I.V. support, respectively.

24 month exposure

Of the 39 placebo subjects from Study 1 entering Study 2, 29 completed 24 months of treatment with GATTEX. The mean reduction in PN/I.V. was 3.11 L/week (an additional 28.3% reduction) from the start of Study 2. Sixteen (55.2%) of the 29 completers achieved a 20% or greater reduction of parenteral support. At the end of study, 14 (48.3%), 7 (24.1%) and 5 (17.2%) achieved a reduction of 1, 2, or 3 days per week in PN/I.V. support, respectively. Two subjects were weaned off their PN/I.V. support while on GATTEX. Of the 12 subjects entering Study 2 directly, 6 completed 24 months of treatment with GATTEX. Similar effects were seen. One of the six subjects was weaned off their PN/I.V. support while on GATTEX.

Study 3 (Placebo-controlled) And Study 4 (Blinded Uncontrolled Extension Of Study 3)

Study 3

Study 3 was a randomized, double-blind, placebo-controlled, three parallel-group, multinational study in 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 treatment groups were compared using the intent-to-treat population of this study which was defined as all randomized patients who were administered at least one dose of study drug. This population contained one less patient in the 0.10 mg/kg/day dose group hence n=32 in this group for all analyses. The primary efficacy endpoint was a graded categorical score that did not achieve statistical significance for the high dose. Further 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

Study 4 was a blinded, uncontrolled extension of Study 3, in which 65 subjects from Study 3 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.

Last reviewed on RxList: 7/10/2014
This monograph has been modified to include the generic and brand name in many instances.

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