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Gattex (Teduglutide) - Description and Clinical Pharmacology

 
 



DESCRIPTION

The active ingredient in GATTEX (teduglutide [rDNA origin]) for injection is teduglutide (rDNA origin), which is a 33 amino acid glucagon-like peptide-2 (GLP-2) analog manufactured using a strain of Escherichia coli modified by recombinant DNA technology. The chemical name of teduglutide is L-histidyl-L-glycyl-L-aspartyl-L-glycyl-L-seryl-L-phenylalanyl-L-seryl-L-aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-aspartyl-L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-L-isoleucyl-L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-L-threonyl-L-aspartic acid. The structural formula is:


Figure 1: Structural formula of teduglutide

Teduglutide has a molecular weight of 3752 Daltons. Teduglutide drug substance is a clear, colorless to light-straw–colored liquid.

Each single-use vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for solution for subcutaneous injection. In addition to the active pharmaceutical ingredient (teduglutide), each vial of GATTEX contains 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium phosphate monohydrate, 3.434 mg dibasic sodium phosphate heptahydrate as excipients. No preservatives are present.

At the time of administration the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for Injection, which is provided in a prefilled syringe. A 10 mg/mL sterile solution is obtained after reconstitution. Up to 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn for subcutaneous injection upon reconstitution.

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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study in Wistar Han rats at subcutaneous doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in the incidences of adenomas in the bile duct and jejunum of male rats.

Teduglutide was negative in the Ames test, chromosomal aberration test in Chinese hamster ovary cells, and in vivo mouse micronucleus assay.

Teduglutide at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

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)

Study 2. Study 2 is an ongoing two-year open-label extension of Study 1 in which 88 subjects receive GATTEX 0.05 mg/kg/day. Ninety-seven percent (76/78) of subjects from Study 1 elected to enroll in Study 2. An additional 12 subjects entered Study 2, who had been optimized and stabilized but not randomized in Study 1 because of closed enrollment. Of responders in Study 1 who entered Study 2, 100% (25/25) sustained their response to GATTEX after one year of continuous treatment. A 20% or greater reduction of parenteral support was achieved in 72% (31/43) 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. Subjects were maintained on GATTEX even if no longer requiring PN/I.V. support. These 6 subjects had required PN/I.V. support for 3 to 18 years, and prior to GATTEX had required between 4 L/week and 13 L/week of PN/I.V. support.

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.

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