Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products, ATC code: A16AX08.

Mechanism of action
The naturally occurring human glucagon-like peptide-2 (GLP-2) is a peptide secreted by L cells of the intestine which is known to increase intestinal and portal blood flow, inhibit gastric acid secretion, and decrease intestinal motility. Teduglutide is an analogue of GLP-2. In several nonclinical studies, teduglutide has been shown to preserve mucosal integrity by promoting repair and normal growth of the intestine through an increase of villus height and crypt depth.

Pharmacodynamic effects
Similar to GLP-2, teduglutide is 33 amino acids in length with an amino acid substitution of alanine by glycine at the second position of the N-terminus. The single amino acid substitution relative to naturally occurring GLP-2 results in resistance to in vivo degradation by the enzyme dipeptidyl peptidase-IV (DPP-IV), resulting in an extended half-life. Teduglutide increases villus height and crypt depth of the intestinal epithelium.

Based on the findings derived from pre-clinical studies (see sections 4.4 and 5.3) and the proposed mechanism of action with the trophic effects on intestinal mucosa, there appears to be a risk for the promotion of small intestinal and/or colonic neoplasia. The clinical studies conducted could neither exclude nor confirm such an increased risk. Several cases of benign colorectal polyps occurred during the course of the trials, however, the frequency was not increased compared to placebo-treated patients. In addition to the need for a colonoscopy with removal of polyps by the time of the initiation of the treatment (see section 4.4.), every patient should be assessed for the need of an enhanced surveillance schedule based on the patient characteristics (e.g., age and underlying disease, previous occurrence of polyps etc.).

Clinical efficacy
Adults
Gattex was studied in 17 patients with SBS allocated to five treatment groups using doses of 0.03, 0.10 or 0.15 mg/kg teduglutide once daily, or 0.05 or 0.075 mg/kg bid in a 21-day open-label, multicenter, dose-ranging study. Treatment resulted in enhanced gastrointestinal fluid absorption of approximately 750-1000 ml/day with improvements in the absorption of macronutrients and electrolytes, decreased stomal or faecal fluid and macronutrients excretion, and enhanced key structural and functional adaptations in the intestinal mucosa. Structural adaptations were transient in nature and returned to baseline levels within three weeks of discontinuing the treatment.In the pivotal phase 3 double-blind, placebo-controlled study in patients with SBS, who required parenteral nutrition, 43 patients were randomised to a 0.05 mg/kg/day dose of Gattex and 43 patients to placebo for up to 24 weeks.

The proportion of teduglutide-treated subjects achieving a 20% to 100% reduction of parenteral nutrition at Week 20 and 24 was statistically significantly different from placebo (27 out of 
43 subjects, 62.8% versus 13 out of 43 patients, 30.2%, p=0.002). Treatment with teduglutide resulted in a 4.4 l/week reduction in parenteral nutrition requirements (from a pre-treatment baseline of 12.9 litres) versus 2.3 l/week (from a pre-treatment baseline of 13.2 litres) for placebo at 24 weeks.
Twenty-one (21) patients treated with teduglutide (48.8%) versus 9 on placebo (20.9%) achieved at least a one day reduction in parenteral nutrition administration (p=0.008).

Ninety-seven percent (97%) of patients (37 out of 39 patients treated with teduglutide) that completed the placebo-controlled study entered a long-term extension study where all patients received 0.05 mg/kg of Gattex daily for up to an additional 2 years. In total 88 patients participated in this extension study, thereof 39 treated with placebo and 12 enrolled, but not randomised, in the previous study; 65 of 88 patients completed the extension study. There continued to be evidence of increased response to treatment for up 2.5 years in all groups exposed to teduglutide in terms of parenteral nutrition volume reduction, gaining additional days off parenteral nutrition per week, and achieving weaning of parenteral support.

Thirty (30) of the 43 teduglutide-treated patients from the pivotal study who entered the extension study completed a total of 30 months of treatment. Of these, 28 patients (93%) achieved a 20% or greater reduction of parenteral support. Of responders in the pivotal study who completed the extension study, 21 out of 22 (96%) sustained their response to teduglutide after an additional 2 years of continuous treatment.

The mean reduction in parenteral nutrition (n=30) was 7.55 l/week (a 65.6% reduction from baseline).
Ten (10) subjects were weaned off their parenteral support while on teduglutide treatment for 30 months. Subjects were maintained on teduglutide even if no longer requiring parenteral nutrition.
These 10 subjects had required parenteral nutrition support for 1.2 to 15.5 years, and prior to treatment with teduglutide had required between 3.5 l/week and 13.4 l/week of parenteral nutrition 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 parenteral support, respectively.

Of the 39 placebo subjects, 29 completed 24 months of treatment with teduglutide. The mean reduction in parenteral nutrition was 3.11 l/week (an additional 28.3% reduction). Sixteen (16, 55.2%) of the 29 completers achieved a 20% or greater reduction of parenteral nutrition. At the end of study, 14 (48.3%), 7 (24.1%) and 5 (17.2%) patients achieved a reduction of 1, 2, or 3 days per week in parenteral nutrition, respectively. Two (2) subjects were weaned off their parenteral support while on teduglutide.

Of the 12 subjects not randomised in the pivotal study, 6 completed 24 months of treatment with teduglutide. The mean reduction in parenteral nutrition was 4.0 l/week (39.4% reduction from baseline – the start of the extension study) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction in parenteral support. At the end of study, 3 (50%), 2 (33%) and 2 (33%) achieved a reduction of 1, 2, or 3 days per week in parenteral nutrition, respectively. One subject was weaned off their parenteral support while on teduglutide.

In another phase 3 double-blind, placebo-controlled study in patients with SBS, who required parenteral nutrition, patients received a 0.05 mg/kg/day dose (n = 35), a 0.10 mg/kg/day dose (n = 32) of teduglutide or placebo (n = 16) for up to 24 weeks.

The primary efficacy analysis of the study results showed no statistically significant difference between the group on teduglutide 0.10 mg/kg/day and the placebo group, while the proportion of subjects receiving the recommended teduglutide dose of 0.05 mg/kg/day achieving at least a 20% reduction of parenteral nutrition at Week 20 and 24 was statistically significantly different versus placebo (46% versus 6.3%, p<0.01). Treatment with teduglutide resulted in a 2.5 l/week reduction in parenteral nutrition requirements (from a pre-treatment baseline of 9.6 litres) versus 0.9 l/week (from a pre-treatment baseline of 10.7 litres) for placebo at 24 weeks.

Teduglutide treatment induced expansion of the absorptive epithelium by significantly increasing villus height in the small intestine.


Sixty-five (65) patients entered a follow-up SBS study for up to an additional 28 weeks of treatment.
Patients on teduglutide maintained their previous dose assignment throughout the extension phase, while placebo patients were randomised to active treatment, either 0.05 or 0.10 mg/kg/day.

Of the patients who achieved at least a 20% reduction of parenteral nutrition at Weeks 20 and 24 in the initial study, 75% sustained this response on Gattex after up to 1 year of continuous treatment.

The mean reduction of weekly parenteral nutrition volume was 4.9 l/week (52% reduction from baseline) after one year of continuous teduglutide treatment.

Two (2) patients on the recommended teduglutide dose were weaned off parenteral nutrition by Week 24. One additional patient in the follow-up study was weaned off parenteral nutrition.

Paediatric population
Teduglutide was studied in a 12-week, open-label, clinical study in 42 paediatric subjects aged 1 year through 14 years with SBS who were dependent on parenteral nutrition. The objectives of the study were to evaluate safety, tolerability, and efficacy of teduglutide compared to standard of care. Three (3) doses of teduglutide, 0.0125 mg/kg/day (n=8), 0.025 mg/kg/day (n=14), and 0.05 mg/kg/day (n=15), were investigated for 12 weeks. Five (5) subjects were enrolled in a standard of care cohort.

Complete weaning
Three subjects (3/15, 20%) on the recommended teduglutide dose were weaned off parenteral nutrition by Week 12. After a 4-week washout period, two of these patients had reinitiated parenteral nutrition support.

Reduction in parenteral nutrition volume
The mean change in parenteral nutrition volume from baseline at Week 12 in the ITT population, based on physician-prescribed data, was -2.57 (±3.56) l/week, correlating to a -39.11% (±40.79) mean decrease, compared to 0.43 (±0.75) l/week, correlating to a 7.38% (±12.76) increase in the standard of care cohort. At Week 16 (4 weeks following the end of treatment) parenteral nutrition volume reductions were still evident but less than observed at Week 12 when subjects were still on teduglutide (mean decrease of -31.80% (±39.26) compared to a 3.92% (±16.62) increase in the standard of care group).

Reduction in parenteral nutrition calories
At Week 12, there was a -35.11% (±53.04) mean change from baseline in parenteral nutrition calorie consumption in the ITT population based on physician-prescribed data. The corresponding change in the standard of care cohort was 4.31% (±5.36). At Week 16, the parenteral nutrition calories consumption continued to decrease with percentage mean changes from baseline of -39.15% (±39.08) compared to -0.87% (±9.25) for the standard of care cohort.

Increase in enteral nutrition volume
Based on prescribed data, the mean percentage change from baseline at Week 12 in enteral volume, in the ITT population, was 25.82% (±41.59) compared to 53.65% (±57.01) in the standard of care cohort.
At Week 16, both the teduglutide and the standard of care cohort showed an increase in enteral volume.

Increase in enteral calories
The increases in enteral nutritional volume corresponded to increases in enteral calories, which were highest at the recommended dose. At Week 12, in the ITT population, the percentage increase from baseline in prescribed enteral calories was 58.80% (±64.20) compared to 57.02% (±55.25) in the standard of care cohort. At Week 16, the enteral calories intake continued to rise with percentage increases from baseline of 64.57% (±57.53) compared to 59.63% (±52.62) in the standard of care cohort.

Reduction in infusion time
The mean decrease from baseline at Week 12 in the number of days/week on parenteral nutrition, in the ITT population based on physician-prescribed data, was -1.36 (±2.37) days/week corresponding to a percentage decrease of -24.49% (±42.46). There was no change from baseline in the standard of care 

cohort. Four subjects (26.7%) on the recommended teduglutide dose achieved at least a three-day reduction in parenteral nutrition needs.

At Week 12, based on subject diary data, subjects showed mean percentage reductions of 35.55% (±35.23) hours per day compared to baseline, which corresponded to reductions in the hours/day of parenteral nutrition usage of -4.18 (±4.08), while subjects in the standard of care cohort showed minimal change in this parameter at the same time point.

No new unexpected safety signals were observed in this trial.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
Teduglutide was rapidly absorbed from subcutaneous injection sites with maximum plasma levels occurring approximately 3-5 hours after dose administration at all dose levels. The absolute bioavailability of subcutaneous teduglutide is high (88%). No accumulation of teduglutide was observed following repeated subcutaneous administration.

Distribution
Following subcutaneous administration, teduglutide has an apparent volume of distribution of 26 litres in patients with SBS.

Biotransformation
The metabolism of teduglutide is not fully known. Since teduglutide is a peptide it is likely that it follows the principal mechanism for peptide metabolism.

Elimination
Teduglutide has a terminal elimination half-life of approximately 2 hours. Following intravenous administration teduglutide plasma clearance was approximately 127 ml/hr/kg which is equivalent to the glomerular filtration rate (GFR). Renal elimination was confirmed in a study investigating pharmacokinetics in subjects with renal impairment. No accumulation of teduglutide was observed following repeated subcutaneous administrations.

Dose linearity
The rate and extent of absorption of teduglutide is dose-proportional at single and repeated subcutaneous doses up to 20 mg.

Pharmacokinetics in subpopulations

Paediatric population
Following subcutaneous administration, similar Cmax of teduglutide across age groups was demonstrated by population pharmacokinetics modeling. However, lower exposure (AUC) and shorter half-life were seen in paediatric patients 1 to 17 years of age, as compared with adults. The pharmacokinetic profile of Gattex in this paediatric population, as evaluated by clearance and volume of distribution, was different from that observed in adults after correcting for body weights.
Specifically, clearance decreases with increasing age from 1 year old to adults. No data are available for paediatric patients with moderate to severe renal impairment and end-stage renal disease (ESRD).

Gender
No clinically relevant gender differences were observed in clinical studies.

Elderly
In a phase 1 study no difference in pharmacokinetics of teduglutide could be detected between healthy subjects younger than 65 years versus older than 65 years. Experience in subjects 75 years and above is limited.

Hepatic impairment
In a phase 1 study the effect of hepatic impairment on the pharmacokinetics of teduglutide following subcutaneous administration of 20 mg teduglutide was investigated. The maximum exposure and the overall extent of exposure to teduglutide following single 20 mg subcutaneous doses were lower (10-15%) in subjects with moderate hepatic impairment relative to those in healthy matched controls.

Renal impairment
In a phase 1 study, the effect of renal impairment on the pharmacokinetics of teduglutide following subcutaneous administration of 10 mg teduglutide was investigated. With progressive renal impairment up to and including end-stage renal disease the primary pharmacokinetic parameters of teduglutide increased up to a factor of 2.6 (AUCinf) and 2.1 (Cmax) compared to healthy subjects.