Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Takeda Pharmaceuticals International AG Ireland Branch, Block 2 Miesian Plaza, 50 – 58 Baggot Street Lower, Dublin 2, D02 HW68, Ireland, medinfoEMEA@takeda.com
Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products
ATC code: A16AX08
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.
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.).
The efficacy data presented are derived from 1 controlled and 1 un-controlled core studies for a 28-week duration, and 2 extension studies for up to 9 cycles (24 weeks per cycle) of teduglutide treatment. These studies included infants 4 months to <12 months corrected gestational age: 10 infants (2 infants aged 4 to <6 months, 8 aged 6 to <12 months) in the controlled study (5 in teduglutide treatment arm and 5 in standard of care arm), 2 infants in the un-controlled study (both treated). From the core controlled study, 6 of the 10 infants completed the study, and continued in the extension study (5 treated and 1 non-treated). From the core uncontrolled study, 2 infants completed the study and continued in the second extension study (both treated). The infants in these studies were treated with teduglutide 0.05 mg/kg/day. Despite the limited sample size in the core and extension studies, clinically meaningful numerical reductions in the requirement for parenteral support were observed.
The controlled core study
Complete weaning:
No subject achieved enteral autonomy, i.e., complete weaning off PS during either core or extension studies.
Reduction in parenteral nutrition volume:
In the controlled core study, based on subject diary data, 3 (60.0%) subjects enrolled in the TED arm and 1 (20.0%) subject in the SOC arm experienced at least 20% reduction in PS volume at end of treatment (EOT) from baseline (2 subjects in the SOC arm had missing data). In the TED arm, the mean change in PS volume at EOT from baseline was -21.5±28.91 ml/kg/day (-24.8%). In the SOC arm, the mean change in PS volume at EOT from baseline was -9.5±7.50 ml/kg/day (-16.8%).
Reduction in parenteral nutrition calories:
In the controlled core study, based on subject diary data, the mean percentage change in PS caloric intake at EOT from baseline was -27.0±29.47% for subjects in the TED arm and -13.7±21.87% in the SOC arm.
Reduction in infusion time:
In the controlled core study, in the TED arm, the change in diary PS infusion time at EOT from baseline was -3.1±3.31 hours/day (-28.9%) and -1.9±2.01 days/week (-28.5%). In the SOC arm, the change in diary PS infusion time at EOT from baseline was -0.3±0.63 hours/day (-1.9%) and no change was observed on the days per week of PS infusion time.
The un-controlled core study
Complete weaning:
No infant subjects reached complete weaning.
Reduction in parenteral nutrition volume:
Among the 2 infants included in and completed the study, a ≥20% reduction in PS volume was recorded in 1 infant during the teduglutide treatment. The mean change in PS volume at EOT from baseline was -26.2±13.61 ml/kg/day (-26.7%).
Reduction in parenteral nutrition calories:
In infants, the mean change in PS caloric intake at EOT from baseline
was -13.8±3.17 kcal/kg/day (-25.7%).
Reduction in infusion time:
There was no change in daily PS usage hours in the 2 infants during the study.
The efficacy data presented are derived from 2 controlled studies in paediatric patients up to 24 weeks duration. These studies included 101 patients in the following age groups: 5 patients 1-2 years, 56 patients 2 to <6 years, 32 patients 6 to <12 years, 7 patients 12 to <17 years, and 1 patient 17 to <18 years. Despite the limited sample size, which did not allow meaningful statistical comparisons, clinically meaningful, numerical reductions in the requirement for parenteral support were observed across all age groups.
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.
Increases in enteral nutrition volume and enteral calories:
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. The corresponding increase in enteral calories was 58.80% (±64.20), compared to 57.02% (±55.25) 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.
An additional 24-week, randomised, double-blind, multicentre study was conducted in 59 paediatric subjects aged 1 year through 17 years who were dependent on parenteral support. The objective was to evaluate safety/tolerability, pharmacokinetics and efficacy of teduglutide. Two doses of teduglutide were studied: 0.025 mg/kg/day (n=24) and 0.05 mg/kg/day (n=26); 9 subjects were enrolled in a standard of care (SOC) arm. Randomisation was stratified by age across dose groups. Results below correspond to the ITT population at the recommended dose of 0.05 mg/kg/day.
Complete weaning:
Three (3) paediatric subjects in the 0.05 mg/kg group achieved the additional endpoint of enteral autonomy by week 24.
Reduction in parenteral nutrition volume:
Based on subject diary data, 18 (69.2%) subjects in the 0.05 mg/kg/day group achieved the primary endpoint of ≥20% reduction in PN/IV volume at end of treatment, compared to baseline; in the SOC arm, 1 (11.1%) subject achieved this endpoint.
The mean change in parenteral nutrition volume from baseline at Week 24, based on subject diary data, was -23.30 (±17.50) ml/kg/day, corresponding to -41.57% (±28.90); the mean change in the SOC arm was -6.03 (±4.5) ml/kg/day (corresponding to a -10.21% [±13.59].
Reduction in infusion time:
At week 24, there was a decrease in the infusion time of -3.03 (±3.84) hours/day in the 0.05 mg/kg/day arm, corresponding to a percentage change of -26.09% (±36.14). The change from baseline in the SOC cohort was -0.21 (±0.69) hours/day (-1.75% [±5.89]).
The mean decrease from baseline at Week 24 in the number of days/week on parenteral nutrition, based on subject diary data, was -1.34 (±2.24) days/week corresponding to a percentage decrease of -21.33% (±34.09). There was no reduction in PN/IV infusion days per week in the SOC arm.
Teduglutide 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 750-1 000 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 teduglutide 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 teduglutide 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 teduglutide 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.
The European Medicines Agency has deferred the obligation to submit the results of studies with Revestive in one or more subsets of the paediatric population in the treatment of SBS (see section 4.2 for information on paediatric use).
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.
Following subcutaneous administration, teduglutide has an apparent volume of distribution of 26 litres in patients with SBS.
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.
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.
The rate and extent of absorption of teduglutide is dose-proportional at single and repeated subcutaneous doses up to 20 mg.
Following subcutaneous administration, similar Cmax of teduglutide, driving the efficacy responses, across age groups (4 months corrected by gestational age to 17 years) was demonstrated by population pharmacokinetics modelling based on PK samples collected in the population following SC 0.05 mg/kg daily dose. However, lower exposure (AUC) and shorter half-life were seen in paediatric patients 4 months to 17 years of age, as compared with adults. The pharmacokinetic profile of teduglutide 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 4 months to adults. No data are available for paediatric patients with moderate to severe renal impairment and endstage renal disease (ESRD).
No clinically relevant gender differences were observed in clinical studies.
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.
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.
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.
Hyperplasia in the gall bladder, hepatic biliary ducts, and pancreatic ducts were observed in subchronic and chronic toxicology studies. These observations were potentially associated with the expected intended pharmacology of teduglutide and were to a varying degree reversible within an 8-13 week recovery period following chronic administration.
In pre-clinical studies, severe granulomatous inflammations were found associated with the injection sites.
Teduglutide was negative when tested in the standard battery of tests for genotoxicity.
In a rat carcinogenicity study, treatment related benign neoplasms included tumours of the bile duct epithelium in males exposed to teduglutide plasma levels approximately 32- and 155-fold higher than obtained in patients administered the recommended daily dose (incidence of 1 out of 44 and 4 out of 48, respectively). Adenomas of the jejunal mucosa were observed in 1 out of 50 males and 5 out of 50 males exposed to teduglutide plasma levels approximately 10- and 155-fold higher than obtained in patients administered the recommended daily dose. In addition, a jejunal adenocarcinoma was observed in a male rat administered the lowest dose tested (animal:human plasma exposure margin of approximately 10-fold).
Reproductive and developmental toxicity studies evaluating teduglutide have been carried out in rats and rabbits at doses of 0, 2, 10 and 50 mg/kg/day subcutaneously. Teduglutide was not associated with effects on reproductive performance, in utero or developmental parameters measured in studies to investigate fertility, embryo-foetal development and pre- and post-natal development. Pharmacokinetic data demonstrated that the teduglutide exposure of foetal rabbits and suckling rat pups was very low.
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