Revestive
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Revestive - Scientific Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Short Bowel Syndrome
Class: Miscellaneous GI agents
Form: Subcutaneous (SC), Powder
Ingredients: teduglutide, dibasic sodium phosphate heptahydrate, L-histidine, mannitol, monobasic sodium phosphate monohydrate, sterile water for injection.

Pharmaceutical Information

Drug Substance

Proper name:teduglutide
Chemical name:2-glycine-1-33-glucagon-like peptide 2 (human); [gly2]-hGLP-2
Molecular formula and molecular mass:C164H252N44O55S, 3752 Daltons
Structural formula:

L-histidyl-L-glycyl-L-aspartyl-L-glycyl-L-seryl-L-phenylalanyl-Lseryl-
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-Lphenylalanyl-
L-isoleucyl-L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-Lglutaminyl-
L-threonyl-L-lysyl-L-isoleucyl-L-threonyl-L-aspartic acid


Physicochemical properties:Teduglutide is a 33 amino acid glucagon-like peptide-2
(GLP-2) analog. Teduglutide is a clear, colorless to light straw colored liquid in
aqueous buffer.
Solubility Properties:Teduglutide is soluble to at least 18 mg/mL in 17.5 mM, pH 7.4
phosphate buffer and at least 50 mg/mL in 60 mM, pH 7.8 phosphate buffer.
Product Characteristics:Teduglutide is a 33 amino acid glucagon-like peptide-2 analog manufactured using a strain of
Escherichia coli modified by recombinant DNA technology.

Clinical Trials

Study Demographics andTrial Design

Study #Trial designDosage, route of
administration and
duration
Study
subjects
enrolled
(n = number)
Mean age
(range
[years])
Gender
Table 1: Summary of patient demographics for clinical trials in Patients with ShortBowel Syndrome (SBS)
Placebo-controlled Studies
CL0600-
020
Phase 3, multicenter,
randomized, doubleblind,
placebocontrolled
study


To evaluate the
efficacy, safety,
tolerability, and
pharmacodynamics of
REVESTIVE
compared with
placebo in subjects
with PN/I.V.
dependent SBS
A: REVESTIVE
0.05 mg/kg/day SC

B: Dose-matching
placebo SC

24 weeks
A: 42

B: 43
51.3
(22 – 78)

49.7
(18 – 82)
M = 20
F = 22

M = 19
F = 24
CL0600-
004
Phase 3, multicenter,
randomized, doubleblind,
placebocontrolled
study


To evaluate the
efficacy, safety,
tolerability and
pharmacokinetics of
REVESTIVE
compared with
placebo in subjects
with PN/I.V.
dependent SBS.
A: REVESTIVE
0.05 mg/kg/day SC

B: REVESTIVE
0.10 mg/kg/day SC

C: Dose-matching
placebo SC

24 weeks
A: 35

B: 32

C: 16
47.1
(20 – 68)

50.3
(19 – 79)

49.4
(20 – 72)
M = 17
F = 18

M = 13
F = 19

M = 7
F = 9
Extension Studies
CL0600-
021
Phase 3, multicenter,
open label, extension
study of CL0600-020


To further study longterm
safety and
efficacy in subjects
who completed,
participated in or
qualified for Study
CL0600-020. Key
secondary efficacy
variables focused on
reductions in PN/I.V.
volume.
REVESTIVE
0.05 mg/kg/day SC

2 years
88
(37 on REVESTIVE
0.05 mg/kg
and 51 on
placebo or not
treated in
Study -020)
50.9
(18 – 82)
M = 41
F = 47
CL0600-
005
Phase 3, multicenter,
randomized, doubleblind
extension study
of CL0600-004


To evaluate the longterm
safety and
tolerability of daily
REVESTIVE dosing
for up to 12 months in
adult subjects with
SBS who were
dependent on PN/I.V.
Key secondary
efficacy variables
focused on reductions
in PN/I.V. volume.
A: REVESTIVE
0.05 mg/kg/day SC

B: REVESTIVE
0.10 mg/kg/day SC

C: REVESTIVE
0.05 mg/kg/day SC

D: REVESTIVE
0.10 mg/kg/day SC

28 weeks
A: 6
B: 7
C: 25
D: 27
42.2
(21 – 59)

56.6
(41 – 73)

46.7
(21 – 67)

49.4
(20 – 80)
M = 2
F = 4

M = 3
F = 4

M = 15
F = 10

M = 13
F = 14

PN/I.V. = parenteral nutrition/intravenous fluid; SC = subcutaneous

Study Results

Study CL0600-020

The efficacy, safety, and tolerability of REVESTIVE was evaluated in a randomized, double-blind, placebo-controlled, parallel-group, multi-national, multi-center clinical trial 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.

The mean age was similar across all treatment groups, with most participating subjects less than 65 years of age. Medical and surgical histories, prior medications, and concomitant medications were consistent with SBS and were generally well balanced between treatment groups and studies.

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 REVESTIVE 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 the REVESTIVE group were considered responders compared to 30% (13/43) in the placebo group (p=0.002). At all visits, change from baseline in actual PN/I.V. volume was greater in the REVESTIVE group compared to the placebo group: at Week 24, the actual mean reduction in weekly PN/I.V. volume was 4.4 L (SD=3.81) for the REVESTIVE group (from pre-treatment baseline of 12.9 L) versus 2.3 L (SD=2.74) for the placebo group (from pre-treatment baseline of 13.2 L/week) (p<0.001). The difference in the corresponding percent change from baseline between the treatment groups was statistically significant at Week 24 (reduction of 32.1% [SD=18.71] in the REVESTIVE group vs 21.0% in the placebo group [SD=24.35]) (p=0.025).

The percentage of subjects with a duration of response for ≥3 consecutive visits was higher in the REVESTIVE group (24/43 subjects, 55.8%) than in the placebo group (12/43 subjects, 27.9%). The distribution of duration of response was statistically significant (p=0.005).

The proportion of subjects with a 20 to 100% reduction or a 2 L reduction in PN/I.V. volume from baseline at Weeks 20 and 24 was higher in the REVESTIVE group (30/43 subjects, 69.8%) than the placebo group (16/43 subjects, 37.2%). The difference was statistically significant (p=0.002).

Twenty-one subjects on REVESTIVE (53.8%) versus 9 on placebo (23.1%) achieved at least a one-day reduction in PN/I.V. support at week 24 (p=0.005).

The mean changes from baseline in PN/I.V. volume by visit are shown in Figure 1.

Figure 1 - Change (+95% CI) in PN/I.V. volume (L/week)


Treatment with REVESTIVE at a dose of 0.05mg/kg/day in double-blind study CL0600-020 demonstrated a benefit for patients with SBS who are dependent on parenteral support. REVESTIVE treatment, resulted in reductions in PN/I.V. support, including reductions in PN/I.V. volume, and at least one day reduction on PN/I.V. in some patients.

Study CL0600-021

CL0600-021 was a 2-year open-label extension of CL0600-020 in which 88 subjects received REVESTIVE 0.05 mg/kg/day. Ninety-seven percent (76/78) of subjects who completed CL0600-020 elected to enroll in CL0600-021 (37 received REVESTIVE; 39 received placebo). An additional 12 subjects entered CL0600-021 who had been optimized and stabilized but not randomized in CL0600-020 because of closed enrollment.

24-month Exposure

Of the 39 placebo subjects from CL0600-020 entering CL0600-021, 29 completed 24 months of treatment with REVESTIVE. The mean reduction in PN/I.V. was 3.11 L/week (an additional 28.3% reduction) from the start of CL0600-021. 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 REVESTIVE. Of the 12 subjects entering CL0600-021 directly, 6 completed 24 months of treatment with REVESTIVE. Similar effects were seen. One of the six subjects was weaned off their PN/I.V. support while on REVESTIVE.

30-month Exposure

Thirty REVESTIVE-treated subjects completed a total duration of 30 months (CL0600-020 followed by CL0600-021 treatment). Of these, 28 subjects (93%) achieved a 20% or greater reduction ofparenteral support. Of responders in CL0600-020 who had completed 2 additional years of continuous treatment with REVESTIVE, 96% (21/22) sustained their response to REVESTIVE. 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 REVESTIVE treatment for 30 months. Subjects were maintained on REVESTIVE 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 REVESTIVE 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.

Results of the long-term extension study, CL0600-021, demonstrated the reproducibility as well as the durability of the beneficial effects of REVESTIVE 0.05 mg/kg/day, without evidence for the development of tolerance for up to 30 months of treatment. PN/I.V. volume reductions in subjects who previously received REVESTIVE translated to additional days off PN/I.V. and, in a subset of subjects, complete weaning from PN/I.V. support. Newly treated subjects also achieved and maintained the similar clinical benefits from 24 months of REVESTIVE treatment.

Study CL0600-004

CL0600-004 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 CL0600-020, subjects were randomized to receive 24 weeks of one of the following treatment regimens: REVESTIVE 0.05 mg/kg/day (n=35), REVESTIVE 0.10 mg/kg/day dose (n=32), or placebo (n=16). 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 REVESTIVE 0.05 mg/kg/day responded versus 6% on placebo (p=0.010).

The mean age was similar across all treatment groups, with most participating subjects less than65 years of age. Medical and surgical histories, prior medications, and concomitant medications were consistent with SBS and were generally well balanced between treatment groups and studies.

Treatment with REVESTIVE at a dose of 0.05mg/kg/day in double-blind study CL0600-004 demonstrated a clinically meaningful benefit for patients with SBS who are dependent on parenteral support. REVESTIVE treatment resulted in reductions in PN/I.V. fluid needed.

Study CL0600-005

CL0600-005 was a blinded, uncontrolled extension of CL0600-004, in which 65 subjects from CL0600-004 received REVESTIVE for up to an additional 28 weeks of treatment. Of responders in CL0600-004 who entered CL0600-005, 75% sustained their response on REVESTIVE after one year of treatment. In the REVESTIVE 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 REVESTIVE treatment. The subjects who had been completely weaned off PN/I.V. support in CL0600-004 (n=2) remained off parenteral support through CL0600-005. During CL0600-005, an additional subject from CL0600-005 was weaned off parenteral support.

Results of the long-term extension study, CL0600-005, demonstrated the reproducibility as well as the durability of the clinical benefits of REVESTIVE 0.05 mg/kg/day, without evidence for the development of tolerance for up to an additional 28 weeks of treatment.

Detailed Pharmacology

Teduglutide is a novel recombinant analog of the human glucagon-like peptide-2 (GLP-2), that differs from GLP-2 in the substitution of glycine for alanine at the second position at the N-terminus.

Teduglutide binds to the human and rat GLP-2 receptor (GLP-2R) with similar affinity compared to native GLP-2. Receptor binding results in intracellular cyclic adenosine 3`-5`- monophosphate (cAMP) levels and activation of several downstream signaling pathways such as protein kinase A (PKA), cAMP response element-binding protein (CREB), and activator protein-1(AP-1). The potency of teduglutide is equivalent to native GLP-2 for the GLP-2R with enhanced biological activity due to resistance to DPP-IV cleavage, resulting in a longer half-life in the circulation.

Most pharmacology studies assessed the intestinotrophic activity of teduglutide in healthy animals through measures of intestinal weight, morphological analysis and in some cases protein and DNA content, barrier function and D-xylose absorption. The intestinotrophic effect was used to elaborate a full pharmacological profile of teduglutide, including an assessment of dose response, optimal treatment regimen, maximum effect and reversibility. Teduglutide showed intestinotrophic activity in mice, rats, ferrets, minipigs, dogs, and monkeys. The intestinotrophic effect follows a sigmoidal dose-response curve with an ED50 of 0.98 mcg/day (equivalent to 0.05 mg/kg/day) in mice. Depending on dose and duration of treatment, the intestinotrophic effect reaches a plateau, and reverses if administration is discontinued. The intestinotrophic effect in mice was independent of a once or twice daily treatment regimen.

Pharmacology studies on the intestinotrophic activity of teduglutide in healthy animals were complemented by studies in various animal models of intestinal disease including total parenteral nutrition (TPN)-induced intestinal hypoplasia, short bowel resection, and various models of induced and spontaneous gastrointestinal damage. Teduglutide has demonstrated the ability to protect the intestinal epithelium from TPN -induced intestinal hypoplasia and enhance intestinal functionality by increasing nutrient absorption and expanding mucosal surface area in models of short bowel resection.

A cardiovascular and respiratory safety pharmacology study was conducted in beagle dogs administered 0.1, 1 and 10mg/kg doses of teduglutide intravenously and no treatment-related effects were observed that were attributed to teduglutide. No effect of teduglutide was noted on the human ether-à-go-go-related gene (hERG) channel or canine cardiac Purkinje fibers. In addition no central nervous system effects were observed in rodents receiving teduglutide at doses well above the targeted clinical therapeutic dose (500 times the recommended daily human dose of 0.05 mg/kg).

The effect of teduglutide is specific to the gastrointestinal tract. Intestinal mucosal absorptive surface area increased as assessed by intestinal weight, mucosal architecture, DNA and protein content. The functional absorptive capacity is increased in normal animals and restored in animals following small bowel resection or TPN-induced intestinal atrophy.

Toxicology

Subchronic and Chronic Toxicity

Hyperplasia in the gallbladder and hepatic biliary ducts of mouse, juvenile minipig and monkey species as well as in the stomach and pancreatic ducts of monkey species were observed in subchronic and chronic toxicology studies at doses ranging from 0.2 to 50 mg/kg/day. These observations were potentially related to the expected intended pharmacology of teduglutide and were to a varying degree reversible within an 8- to 13-week recovery period following chronic administration.

Injection Site Reactions

In pre-clinical studies, severe granulomatous inflammations were found associated with the injection sites.

Carcinogenesis and Mutagenesis

Carcinogenic potential of teduglutide was assessed in 2-year subcutaneous carcinogenicity studies in rats and mice. In a 2-year carcinogenicity study in Wistar Han rats at subcutaneous doses of 3, 10 and 35 mg/kg/day (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. No malignant tumors were observed.

In a 2-year carcinogenicity study in Crl:CD1(ICR) mice at subcutaneous doses of 1, 3.5 and 12.5 mg/kg/day (20, 70 and 250 times the recommended daily human dose of 0.05 mg/kg, respectively), teduglutide caused a significant increase in papillary adenomas in the gallbladder; it also caused adenocarcinomas in the jejunum in male mice at the high dose of 12.5 mg/kg/day (about 250 times the recommended human dose).

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

Reproductive and Developmental Toxicity

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 (1000 times the recommended daily human dose of 0.05 mg/kg). Teduglutide was not associated with effects on reproductive performance, in utero or developmental parameters measured in studies to investigate fertility, and embryo-fetal development and pre- and post-natal development. Pharmacokinetic data demonstrated that the teduglutide exposure of fetal rabbits and suckling rat pups was very low.