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Background
Short bowel syndrome (SBS) is a condition that results from partial or complete surgical resection of the small and/or large intestine. The ensuing mal-absorption of a conventional diet with associated diarrhea and weight loss often leads to a dependency on parenteral nutrition (PN) and/or intravenous fluids. A natural compensatory process of intestinal adaptation occurs in the years following bowel resection as the body responds to a lack of sufficient functional nutrient-processing intestinal surface area. The adaptive process improves bowel function but is a highly variable process, resulting in different levels of symptom control and PN/intravenous fluids independence among patients. Intestinal rehabilitation is the strategy of maximizing the absorptive capacity of the remnant gastro-intestinal tract. The approaches for achieving this goal have been limited to dietary intervention, anti-diarrheal and anti-secretory medications, as well as surgical bowel reconstruction. A targeted pharmacotherapy, teduglutide, has now been developed to improve intestinal absorption (Seidner et al, 2013).
Teduglutide, a human recombinant analog of glucagon-like peptide 2 (GLP-2) is designed to restore intestinal structural and functional integrity by promoting growth of the intestinal mucosa as well as reducing gastric emptying and secretion. Available evidence has demonstrated a desirable benefit-to-risk profile in regards to its safety and effectiveness; enhanced absorption has been shown in clinical trials by a reduction in PN/intravenous fluids requirements in patients with SBS treated with teduglutide (Vipperla and O'Keefe, 2011; Norholk et al, 2012).
Jeppesen et al (2005) examined the safety and effectiveness of teduglutide in SBS patients with and without a colon in continuity. Teduglutide was given subcutaneously for 21 days once- or twice-daily to 16 SBS patients in the per-protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), 1 with less than 50 % colon in continuity (dose 0.03 mg/kg/day), and 5 with greater than or equal to 50 % colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D-xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last 3 days of treatment, and after 3 weeks of follow-up. Pre-study fasting native GLP-2 levels were determined for the 5 patients with greater than or equal to 50 % colon in continuity. Pooled across groups and compared with baseline, teduglutide increased absolute (+743 (477) g/day; p < 0.001) and relative (+22 (16) %; p < 0.001) wet weight absorption, urine weight (+555 (485) g/day; p < 0.001), and urine sodium excretion (+53 (40) mmol/day; p < 0.001). Teduglutide decreased fecal wet weight (-711 (734) g/day; p = 0.001) and fecal energy excretion (-808 (1,453) kJ/day (-193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, teduglutide significantly increased villus height (+38 (45) %; p = 0.030), crypt depth (+22 (18) %; p = 0.010), and mitotic index (+115 (108) %; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg edema. The improvements in intestinal absorption and decreases in fecal excretion noted after treatment had reversed after the drug-free follow-up period. The authors concluded that teduglutide, at 3 dose levels for 21 days, was safe and well-tolerated, intestine-trophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.
In a 24-week placebo-controlled study, Jeppesen et al (2011) evaluated the ability of teduglutide to reduce parenteral support in patients with SBS with intestinal failure (SBS-IF). A total of 83 patients were randomized to receive subcutaneous teduglutide 0.10 mg/kg/day (n = 32), 0.05 mg/kg/day (n = 35) or placebo (n = 16) once-daily. Subjects were adults with SBS who were dependent on PN/intravenous support for at least 12 months and required PN at least 3 times per week. Parenteral fluids were reduced at 4-week intervals if intestinal fluid absorption (48-hr urine volumes) increased greater than or equal to 10 %. Responders were subjects who demonstrated reductions of greater than or equal to 20 % in parenteral volumes from baseline at weeks 20 and 24. The primary efficacy end point, a graded response score (GRS), took into account higher levels and earlier onset of response, leading to longer duration of response. The intensity of the response was defined as a reduction from baseline in parenteral volume (from 20 % to 100 %), and the duration of the response was considered the response at weeks 16, 20 and 24. The results were tested according to a step-down procedure starting with the 0.10 mg/kg/day dose. Using the GRS criteria, teduglutide in a dose of 0.10 mg/kg/day did not have a statistically significant effect compared with placebo (8/32 versus 1/16, p = 0.16), while teduglutide in a dose of 0.05 mg/kg/day had a significant effect (16/35, p = 0.007). Since parenteral volume reductions were equal (353 +/- 475 and 354 +/- 334 ml/day), the trend towards higher baseline parenteral volume (1,816 +/- 1,008 versus 1,374 +/- 639 ml/day, p = 0.11) in the 0.10 mg/kg/day group compared with the 0.05 mg/kg/day group may have accounted for this discrepancy. Three teduglutide-treated patients were completely weaned off parenteral support. Serious adverse events were distributed similarly between active treatment groups and placebo. Villus height, plasma citrulline concentration (a biomarker of mucosal mass) and lean body mass were significantly increased with teduglutide compared with placebo. The authors concluded that teduglutide was safe, well-tolerated, intestine-trophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS-IF.
In a prospective study, Jeppesen et al (2012) examined if teduglutide reduces parenteral support in patients with SBS-IF. These investigators performed a 24-week study of patients with SBS-IF who were given subcutaneous teduglutide (0.05 mg/kg/day; n = 43) or placebo (n = 43) once-daily. Subjects were adults with SBS who were dependent on PN/intravenous support for at least 12 months and required PN at least 3 times per week. Parenteral support was reduced if 48-hr urine volumes exceeded baseline values by greater than or equal to 10 %. The primary efficacy end point was number of responders (patients with greater than 20 % reduction in parenteral support volume from baseline at weeks 20 and 24). There were significantly more responders in the teduglutide group (27/43 [63 %]) than the placebo group (13/43 [30 %]; p = 0.002). At week 24, the mean reduction in parenteral support volume in the teduglutide group was 4.4 +/- 3.8 L/week (baseline 12.9 +/- 7.8 L/week) compared with 2.3 +/- 2.7 L/week (baseline 13.2 +/- 7.4 L/week) in the placebo group (p < 0.001). The percentage of patients with a 1-day or more reduction in the weekly need for parenteral support was greater in the teduglutide group (21/39 [54 %]) than in the placebo group (9/39 [23 %]; p = 0.005). Teduglutide increased plasma concentrations of citrulline. The distribution of treatment-emergent adverse events that led to study discontinuation was similar between patients given teduglutide (n = 2) and placebo (n = 3). The authors concluded that 24 weeks of teduglutide treatment was generally well-tolerated in patients with SBS-IF. Treatment with teduglutide reduced volumes and numbers of days of parenteral support for patients with SBS-IF
O'Keefe et al (2013) examined the 12-month tolerability and effectiveness of teduglutide to reduce PN dependency. Patients who received teduglutide (0.05 or 0.10 mg/kg/day) for 24 weeks in a randomized controlled trial were eligible for a 28-week double-blind extension study; 52 patients were given 52 weeks of the same doses of teduglutide. These researchers investigated the safety, tolerability and clinical effectiveness (defined as a clinically meaningful = 20 % reduction in weekly PN volume from baseline) at week 52. The most common adverse events reported included abdominal pain (25 %), headache (35 %), and nausea (31 %); 7 patients withdrew because of adverse events (gastro-intestinal disorders in 4). Both groups had progressive reduction in PN. At week 52, 68 % of the 0.05 mg/kg/day and 52 % of the 0.10 mg/kg/day dose group had a greater than 20 % reduction in PN, with a reduction of = 1 day of PN dependency in 68 % and 37 %, respectively. Four patients achieved complete independence from PN. The authors concluded that for patients with SBS-IF, the effectiveness of teduglutide was maintained over 52 weeks, and the safety profile was sufficient for it to be considered for long-term use.
On December 21, 2012, the Food and Drug Administration (FDA) approved teduglutide (Gattex) for the treatment of adults with SBS who need additional nutrition from intravenous feeding (parenteral nutrition). It is injected subcutaneously once-daily (0.05 mg/kg of body weight) to improve intestinal absorption of fluids and nutrients, reducing the frequency and volume of PN. The most common side effects of teduglutide identified in clinical trials were abdominal distension, abdominal pain, headaches, injection site reactions, nausea, and upper respiratory tract infection. Patients treated with teduglutide have a potential increased risk of developing biliary tract disease, cancer and polyps in the intestine, gallbladder disease, obstructions in the intestine, and pancreatic disease. To ensure that the benefits of teduglutide outweigh the potential risks, the drug is being approved with a Risk Evaluation and Mitigation Strategy, consisting of a communication plan and training for prescribers. To study teduglutide’s long-term safety, the FDA is requiring a post-market study of SBS patients treated with the drug in a routine clinical setting to further evaluate the drug’s potential increased risk to cause colorectal cancer and other conditions. Patients in this study will be followed for at least 10 years.
In addition to being used as a treatment of SBS-IF, teduglutide has been explored as a therapeutic agent in a variety of clinical settings.
Yazbeck (2010) stated that teduglutide has prolonged biological activity compared with native GLP-2, and pre-clinical studies demonstrated significant intestine-trophic activity in models of SBS, experimental colitis and chemotherapy-induced intestinal mucositis. A phase II clinical trial for teduglutide in Crohn's disease (CD) observed remission rates of 55.6 % in patients. At the time of publication, pre-clinical studies for chemotherapy-induced mucositis and pediatric indications were ongoing.
In a pilot, randomized, placebo-controlled, double-blinded, dose-ranging study, Buchman et al (2010) evaluated the effectiveness of teduglutide in the treatment of moderate-to-severe CD. Subjects were randomized 1:1:1:1 to placebo or 1 of 3 doses of teduglutide (0.05, 0.10, or 0.20 mg/kg/day) delivered as a daily subcutaneous injection for 8 weeks. The primary outcome measure was the percentage of subjects in each group that responded to treatment, defined as a decrease in Crohn's Disease Activity Index (CDAI) score to less than 150 or a decrease of greater than 100 points. At week 8 there was an optional 12-week open-label period of treatment with teduglutide 0.10 mg/kg/day. A total of 100 subjects were enrolled and 71 completed the study. The mean baseline CDAI score was 290.8 +/- 57.6 and was similar across groups. There were numerically higher response and remission rates in all teduglutide-treated groups as compared with placebo, although the percentage of subjects who achieved a clinical response or remission was more substantial, and seen as early as week 2 of treatment in the highest dose (0.2 mg/kg/day) group (44 % response and 32 % remission versus 32 % response and 20 % remission in the placebo group). Of subjects who had not achieved remission during the 8-week placebo-controlled phase in the higher-dose group, 50 % achieved remission during the more prolonged, open-label treatment phase. Plasma citrulline was similar across groups at baseline, but increased substantially over time in all teduglutide groups when compared with placebo at week 8. Adverse events were not different between placebo and active treatment groups. The authors concluded that teduglutide is a novel and potentially effective therapy for inducing remission and mucosal healing in patients with active moderate-to-severe CD. Moreover, they stated that further clinical investigation of this growth factor is warranted.
Tee and colleagues (2011) noted that recent multi-center, placebo-controlled studies of teduglutide in SBS patients reported meaningful reductions in PN requirements with good safety profiles. The reparative and immuno-modulatory effects of teduglutide may also be beneficial in patients with inflammatory bowel disease as reported in small pilot studies. However, safety concerns regarding possible carcinogenic properties during long-term use require ongoing evaluation.
Hornby and Moore (2011) stated that GLP-2 has gained interest as a therapeutic most notably by reducing reliance on total PN in patients with SBS. Benefits of short-term GLP-2 treatment are emerging in pre-clinical models, such as post-operative ileus, gastro-intestinal mucositis, and conditions of altered intestinal permeability. The therapeutic utility of GLP-2 receptor agonists is limited by concern that it predisposes patients to gastro-intestinal cancers, or their re-occurrence in cancer patients. This affects the types of diseases treated and, possibly, the duration of dosing. The authors concluded that GLP-2 is therapeutically attractive in diseases to enhance absorptive capacity, restore mucosal health and reduce inflammation. Moreover, they stated that long-term surveillance studies are needed to weigh the benefits of GLP-2 treatment against the potential effects on co-morbidities and increased risk of intestinal carcinogenesis.
Korner et al (2012) stated that GLP-2, despite its known trophic and anti-inflammatory intestinal actions translated into preliminary clinical studies using the GLP-2 analog teduglutide for treatment of SBS and CD, remains poorly characterized in terms of expression of its receptor in tissues of interest. These researchers evaluated the GLP-2 receptor expression in 237 tumor and 148 non-neoplastic tissue samples with in-vitro receptor autoradiography. A GLP-2 receptor expression was present in 68 % of gastro-intestinal stromal tumors. Furthermore, GLP-2 receptors were identified in the intestinal myenteric plexus, with significant up-regulation in active CD. The GLP-2 receptors in gastro-intestinal stromal tumors may be used for clinical applications like in-vivo targeting with radiolabelled GLP-2 analogs for imaging and therapy. Moreover, the over-expressed GLP-2 receptor in the myenteric plexus may represent the morphological correlate of the clinical target of teduglutide in CD.
The OptumInsight™ Health Technology Alert’s on “Gattex (teduglutide [rDNA origin]): Glucagon-like peptide 2 for the treatment of short bowel syndrome” (2013) states that off-label uses of Gattex may include treatment of enteropathy, chemotherapy- or radiation-induced enteritis, and CD. Furthermore, it notes that Gattex is undergoing clinical trials for the treatment CD, necrotizing enterocolitis, and chemotherapy-induced mucositis.
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