Teduglutide (Gattex)

Number: 0849

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

Scope of Policy

This Clinical Policy Bulletin addresses teduglutide (Gattex) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of teduglutide (Gattex) is required of all Aetna participating providers and members in applicable plan designs. For precertification, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Aetna considers teduglutide (Gattex) medically necessary for the treatment of members with short bowel syndrome (SBS) who meet either of the following criteria:

   1. Adult members who have been dependent on parenteral nutrition and/or intravenous (IV) fluids for at least 12 months and are receiving parenteral nutrition and/or IV fluids at least 3 times a week; or
   2. Members less than 18 years of age who are receiving parenteral nutrition and/or IV fluids to account for at least 30% of caloric and/or fluid/electrolyte needs.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of teduglutide therapy medically necessary for treatment of short bowel syndrome (SBS) for members who meet either of the following:

   1. Members who are using the requested medication for SBS and who remain dependent on parenteral nutrition and/or intravenous (IV) fluids and whose requirement for parenteral support has decreased by at least 20% from baseline while on teduglutide therapy; or
   2. Members who are using the requested medication for SBS and who was previously dependent on parenteral nutrition and/or IV fluids has been able to wean off the requirement for parenteral support while on teduglutide therapy.

3. Related Policies

   1. CPB 0061 - Nutritional Support
   2. CPB 0170 - Growth Hormone (GH) and Growth Hormone Antagonists
   3. CPB 0342 - Intestinal Rehabilitation Programs

Dosage and Administration

Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. Below includes dosing recommendations as per the FDA-approved prescribing information. 

Lyopholized teduglutide powder for solution is available as Gattex in 5 mg single-dose vials for adult self-administration or caregiver administration. Self-administration in pediatrics has not been tested. Use of the Gattex 5 mg kit is not recommended in pediatrics weighing less than 10 kg.

The recommended dosage of teduglutide (Gattex) for both adults and pediatrics is 0.05 mg/kg once daily by subcutaneous injection.

The recommended dosage in adult and pediatrics with moderate to severe renal impairment and end-stage renal disease (estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m²) is 0.025 mg/kg once daily.

Source: Takeda Pharmaceuticals America, Inc., 2022

Experimental and Investigational

Aetna considers teduglutide experimental and investigational for all other indications including the following (not an all-inclusive list):

• Chemotherapy-induced enteritis
• Enterocutaneous fistula
• Gastrointestinal mucositis (including chemotherapy-induced mucositis)
• Gastrointestinal stromal tumors
• Graft-verus-host disease (GVHD)
• Inflammatory bowel disease (Crohn's disease and ulcerative colitis)
• Intestinal anastomotic healing
• Necrotizing enterocolitis
• Post-operative ileus
• Radiation-induced enteritis
• Radiation-induced intestinal injury
• Routine use following small bowel transplantation
• Type-2 diabetes mellitus.

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
HCPCS codes covered if selection criteria are met:
There is no specific HCPCS Code for Teduglutide (Gattex)
ICD-10 codes covered if selection criteria are met:
K91.2	Postsurgical malabsorption, not elsewhere classified [short bowel syndrome]
ICD-10 codes not covered for indications listed in the CPB (not all inclusive) :
C26.0	Malignant neoplasm of intestinal tract, part unspecified [Gastro-intestinal stromal tumors]
C16.0 - C19	Malignant neoplasm of stomach, small intestine, colon and rectosigmoid junction
C78.4	Secondary malignant neoplasm of small intestine
C78.5	Secondary malignant neoplasm of large intestine and rectum
D89.810 - D89.813	Graft-versus-host disease
E11.0 - E11.9	Type 2 diabetes mellitus
K12.31	Oral mucositis (ulcerative) due to antineoplastic therapy
K50.00 - K52.9	Crohn's disease [regional enteritis]
K56.0	Paralytic ileus [post-operative ileus]
K56.7	Ileus, unspecified [post-operative]
K56.7	Ileus, unspecified [post-operative]
K63.2	Fistula of intestine
K91.89	Other postprocedural complications and disorders of digestive system [post-operative ileus]
K92.81	Gastrointestinal mucositis (ulcerative)
P77.1 - P77.9	Necrotizing enterocolitis in newborn
T66.xxxA	Radiation sickness, unspecified, initial encounter [enteritis]
Z94.84	Stem cells transplant status

---

Background

U.S. Food and Drug Administration (FDA)-Approved Indication

• Gattex is indicated for the treatment of adult and pediatric patients 1 year of age and older with short bowel syndrome (SBS) who are dependent on parenteral support.

Teduglutide is available as Gattex (Takeda Pharmaceuticals America, Inc), which is a glucagon-like peptide-2 (GLP-2) analog, 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).

Gattex label carries warnings and precautions for acceleration of neoplastic growth, intestinal obstruction, biliary and pancreatic disease, fluid overload (including congestive heart failure), and potential for increased absorption of oral medications (e.g., benzodiazepines). In adults and pediatric patients, colonoscopy is recommended after 1 year of treatment. Obtain bilirubin, alkaline phosphatase, lipase, amylase every 6 months. If clinically meaningful changes are seen, further evaluation is recommended including imaging, and reassess continued Gattex treatment. The most common adverse reactions (10% or more) include abdominal pain, nausea, upper respiratory tract infection, abdominal distension, injection site reaction, vomiting, fluid overload, and hypersensitivity. 

Short Bowel Syndrome

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).  

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). Teduglutide is a human recombinant analog of glucagon-like peptide 2 (GLP-2) and is designed to restore intestinal structural and functional integrity by promoting growth of the intestinal mucosa as well as increasing intestinal and portal blood flow and reducing gastric emptying and secretion. These effects lead to greater surface area in the gut and slower transit time which allow for greater nutrient absorption. 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. 

On May 17, 2019 the U.S. Food and Drug Administration (FDA) approved extending the indication of Gattex (teduglutide) for injection to pediatric patients 1 year of age and older with Short Bowel Syndrome (SBS) who need additional nutrition or fluids from intravenous (IV) feeding (parenteral support). In children, SBS is a life-threatening, chronic, and rare malabsorption disorder resulting from surgical removal of a large portion of the intestine, which is typically due to congenital or acquired conditions of the newborn or trauma. Children with SBS are unable to absorb enough nutrients and fluids from what they eat and drink alone. A goal of SBS treatment is to restore the remaining intestine’s ability to absorb nutrients and reduce long-term dependence on parenteral support (PS). 

Available evidence has demonstrated a desirable benefit-to-risk profile in regard 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.

Hornby and Moore (2011) stated that GLP-2 has gained interest as a therapeutic most notably by reducing reliance on total parenteral nutrition (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.

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.

DiBaise (2014) provided an update of recent advances in the areas of SBS and small bowel transplantation (SBT).  Recent reports from 2 of the largest multi-center randomized, controlled trials (RCTs) in patients with SBS supported the safety and effectiveness of teduglutide as an aid to parenteral nutrition weaning.  In well selected SBS patients, outcomes as diverse as survival, macronutrient absorption and parenteral nutrition weaning were improved after autologous gastro-intestinal reconstructive surgery.  Small bowel transplantation is no longer considered investigational and given improved outcomes noted in recent reports, indications for transplantation are expanding.  Although SBT early survival rates are approaching those of other organ allografts, long-term graft survival remains suboptimal.  These investigators stated that recently available trophic factors hold promise as aids in restoring freedom from parenteral nutrition support; however, their long-term benefits, preferred timing of administration in relation to the onset of SBS, optimal patient selection for use, duration of treatment and cost effectiveness require further study.  The authors concluded that despite recent evidence of improved early survival after SBT, more dedicated research is needed to design more effective strategies to better tolerize small bowel grafts, prevent rejection and, ultimately, improve long-term outcomes. 

Pediatric Short Bowel Syndrome

In a 12-week, open-label, multi-center clinical trial, Carter and colleagues (2017) determined the safety and pharmacodynamics/efficacy of teduglutide in children with SBS-IF.  This study enrolled patients aged 1 to 17 years with SBS-IF who required PN and showed minimal or no advance in enteral nutrition (EN) feeds.  Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/day [n = 8], 0.025 mg/kg/day [n = 14], 0.05 mg/kg/day [n = 15]) or received standard of care (SOC, n = 5).  Descriptive summary statistics were used.  All patients experienced greater than or equal to 1 treatment-emergent AE; most were mild or moderate.  No serious teduglutide-related treatment-emergent AEs occurred.  Between baseline and week 12, prescribed PN volume and calories (kcal/kg/day) changed by a median of -41 % and -45 %, respectively, with 0.025 mg/kg/day teduglutide and by -25 % and -52 % with 0.05 mg/kg/day teduglutide.  In contrast, PN volume and calories changed by 0 % and -6 %, respectively, with 0.0125 mg/kg/day teduglutide and by 0 % and -1 % with SOC.  Per patient diary data, EN volume increased by a median of 22 %, 32 %, and 40 % in the 0.0125, 0.025, and 0.05 mg/kg/day cohorts, respectively, and by 11 % with SOC; 4 patients achieved independence from PN, 3 in the 0.05 mg/kg/day cohort and 1 in the 0.025 mg/kg/day cohort.  The authors concluded that teduglutide was well-tolerated in pediatric patients with SBS-IF; teduglutide 0.025 or 0.05 mg/kg/day was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS-IF.  The drawbacks of this study included its short-term (12 weeks), open-label design, and small sample size (n = 37 in the teduglutide groups).

The expanded approval in pediatric patients was based on a 24-week pediatric study (Study 5,TED-C14-006, NCT02682381) which demonstrated teduglutide helped reduce the volume of daily parenteral support required and time spent administering parenteral support. Some children even achieved complete freedom from parenteral support. Fifty-nine pediatric patients with SBS aged 1 year through 17 years chose whether to receive teduglutide or standard of care (SOC). Patients who chose to receive teduglutide treatment were subsequently randomized in a double-blind manner to 0.025 mg/kg/day (n=24) or 0.05 mg/kg/day (n=26), while 9 patients enrolled in the SOC arm. The recommended dosage of teduglutide is 0.05 mg/kg/day. Patients treated with 0.05 mg/kg had a mean age of 6 years at baseline. The most common reasons for intestinal resection leading to SBS were gastroschisis (54%, 14/26), midgut volvulus (23%, 6/26), and necrotizing enterocolitis (12%, 3/26). Stoma was present in 19% (5/26) of patients, and the most common type was jejunostomy (80%, 4/5). The mean length of remaining small intestine was 47 (±28) cm (range: 9 to 120 cm). In the 25 patients who had remaining colon, the colon was in continuity in 22 patients. At baseline, the mean parenteral support volume was 60 (±29) mL/kg/day (range: 24 to 133 mL/kg/day) [8 (±4) L/week (range: 3 to 19 L/week)] and mean parenteral support infusion time was 7 (±1) days/week (range: 5 to 7 days/week) and 11 (±3) hours/day (range: 7 to 20 hours/day). 

Randomization to the teduglutide dose groups was stratified by age. At the end of the 24-week study, 69% of patients (18/26) who took teduglutide 0.05 mg/kg each day reduced parenteral support volume by 20% or more. Based on patient-diary data, patients who received teduglutide 0.05 mg/kg/day experienced a 42% mean reduction in parenteral support  volume (mL/kg/day) from baseline (-23 mL/kg/day from baseline). At week 24, 38% of patients (10/26) were able to reduce parenteral support infusion by at least 1 day per week. Patients reduced their parenteral support infusion time by 3 hours per day on average compared to baseline. In addition, during this study 3 out of 26 (12%) children who received teduglutide 0.05 mg/kg/day completely weaned off parenteral support. 

Study 6 (SHP633-304, NCT02954458) was a prospective, open-label, long-term extension study of pediatric patients who completed Study 5. In the extension study, patients received additional treatment with teduglutide 0.05 mg/kg subcutaneously once daily if they deteriorated or stopped improving after discontinuation of prior teduglutide treatment. Of the 15 patients who initially responded in Study 5 and enrolled in Study 6, 13 patients (87%) required additional treatment with teduglutide. Efficacy results at the end of the first 24-week treatment period in Study 6 (total treatment for a mean of 40 weeks) were similar to those achieved at the end of 24 weeks treatment in Study 5. One additional patient treated with 0.05 mg/kg in Study 5 eventually achieved enteral autonomy during follow-up in Study 6.

Teduglutide has a demonstrated safety profile that is similar overall in pediatric and adult patients.

Chemotherapy-Induced Mucositis

Hytting-Andreasen and colleagues (2018) noted that mucositis is a side effect of chemotherapy seen in the digestive tract, with symptoms including pain, diarrhea, inflammation and ulcerations.  These investigators examined if endogenous glucagon-like peptide -1 and -2 (GLP-1 and GLP-2) are implicated in intestinal healing after chemotherapy-induced mucositis.  These researchers used a transgenic mouse model Tg(GCG.DTR)(Tg) expressing the human diphtheria toxin receptor in the proglucagon-producing cells.  Injections with diphtheria toxin ablated the GLP-1 and GLP-2 producing L-cells in Tg mice with no effect in wild-type (WT) mice.  Mice were injected with 5-fluorouracil or saline and received vehicle, exendin-4, teduglutide (gly2-GLP-2), or exendin-4/teduglutide in combination.  The end-points were body weight change, small intestinal weight, morphology, histological scoring of mucositis and myeloperoxidase levels.  Ablation of L-cells led to impaired GLP-2 secretion; increased loss of body weight; lower small intestinal weight; lower crypt depth, villus height and mucosal area; and increased the mucositis severity score in mice given 5-fluorouracil.  WT mice showed compensatory hyper-proliferation as a sign of regeneration in the recovery phase.  Co-treatment with exendin-4 and teduglutide rescued the body weight of the Tg mice and led to a hyper-proliferation in the small intestine, whereas single treatment was less effective.  The authors concluded that the ablation of L-cells led to severe mucositis and insufficient intestinal healing, shown by severe body weight loss and lack of compensatory hyper-proliferation in the recovery phase.  Co-treatment with exendin-4 and teduglutide could prevent this.  Because both peptides were needed, the authors concluded that both GLP-1 and GLP-2 were essential for intestinal healing in mice.  Moreover, they stated that whether the individual L-cell function in humans is critical for intestinal healing as a response to chemotherapy-induced mucositis needs further investigation.

Enterocutaneous Fistula

Yeh et al (2022) stated that enterocutaneous fistula (ECF) is a complication of surgery or IBD associated with disproportionately high healthcare costs, morbidity, and mortality.  These researchers carried out a proof-of-concept (POC), feasibility, open-label, randomized, cross-over, pilot study to examine the safety and effectiveness of the use of teduglutide (TED) in the treatment of ECF.  Adults (aged greater than 18 years) with low-output (less than 200 ml/day) ECF were randomized to 2 months of continuing SOC followed by cross-over to 2 months of SOC + TED or the reverse order.  The primary effectiveness endpoint was decrease in fistula volume by 20 % of baseline 3-day average.  Secondary effectiveness endpoints included fistula resolution and health-related quality of life (HR-QOL) questionnaire scores.  A total of 6 out of 10 planned subjects were randomized and completed the study, which was terminated early due to slow enrollment during the Covid-19 pandemic.  Overall subject compliance with daily TED injections was high (98 %); 5 of the 6 enrolled subjects met the definition for the primary effectiveness endpoint; these clinical responses were not observed during the SOC arm in these subjects.  One subject experienced complete fistula closure during TED treatment; AEs during treatment were uncommon, minor, and usually resolved despite ongoing treatment; and QOL survey responses were highly variable and did not correlate with fistula changes.  The authors concluded that 2 months of teduglutide treatment was feasible, well-tolerated, and resulted in observable decreases in ECF drainage in the majority of subjects, including spontaneous closure in one subject.  These researchers stated that this therapy showed promise; however, larger, multi-center clinical trials are needed to confirm these preliminary findings.

Graft-Versus-Host Disease 

Norona et al (2020) stated that acute graft-versus-host disease (GVHD) is a life-threatening complication following allogeneic hematopoietic cell transplantation (allo-HCT).  Although currently used GVHD treatment regimens target the donor immune system, these researchers examined an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs).  GLP-2 is an enteroendocrine tissue hormone produced by intestinal L cells.  These investigators observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD.  Treatment with the GLP-2 agonist, teduglutide, reduced de-novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models.  Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of anti-microbial peptides and caused microbiome changes.  GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes.  Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of non-relapse mortality in patients undergoing allo-HCT.  The authors concluded that these findings indicated that L cells were a target of GVHD and that GLP-2-based treatment of acute GVHD restored intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects.  These researchers stated that teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials. 

Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis)

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.

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.

Blonski et al (2013) noted that the currently available medications for treatment of CD include aminosalicylates, corticosteroids, antibiotics, immunomodulators and biologic agents (e.g., adalimumab, certolizumab pegol, infliximab, and natalizumab).  These agents target the immune and inflammatory pathways of CD, while there is a shortage of agents that target the barrier functions of the gut that are impaired in CD.  Glucagon-like peptide 2 is an enterogastrone with strong trophic effects on the intestinal mucosa.  Teduglutide, the analog of glucagon-like peptide has been already approved by the FDA as a treatment of SBS.  These researchers discussed the potential use of teduglutide in patients with CD.  As there has been only 1 randomized placebo- controlled trial of teduglutide in CD, there is a shortage of data regarding the effectiveness of this agent in CD.  The literature search was performed using Medline database with the use of the following key words: teduglutide, glucagon-like peptide-2, CD and inflammatory bowel disease.  The authors stated that based on available data, it can be concluded that this agent seems to be a promising medication in CD and further trials are needed to define the place of teduglutide in treatment of CD.

Kochar and colleagues (2017) stated that because of the rarity of SBS, real-world safety or efficacy data are not available in patients with CD and SBS treated with teduglutide.  In a retrospective, cohort study, these investigators evaluated teduglutide's safety and efficacy in CD patients with SBS.  This study was conducted at 3 tertiary centers in the U.S. between 2012 and 2014.  Demographic, clinical, and therapeutic data were retrieved from medical record systems.  A total of 13 CD patients were included, 8 (62 %) of whom were on concomitant immunosuppression.  Median duration of teduglutide therapy was 365 days (interquartile range [IQR], 122 to 482 days) and 9/13 patients (69 %) remain on therapy.  At teduglutide initiation, 69 % were on PN.  At conclusion of follow-up, 1 patient was on PN.  All patients were on intravenous fluids (IVF) before teduglutide; median IVF were 9,000 ml/week (IQR, 7,000 to 14,000 ml/week); IVF requirements decreased by a median of 3,100 ml/week (IQR, 2,400 to 8,400 ml/week); 6 patients (46 %) ceased IVF.  Adverse events (AEs) attributed to teduglutide were obstructive symptoms (n = 1), pancreatitis (n = 1), asymptomatic lipase and amylase elevation (n = 1), nausea (n = 1), and abdominal pain (n = 1).  Catheter-related sepsis occurred in 4 patients.  The authors concluded that this was the first report evaluating the safety and effectiveness of teduglutide in a cohort of CD patients with SBS requiring PN; more than 50 % of the cohort was on concomitant immunosuppression.  These investigators stated that teduglutide appeared to be safe and the majority of patients were weaned off PN.

Melo et al (2021) noted that the roles dipeptidyl peptidase 4 (DPP4), aminopeptidase N (APN), and their substrates in autoimmune diseases are being increasingly recognized; however, their significance in inflammatory bowel diseases (IBD) is not clearly understood.  In a systematic review, these investigators examined the pathophysiological processes related to these ectopeptidases while comparing findings from pre-clinical and clinical settings.  This review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.  These researchers carried out a literature search in PubMed, SCOPUS, and Web of Science to identify all reports from inception until February 2020.  The search included validated animal models of intestinal inflammation and studies in IBD patients.  Quality assessment was conducted using SYRCLE's risk of bias tool and CASP qualitative and cohort checklists.  From the 45 included studies, 36 were conducted in animal models and 12 in humans (3 reports included both).  Overall, the methodological quality of preclinical studies was acceptable.  In animal models, DPP4 and APN inhibition significantly improved intestinal inflammation.  Glucagon-like peptide (GLP)-1 and GLP-2 analogs and GLP-2-relase-inducing drugs also showed significant benefits in recovery from inflammatory damage.  A non-significant trend toward disease remission with the GLP-2 analog teduglutide was observed in the sole interventional human study.  All human studies reported an inverse correlation between soluble DPP4/CD26 levels and disease severity, in accordance with the proposal of DPP4 as a biomarker for IBD.  The authors concluded that the use of DPP4 inhibitors and analogs of its substrates had clear benefits in the treatment of experimentally induced intestinal inflammation.  Moreover, these investigators stated that further research is needed to validate their potential diagnostic and therapeutic applications in IBD patients.

The authors stated that this systematic review had several drawbacks.  First, stemming from the inherent limitations of the included reports, the overall quality of pre-clinical experimental studies was less than desirable.  Protocol variations within the “same” model and the considerable variability of animal strains and species did not allow for a reliable comparison between experiments.  Second, under-reporting of the protocol execution and the subjective nature of the quality assessment tools also limited the internal validity and the extrapolation of data from animal to human subjects.  Third, most reports with human populations suffered for having a cross-sectional design (only 1 study was a prospective cohort) or low sample size, and only one had an interventional approach akin to animal studies.

Intestinal Anastomotic Healing

Costa and colleagues (2018) analyzed the response of tissue growth factors to surgical injury and teduglutide administration on an animal model of intestinal anastomosis.  Wistar rats (n = 59) were distributed into 4 groups: "ileal resection" or "laparotomy", each one sub-divided into "post-operative teduglutide administration" or "no treatment"; and sacrificed at the 3rd or the 7th day, with ileal sample harvesting.  Gene expression of insulin-like growth factor 1 (Igf1), vascular endothelial growth factor a (Vegfa), transforming growth factor β1 (Tgfβ1), connective tissue growth factor (Ctgf), fibroblast growth factor 2 (Fgf2), fibroblast growth factor 7 (Fgf7), epidermal growth factor (Egf), heparin-binding epidermal-like growth factor (Hbegf), platelet-derived growth factor b (Pdgfb) and glucagon-like peptide 2 receptor (Glp2r) was studied by real-time polymerase chain reaction (rt-PCR).  Up-regulation of Fgf7, Fgf2, Egf, Vegfa and Glp2r at the 3rd day and of Pdgfb at the 7th day was verified in the peri-anastomotic segment.  Teduglutide administration was associated with higher fold-change of relative gene expression of Vegfa (3.6 ± 1.3 versus1.9 ± 2.0, p = 0.0001), Hbegf (2.2 ± 2.3 versus 1.1 ± 0.9, p = 0.001), Igf1 (1.6 ± 7.6 versus 0.9 ± 0.7, p = 0.002) and Ctgf (1.1 ± 2.1 versus 0.6 ± 2.0, p = 0.013); and lower fold-change of Tgfβ1, Fgf7 and Glp2r.  The authors concluded that these findings underscored the recognized role of Igf1 and Hbegf as molecular mediators of the effects of teduglutide and suggested that other humoral factors, like Vegfa and Ctgf, may also be relevant in the peri-operative context.  Induction of Vegfa, Igf1 and Ctgf gene expressions might indicate a favorable influence of teduglutide on the intestinal anastomotic healing.

Radiation-Induced Intestinal Injury

Gu and colleagues (2017) noted that although radiotherapy is a highly effective treatment for abdominal or pelvic cancer patients, it can increase the incidence of severe gastro-intestinal (GI) toxicity.  As an intestinal growth factor, GLP-2 has been shown to improve the pre-clinical models of both SBS and IBD by stimulating intestinal growth.  Teduglutide ([Gly2]GLP-2) has a prolonged half-life and stability as compared to the native GLP-2 peptide, but still requires daily application in the clinic.  These researchers designed and prepared a new degradation-resistant GLP-2 analog dimer, designated GLP-2②, with biotechnological techniques.  The purity of GLP-2②reached 97 % after ammonium sulfate precipitation and anion exchange chromatography purification, and the purification process was simple and cost-effective.  These investigators next confirmed that the GLP-2② exhibited enhanced activities compared with [Gly2]GLP-2, the long-acting, degradation-resistant analog.  Notably, GLP-2② offered a pharmacokinetic and therapeutic advantage in the treatment of radiation-induced intestinal injury over [Gly2]GLP-2.  These investigators further demonstrated that GLP-2② rapidly activated divergent intra-cellular signaling pathways involved in cell survival and apoptosis.  The authors concluded that these findings revealed a potential novel and safe peptide drug for limiting the adverse effect of radiotherapy on the GI system.

Type-2 Diabetes Mellitus

Wismann and co-workers (2018) noted that analogs of several GI peptide hormones have been developed into effective medicines for treatment of diseases such as type-2 diabetes mellitus (T2DM), obesity and SBS.  These researchers examined if the combination of GLP-1 and GLP-2 into a potent co-agonist could provide additional benefits compared to existing monotherapies.  A short-acting (GUB09-123) and a half-life extended (GUB09-145) GLP-1/GLP-2 co-agonist were generated using solid-phase peptide synthesis and tested for effects on food intake, body weight, glucose homeostasis, and gut proliferation in lean mice and in diabetic db/db mice.  Sub-chronic administration of GUB09-123 to lean mice significantly reduced food intake, improved glucose tolerance, and increased gut volume, superior to monotherapy with the GLP-2 analog teduglutide.  Chronic administration of GUB09-123 to diabetic mice significantly improved glycemic control and showed persistent effects on gastric emptying, superior to monotherapy with the GLP-1 analog liraglutide.  Due to the short-acting nature of the molecule, no effects on body weight were observed, whereas a marked and robust intestine-trophic effect on mainly the small intestine volume and surface area was obtained.  In contrast to GUB09-123, sub-chronic administration of a half-life extended GUB09-145 to lean mice caused marked dose-dependent effects on body weight while maintaining its potent intestine-trophic effect.  The authors concluded that these findings demonstrated that the GLP-1/GLP-2 co-agonists had effects on gut morphometry, showing a marked increase in intestinal volume and mucosal surface area.  Furthermore, effects on glucose tolerance and long-term glycemic control were evident.  Effects on body weight and gastric emptying were also observed depending on the pharmacokinetic properties of the molecule.  These investigators suggested that this novel co-agonistic approach could exemplify a novel concept for treatment of T2DM or SBS; moreover, they stated that more in-depth studies in models of GI diseases and obesity are still needed to validate the full potential of GLP-1/GLP-2 co-agonism.

---

References