Teduglutide for pediatric short bowel syndrome patients

Beatrice E. Rosete, Danielle Wendel & Simon P. Horslen

To cite this article: Beatrice E. Rosete, Danielle Wendel & Simon P. Horslen (2021): Teduglutide for pediatric short bowel syndrome patients, Expert Review of Gastroenterology & Hepatology, DOI: 10.1080/17474124.2021.1913052
To link to this article: https://doi.org/10.1080/17474124.2021.1913052

Published online: 26 Apr 2021.

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Teduglutide for pediatric short bowel syndrome patients
Beatrice E. Rosete a,b, Danielle Wendel c,d and Simon P. Horslen c,d
aDepartment of Pharmacy, Seattle Children’s Hospital, Seattle, WA, USA; bSchool of Pharmacy, University of Washington, Seattle, WA, USA; cDepartment of Gastroenterology, Hepatology and Nutrition, Seattle Children’s Hospital, Seattle, WA, USA; dDepartment of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA

Introduction: The goal for pediatric short bowel syndrome (SBS) patients is intestinal adaptation. Until recently, the medical management of pediatric SBS has centered on the prevention and treatment of complications in order to allow time for adaptation. Teduglutide, glucagon-like peptide 2 (GLP-2) analog, has recently been approved for use in pediatric SBS patients greater than 1 year of age as a novel agent to augment intestinal adaptation.
Areas covered: This article reviews the pharmacology, safety, efficacy, and tolerability of GLP-2 analog
teduglutide in pediatric patients greater than 1 year of age. We review all current studies and discuss teduglutide’s place in pediatric SBS therapy.
Expert opinion: Teduglutide marks the first successful pharmacological intervention that augments the natural process of adaptation safely and effectively in SBS pediatric patients. More studies and further development are needed to optimize its potential in other pediatric patients.
Received 15 January 2021
Accepted 1 April 2021
Short bowel syndrome; pediatrics; glucagon-like peptide 2 analogue; teduglutide; revestive; gattex; glp-2 analogue

⦁ Introduction
Intestinal failure results from the inability of the intestine to adequately digest and absorb the nutrients and fluid to promote growth and development requiring the use of parenteral nutri- tion (PN) to maintain protein and energy metabolism. The pri- mary cause of intestinal failure is short bowel syndrome (SBS) which results from a loss of functional intestinal length and is the focus of this review. Many cases of pediatric SBS, both congenital or acquired present soon after birth such as necrotizing enter- ocolitis, gastroschisis, intestinal atresia, and volvulus [1].
The goal of treatment for SBS is intestinal adaptation, the process by which the remaining intestine undergoes structural and functional changes after resection, leading to reduction of PN dependence. Enteral nutrition (EN) is required to promote this process in part by stimulating release of gastrointestinal (GI) hor- mones, growth factors, and digestive secretions; because of this, enteral nutrition is started as soon as possible after resection [2]. The process of adaptation starts immediately after resection and is most significant in the first 2–3 years [3]. In order to allow time for this process to occur, it is necessary to closely monitor and adjust parenteral and enteral intake as well as prevent and treat compli- cations associated with SBS, long-term PN, and central venous access. Significant advances in the care of children with SBS have occurred over the past two decades with the rise of multi- disciplinary intestinal rehabilitation teams resulting in decreased morbidity and mortality leading to survival rates over 90% [4,5].
Until recently, the medical management of SBS has centered on the prevention and treatment of complications of SBS in order to allow time for adaptation without additional pharmacologic options to augment the process. Hormones and growth factors

such as octreotide, growth hormone, glutamine, and oral insulin have been targeted as potential therapeutic options with limited success [6–9].
In May 2019, the United States Food and Drug
Administration approved teduglutide (marketed as Gattex® in the United States and Revestive® in Europe) for use in patients with SBS over the age of 1 year who
require parenteral nutrition or fluid support. Teduglutide is an analog of the glucagon-like peptide 2 (GLP-2) hormone, an enteroendocrine hormone produced by the intestinal L-cells in the terminal ileum and proximal colon in response to luminal nutrients [10,11]. Native GLP-2 is known to increase intestinal and portal blood flow and to slow gastric acid secretion and intestinal motility lead- ing to improved nutrient and fluid absorption allowing increased feeds, and reduced PN [11–14]. Teduglutide binds to the GLP-2 receptors in the intestine activating the release of mediators such as ErbB ligands, insulin-like growth factor 1, nitric oxide, and keratinocyte growth factor leading to these same effects [11,12,15,15,16]. In adults, these mediators have been shown to increase villus height and intestinal absorption [11,12,15,17]. Four studies have focused on pediatric patients all showing these same effects. This article is a review of the current literature and use of teduglutide in pediatric SBS patients.

⦁ Pharmacodynamics
Teduglutide differs from GLP-2 by a single amino acid sub- stitution, which allows resistance to in vivo degradation and slower catabolism (Figure 1) [11,12,18,19]. As a result, the half-

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Article highlights

⦁ Short bowel syndrome (SBS) is the primary cause of intestinal failure in pediatric patients with the goal of treatment being intestinal adaptation.
⦁ Until recently, the medical management on SBS has centered on prevention and treatment of complications to provide time for intestinal adaptation.
⦁ The introduction of GLP-2 analogue teduglutide marks the first successful pharmacological intervention that augments the natural process of adaptation with many reviews and studies showing safety and tolerability in adults.
⦁ Reviewing the current literature and use in pediatrics, teduglutide has been shown to be effective, decreasing PN requirements and increasing enteral autonomy and intestinal growth.
⦁ Teduglutide has also been shown to have no major safety concerns in pediatrics, but some adverse effects that may be confounded by underlying disease.
⦁ Optimizing potential use of teduglutide includes assessing multiple factors including appropriate candidates and drug delivery form, timing, and administration and pediatric patients may benefit most from a specialized intestinal rehab program.
⦁ There may be more potential for teduglutide in other patient popu- lations and different formulations, but further translational research is needed.

life of teduglutide is significantly longer than that of endo- genous GLP-2 allowing increased potency. Teduglutide has been associated with improvements in intestinal absorption and increased mucosal growth in multiple studies in adults with more recent studies in pediatrics showing similar end- points [17,20].
Improvements in intestinal absorption are shown in studies through decreased PN requirements even to the point of enteral autonomy. In the initial 12-week open-label pediatric study, teduglutide decreased PN volume and calories by 41% and 45%, respectively, with the 0.025 mg/kg dose and by 25% and 52% in the 0.05 mg/kg dose. Four out of the 27 patients achieved complete independence from PN during the 12 weeks of the study [17]. A 24-week multicenter study of 59 pediatric patients found that 69% of patients on treatment dosing teduglutide (0.05 mg/kg) were able to significantly decrease PN volume requirements by at least 20% in 24 weeks of therapy (p < 0.05) [20]. The mean PN volume decreased by 36% in patients on 0.025 mg/kg teduglutide and
42% in those on 0.05 mg/kg [20]. Similarly, in the adult pilot study including 16 SBS patients, teduglutide significantly decreased fecal wet weight compared to baseline by about 711 gm/day (p = 0.001) with an increase in relative absorption of 22% (p < 0.001) and absolute wet weight of 742 gm/day (p < 0.001) [14].
A histological study by Tappenden et al. supports teduglu- tide’s intestinal growth property and demonstrated significant increase in small bowel villus height when patients were on
0.1 mg/kg/day or 0.05 mg/kg/day when compared with base- line (p = 0.002 and p = 0.007, respectively) [21]. They also found increased mucosal RNA concentrations in the small intestine for both groups (p < 0.001) and increased mean crypt depth in the small intestine in the group on 0.1 mg/ kg/day (p = 0.044) [21]. In addition to histological result in adult patients, it has been found that plasma citrulline, an amino acid produced by enterocytes and a possible biomarker of enterocyte mass, increased significantly in PN-dependent SBS adult patients (p < 0.0001) [22]. In the pediatric study including citrulline, the results were clouded by variable base- line values and, while there was an increase in median change of plasma citrulline, the absolute values appear unchanged [17].

⦁ Pharmacokinetics
⦁ Absorption
Teduglutide administered subcutaneously has 88% bioavail- ability and is rapidly absorbed, reaching maximum plasma concentrations at 3 to 5 hours following administration. Following a therapeutic dose of 0.05 mg/kg subcutaneously in adult SBS patients the median peak concentration (Cmax) was 36 ng/mL and the median area under curve (AUC) at steady state was 0.15 mcg*hr/mL. Both AUC and Cmax were proportionate to dose [11,23]. Pediatric Cmax and AUC is similar to that of adults with Cmax slightly variable with age group (see Table 1 below), but around 30 ng/mL. AUC at steady state is similar in teens at 0.154 mcg*hr/mL, but lower in younger pediatrics (1 to 11 years old) at 0.128 mcg*hr/mL (Table 1). Teduglutide was not shown to accumu- late even after multiple subcutaneous administrations [11].

Figure 1. Teduglutide and GLP-2 structures.
Teduglutide differs from GLP-2 by a single amino acid substitution of the alanine substituted by glycine at the location shown ab.

Table 1. Teduglutide pharmacokinetics following single subcutaneous doses of
0.05 mg/kga.
4.2. Pediatric clinical trials

Parameters (Mean ± standard deviation)

Age Cmax (ng/mL) AUC (mcg*hr/mL) CL/F (L/hr) t 1/2 (hr) 1 to 11 years 33.5 ± 11.5 0.128 ± 0.0567 7.45 ± 2.1 0.7 ± 0.2
12 to 17 years 29.7 ± 8.4 0.154 ± 0.0176 13 ± 2.3 1 ± 0.001
Adults 36 0.15 8.38 1.3 b

Cmax – maximum concentration, AUC – area under curve, Cl/F – total body clearance, t ½ – elimination half life
⦁ Table derived from Gattex package insert Table 2 [11]
⦁ Half-life in adult SBS patients. Healthy adult subjects have a longer t ½ of about 2 hours [11].

⦁ Distribution
Teduglutide has a volume of distribution of 0.1 L/kg [11].

⦁ Metabolism
The metabolic pathway was not investigated in humans but is believed to be similar to endogenous catabolism of GLP-2 by degradation into smaller peptides and amino acids by dipep- tidyl peptidase IV (DPP-IV) [11,12,22]. Due to the amino acid substitution, catabolism is slower and results in around a 1 hour half-life which is greater than that of endogenous GLP-2 at 7 minutes (Table 1) [10].

⦁ Excretion
The plasma clearance of Teduglutide is about 123 mL/kg/hr similar to GFR as it is removed primarily by the kidney via glomerular filtration and tubular metabolism [11]. As a result, renally impaired patients require dose consideration. The terminal half-life (t ½) is dependent on renal function and known to be 1.3 hours in SBS patients and 2 hours in healthy subjects with faster clearance in pediatrics based on age group [11,18]. Table 1 demonstrates faster clearance and less bioavailability in patients 1 to 11 years of age in comparison to faster clearance and slightly less bioavailability in teenage pediatric patients.

⦁ Clinical efficacy
⦁ Adult clinical trials
Clinical studies in adults have demonstrated efficacy, safety and tolerability of teduglutide [14,22,24–26]. Multiple studies have demonstrated reduction in PN support in SBS patients with significantly greater response when compared to that of placebo [14,15,22,24,26]. The third trial of Study of Teduglutide Effectiveness in Parenteral Nutrition-dependent Short-bowel syndrome subjects (STEPS-3) showed a twofold decreased PN requirement in those adults on teduglutide when compared to placebo with 54% of patients in the tedu- glutide group having greater than a 1 day reduction in weekly PN requirement when compared to 23% in placebo (p = 0.05) [25]. Four patients in the 52 week study and two patients in the STEPS-3 study were able to be completely weaned off PN while receiving 0.5 mg/kg of teduglutide [14,24–26].
A 12-week prospective open-label multicenter study was con- ducted on 42 patients ages 1 to 17 years of age with SBS in the United States and United Kingdom [17]. The study had a standard of care (SOC) and 3 treatment arms of with varia- tions in daily subcutaneous dose. Teduglutide treatment group 1 received 0.0125 mg/kg, group 2 received 0.025 mg/ kg, and group 3 received 0.05 mg/kg. Due to the limited results and small patient sample, the study was descriptively analyzed. Teduglutide treatment was associated with trends toward decrease PN volume and calorie requirements starting as early as 4 weeks in groups 2 and 3. At the end of the 12- week period, prescribed PN volume median decreased by
2.3 L/wk and 1.3 L/wk in these two treatment groups, respec- tively. The median PN volumes showed no change for SOC and treatment group 1. The PN calories decreased by a median of 17 kcal/kg/day in both the treatment groups 2 and 3. The SOC patients and treatment group 1 patients showed a decrease in PN by 2 kcal/kg/day and 1 kcal/kg/ day, respectively. Of the teduglutide treatment groups, one patient in treatment group 1 and three patients in treatment group 3 achieved PN independence. In addition, teduglutide group 3 had an average of 1.3 days less PN per week. Plasma citrulline levels increased in all teduglutide cohorts at week 12 suggesting increased intestinal epithelial mass. Overall, the teduglutide groups who received 0.025 mg/kg and 0.05 mg/ kg both showed trend of PN reduction and EN improvement demonstrating improvement in intestinal adaptation and absorption with teduglutide also reflected in plasma citrulline.
A phase 3 open-label, multicenter longer-term extension study conducted in patients who completed the first 12-week study (NCT01952080) evaluated the clinical efficacy and long- term safety of teduglutide in pediatric patients ages 1 to 17 years with SBS in the United States and United Kingdom [27]. This study collected retrospective and observational data starting where the prior 12-week study had ended. 29 of 40 patients from the prior study consented to data collection. 24 of these patients did not receive teduglutide during the data collection time frame and five were restarted on teduglutide at around weeks 78 to 96 for a median duration of 24.9 weeks. The change in PN volume requirements from baseline was minimal in the group who did not continue teduglutide after initial study, they were able to maintain the current amount of reduced PN they were on at teduglutide cessation. The group that restarted teduglutide showed continued decrease in PN volume requirements after re-initiation. The mean percentage change from baseline in these five patients was 23.3% increase prior to re-initiation and 38.6% reduction from base- line at week 120. These same five patients demonstrated a mean decrease of 3.8 days of PN per week at week 120 in comparison to 1.4 days prior to reinitiation. This retrospective study demonstrated the benefits of continued teduglutide therapy leading to continued PN reduction and 40% enteral autonomy in patients who restarted teduglutide therapy in comparison to those who stopped therapy.
A 24-week, open-label phase III multicenter study was con-
ducted on 59 pediatric patients from 1 to 17 years of age

requiring PN for SBS in North America and Europe [20]. Patients were enrolled in the teduglutide or standard of care (SOC) treatment arms. Those patients and families who chose teduglutide were randomized to receive once daily subcuta- neous injections of 0.025 mg/kg or 0.05 mg/kg. The primary endpoint was a ≥ 20% reduction in PN volume at week 24 compared with baseline. Of the 59 patients, 9 received the standard of care, 26 received 0.05 mg/kg teduglutide and 24 received 0.025 mg/kg teduglutide. All patients completed the study including 24 weeks and 4 weeks of follow-up. The primary efficacy endpoint of ≥20% PN volume reduction was achieved by 54% (n = 13) of patients in the teduglutide
0.025 mg/kg treatment arm and 69% (n = 18) of patients in the teduglutide 0.05 mg/kg treatment arm in comparison with only 1 patient in the SOC group (11%). These results showed statistical differences in response compared with the SOC group to be 43% greater in the 0.025 mg/kg teduglutide group (p = 0.03, 95%CI: 5.5–63.2) and 58% greater in the
0.05 mg/kg teduglutide group (p = 0.004, 95%CI: 20.5–75.1). Teduglutide treatment resulted in meaningful clinical reduc- tions of PN from baseline to week 24 with percentage of volume changes 36% in the teduglutide 0.025 mg/kg treat- ment group and 42% in the 0.05 mg/kg teduglutide group. There was also a decrease of 10% in the SOC arm. Reductions were associated with substantial increase in enteral nutrition volume and calories. Z-scores were collected and used to classify nutritional status in pediatric patients. No significant changes were found in weight, height, and BMI z-scores or in urine and stool output demonstrating that these reductions in PN did not affect overall nutrition status for any of the patients. In addition, there was an increase of plasma citrulline levels consistent with teduglutide induced increase in intest- inal epithelial mass which decreased after discontinuation of treatment suggesting necessity of continued therapy to main- tain these effects. In addition, five patients developed enteral autonomy during the study, two from the 0.025 mg/kg tedu- glutide group and three from the 0.05 mg/kg teduglutide group. This 24-week study demonstrated decreased PN dependency and even enteral autonomy with continued growth.
A more recent prospective 12-month study of 17 pediatric patients ages 1 to 18 with intestinal failure secondary to SBS in Spanish hospitals presents the first real-life study conducted in pediatrics and demonstrated improved results compared to adult patients [28]. All patients were treated with teduglutide
0.05 mg/kg daily via subcutaneous injection. Of the 16 patients that completed the study, 11 achieved enteral auton- omy with results as early as autonomy in three patients at 3 months. Stool output was improved overall and citrulline levels increased from 20 µmol/L average to 37.5, 46.8 and 37.9 µmol/L at 3, 6 and 12 months after teduglutide initiation, respectively. This first real-life study demonstrates great ben- efits of teduglutide and the need for additional studies for longer term data.

⦁ Safety and tolerability
As with any pro-proliferative treatment, there is the potential for growth-associated complications, especially with long-term
use. While polyp formation has been seen in adult post- marketing surveillance studies in patients on teduglutide, the duration of follow up is not sufficient to determine if teduglu- tide is associated with increased polyp formation [25]. There are registries currently underway to look at these questions in adults receiving the drug (ClinicalTrials.gov identifier: NCT01990040), but data so far has shown no increased risk of malignancy or high-grade dysplasia in adults. There has not been long enough exposure to the medication in pediatric patients to comment on these risks. For adults, colonoscopy screening is recommended because of the risk of growth- associated complications.
With the known risk of polyp formation with the potential for malignancy and the expected long duration of treatment for children, it is imperative to screen for these risks. Fecal occult blood testing is recommended for pediatric patients prior to the start of medication and colonoscopy if positive. Colonoscopy is also recommended after 1 year of treatment and every 5 years thereafter while on continuous treatment with teduglutide as well as with new or unexplained bleeding. Other potential complications associated with teduglutide include fluid overload secondary to improved absorption, hepatobiliary and pancreatic issues, as well as intestinal obstruction [11].
The pediatric trials of teduglutide reported minimal side effects, most of which are common at baseline in children with short bowel syndrome and were not clearly drug related. Vomiting was the most common, followed by upper respira- tory infection, catheter-related complications, and fever. Neither polyps nor neoplasia was found during colonoscopies performed during the studies. Adverse events of concern based on the mechanism of action of teduglutide such as intestinal obstruction, fluid overload, congestive heart failure, or increased absorption of oral medications were not seen. No participants died during either trial [17,20].
In the 12-week study, treatment-emergent serious adverse events (TESAE) were seen in 17 patients receiving drug (46%) and 3 patients in the SOC group (60%). Those that were seen in
>2 patients included fever, central-line infection, and catheter- related complications. There were no hepatobiliary or pancreatic adverse events reported in the 12-week study. There was no discontinuation of medication secondary to adverse events [17]. During the 24-week study, TESAE were reported in 35 patients receiving teduglutide (70%) and 4 patients in the SOC group (44%). Three patients experienced non- medication related hepatobiliary disorders with 1 of each of the following: cholelithiasis, cholestasis, and liver disorder. These effects may be due to the known effects of GLP-2 to increase gallbladder volume capacity and delay emptying [29]. One patient experienced an increased lipase also thought to be unrelated to the medication. Two patients were admitted for TESEA, one with a fecaloma later clarified to be a ‘hard stool’ and a second with an adynamic ileus without small bowel obstruction. The drug was held for a brief period in
both cases without recurrence upon resumption [20].
The most recent safety data analysis of pediatric patients ages 1 to 17 years with SBS IF treated with teduglutide pooled safety data from four clinical studies from both North America and Europe (NCT01952080, EudraCT 2013–004588-40,

NCT02672381, EudraCT 2015–002252-27). This study followed 89 patients from these four clinical studies with a median of 52 weeks of teduglutide treatment and 83 weeks of prospec- tive follow-up building on the previous 2 core studies. The results showed no new safety data, but confirmed the same expected adverse effects as those in prior studies with most frequent including vomiting, fever, upper respiratory tract infection, cough, and central-line infection. Only three serious adverse events were determined by investigators to be tedu- glutide related. Of the three, two were in the prior 24-week study including the patient with adynamic ileus and one with fecaloma. The third was a boy with history small intestinal bacterial overgrowth who had an event of D-lactic acidosis shortly after an interruption in teduglutide treatment. This event was later determined by the sponsor to be related to underlying disease and likely unrelated to teduglutide treat- ment. For all patients the drug was held, the condition resolved and teduglutide was continued without recurrence. This analysis confirmed the prior two study results which demonstrated that teduglutide is well tolerated with no major safety concerns, but some adverse effects that may be confounded by underlying disease state [30].

⦁ Expert opinion
From the development of PN in the 1960s, to intestinal trans- plantation in the 1990s, and intestinal rehabilitation teams in the 2000s, intestinal failure, and SBS have gone from unsurvi- vable conditions to those in which there is over 90% survival [4,5,31,32]. These changes have occurred secondary to improvements in monitoring, preventing, and treating the many complications associated with short bowel syndrome, long-term PN, and the associated central venous access. The introduction of the GLP-2 analog teduglutide marks the first successful pharmacological intervention that augments the natural process of adaptation. At our institution, teduglutide has increased intestinal adaptation, decreased PN require- ments, and improved enteral nutrition in several of our pedia- tric patients which has led to an improved quality of life.
With the close monitoring required for SBS patients, and specifically those being treated with teduglutide, it is impera- tive that patients be referred to an intestinal rehabilitation center for this specialized care as we have at our institution. As many children with SBS are not managed by a multidisciplinary intestinal rehabilitation team, education regarding teduglutide, appropriate candidates for therapy, and recommendation for referral to a center with experience to help guide its use and any other emerging therapies is needed focusing on community providers and surgeons.
To date there have been no published cost-effectiveness studies looking at teduglutide. After their own review, the National Health Services in Britain decided not to recommend coverage of the medication. This decision was made because the amount of PN patients were on decreased with teduglu- tide, but in most cases it was not eliminated completely mak- ing the cost-effectiveness unacceptable. This decision emphasizes the need for improved understanding of which patients will benefit the most from treatment. While it will be
important to identify patients that will be able to discontinue PN, the effects on pediatric quality of life are also important yet difficult to study as they may not be accurately reflected by the current validated pediatric quality of life measures. Some of the effects we have seen in our patients treated with teduglutide, which have not been reflected in the pub- lished data, include having significant reduction in stool out- put and as a result both child and parent being able to sleep through the night without an episode of fecal incontinence and the ability to go swimming without fear of contamination of the central line in children who were able to discontinue parenteral support. Dedicated pediatric registries, such as the international registry being established by the Intestinal Rehabilitation and Transplant Association, are needed to clo- sely monitor children receiving teduglutide so that we can better understand the ideal indications for treatment.
In the search for ideal candidates, two groups that may benefit from the augmented adaptation provided by teduglu- tide are infants less than 1 year of age and intestinal transplant patients. Currently, the most warranted study would be those children younger than 1 year of age. We know that adaptation begins just after intestinal resection and eventually decreases over time, but most short bowel syndrome patients develop the condition in the neonatal period months before the youngest age at which teduglutide is approved for use. Use of a hormone analog during this crucial time of adaptation may alter the need for parenteral support long-term although identifying the appropriate patients, dose, and duration of treatment would remain a challenge and we would welcome studies designed to address these questions.
There has also been interest in the potential for the use of teduglutide and hormone analogues in intestinal transplant patients. Ischemia-reperfusion injury and allograft rejection may injure enteroendocrine cells along with the more familiar cellular components of a transplanted intestinal graft. Following sub-lethal insult to such an allograft, prolonged and even persistent high fluid losses from the bowel may persist despite apparent histologic recovery of the mucosa. Might this be a manifestation of loss of functional enteroendo- crine cells and thus studies of enteral hormonal replacement are probably warranted [33,34]? In the more distant future, tissue engineering may be able to produce lab-grown intes- tine which, depending on the ability to incorporate enteroen- docrine cells, may require developmental support from hormone analogs such as teduglutide.
In the pediatric drug trials, the injections are via a small gauge needle and tended to be relatively painless with many of our patients tolerating it even when given while they sleep. Now that the drug is commercially available, it is only available in a kit with a larger needle leading some families to request an alternative that is less painful. Although needle size may seem like a minor issue, it has effects on medication compli- ance and is one of the sources of concern for families in starting this potentially life-long daily injection. Other future research directions that could further reduce this burden include longer lasting formulations, such as glepaglutide (Zealand Pharma) and apraglutide (VectivBio) both of which are in the early stages of development, as well as changes to

the route of administration such as oral, depo, or pump deliv- ery [35,36].
In addition to candidate selection and drug delivery, there are also questions about how and when it is best to administer the drug. As native enteroendocrine hormones are released based on exposure to enteral nutrition, the specific timing of hormone analog dosing either pre- or postprandially may change the effectiveness of the drug. Furthermore, while var- ious growth factors and hormone analogs such as octreotide, growth hormone, glutamine, oral insulin, and glucagon-like peptide 1 have been trialed in isolation in SBS patients, none have successfully developed into pharmaceutical production. More recently, there have been promising trials that combine hormones, specifically GLP-1/GLP-2 co-agonists [37,38], to bet- ter approximate the native spectrum of hormones to which the intestine is exposed. This approach may eventually lead to tailoring of treatment and precision medicine whereby a patient could be tested for endogenous levels of enteroen- docrine hormones and provided with those in which they are lacking or development of certain hormonal combinations that are identified to work best depending on primary diag- noses or remaining intestinal anatomy.
With the rapid advances achieved in care for this vulnerable population of medically complex children, this is an exciting time to be involved in the care of patients with pediatric SBS. While teduglutide represents a new frontier of treatment, further translational research is needed to promote this for- ward progress and continue improvements to patient health with increased focus to both patient and family quality of life.

Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Their insti- tution and authors have participated in teduglutide trials with all grants paid to Seattle Children’s Research Institute, but authors have not received any personal funding or benefited from these trials in any way.

Reviewer disclosures
One reviewer would like to disclose that they have been involved as a researcher in the phase III study in adults to test the effect of Teduglutide on intestinal failure. The study has been finished more than 5 years ago. They also have received honoraria from Shire for scientific presentations in several symposia and that their institution has received research funding from Shire for basic science of intestinal failure and the effect of Teduglutide in mice. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Beatrice E. Rosete http://orcid.org/0000-0001-9106-7558 Danielle Wendel http://orcid.org/0000-0001-5140-2956 Simon P. Horslen http://orcid.org/0000-0001-5949-7363

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•• Pivitol Phase III study demonstrating the initial safety and phar-
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⦁ Phase III trial studying longer terms effects of teduglutide in
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⦁ Long-term follow-up of initial teduglutide studies which paved
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⦁ First real-life data demonstrating outcomes in the pediatric
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⦁ Hvistendahl M, Naimi R, Enevoldsen L, et al. Hvistendahl MK, Naimi RM, Enevoldsen LH, Madsen JL, Fuglsang S, Jeppesen PB.Effect of glepaglutide, a long-acting glucagon-like peptide-2 analog, on gastrointestinal transit time and motility in patients with short bowel syndrome: findings from a randomized trial. JPEN J Parenter Enteral Nutr. 2020 Nov;44(8):1535–1544. .
⦁ Slim G, Lansing M, Wizzard P, et al. Novel long-acting GLP-2 analo- gue, FE 203799 (apraglutide), enhances adaptation and linear intestinal growth in a neonatal piglet model of short bowel syn- drome with total resection of the ileum. JPEN J Parenter Enteral Nutr. 2019 Sep;43(7):891–898.
⦁ Wismann P, Pedersen SL, Hansen G, et al. Novel GLP-1/GLP-2 co-agonists display marked effects on gut volume and improves glycemic control in mice. Physio Behav. 2018;192(72):72–81.
⦁ Hvistendahl M, Brandt C, Tribler S, et al. Effect of liraglutide treat- ment on jejunostomy output in patients with short bowel syn- drome: an open-label pilot study. JPEN J Parenter Enteral Nutr. 2018 Jan;42(1):112–121.

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