REVIEW URRENT C OPINION

New approaches to the treatments of short bowel syndrome-associated intestinal failure Palle B. Jeppesen

Purpose of review Teduglutide, a recombinant analog of human glucagon-like peptide 2, has recently been approved in the US and Europe (Gattex and Revestive, respectively) as the first targeted treatment of short bowel syndromeassociated intestinal failure (SBS-IF). Glucagon-like peptide 2 improves structural and functional intestinal adaptation following intestinal resection by decelerating a rapid gastric emptying, by decreasing gastric hypersecretion, by increasing intestinal blood flow and by promoting intestinal growth. This review summarizes the findings from phase 2 and 3 studies preceding the US Food and Drug Administration and the European Medicines Agency approval of subcutaneous teduglutide for this orphan condition. Recent findings In a 3-week, phase 2, metabolic balance study, teduglutide increased intestinal wet weight absorption by approximately 700 g/day and reduced fecal energy losses by approximately 0.8 MJ/day (200 kcal/ day). In two subsequent 24-week, phase 3 studies, teduglutide reduced the need for parenteral support in the same magnitude. Teduglutide had an acceptable tolerability profile, where adverse events generally were of gastrointestinal origin consistent with the known mechanism of action. Summary Teduglutide will add incremental benefit to the limited medical treatment armamentarium in SBS patients by maximizing intestinal absorption, decreasing fecal losses, thereby decreasing or even eliminating the need for parenteral support. Future research should target and implement other key hormones with similar and possible additive or synergistic effects, thereby further promoting structural and functional adaptation and intestinal rehabilitation in these severely disabled SBS patients. Keywords Gattex, intestinal failure, Revestive, short bowel syndrome, teduglutide

INTRODUCTION Recently, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the glucagon-like peptide 2 (GLP-2) analog, teduglutide (Gattex and Revestive, respectively), for the treatment of patients with short bowel syndromeassociated intestinal failure (SBS-IF). On the basis of a brief presentation of the pathophysiology and consequences of the SBS and the need for parenteral support, this article reviews the clinical data that provide the scientific rationale for the positioning and use of teduglutide in this orphan condition.

SHORT BOWEL SYNDROME, INTESTINAL INSUFFICIENCY AND FAILURE, PARENTERAL SUPPORT AND HOME PARENTERAL NUTRITION In healthy individuals, the body homeostasis, composition and function is maintained by adequate www.co-gastroenterology.com

digestion and absorption of macronutrients, fluid, electrolytes, trace elements and vitamins. Insufficient oral intake or inadequate intestinal assimilation will lead to intestinal failure and a need for parenteral support. The main cause of intestinal failure is SBS. SBS is seen after intestinal resection, but extensive parenchymal and mucosal disease may also diminish the intestinal absorptive capacity and lead to ‘functional’ SBS. Neuromuscular disorders may cause chronic intestinal pseudo-obstruction and ultimately intestinal failure due to a Department of Medical Gastroenterology, Rigshospitalet, Copenhagen, Denmark Correspondence to Palle B. Jeppesen, Department of Medical Gastroenterology CA-2121, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel: +45 35452452; fax: +45 35452913; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:182–188 DOI:10.1097/MOG.0000000000000046 Volume 30  Number 2  March 2014

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Short bowel syndrome-associated intestinal failure Jeppesen

KEY POINTS  The GLP-2 analog, teduglutide, ameliorates some of the pathophysiological features of the SBS. GLP-2 or teduglutide tends to restore a more normal gastric emptying and intestinal transit, reduce gastric and intestinal hypersecretion, and to enhance bowel trophicity.  These structural and functional improvements in the process of intestinal adaptation improve intestinal absorption and reduce fecal excretions.  In SBS patients with intestinal failure, the consequent improvements in intestinal absorption facilitate weaning from parenteral support.  Depending on the degree of intestinal failure and the response of the individual SBS patient to treatment, the reduction in parenteral support in relation to teduglutide may entirely eliminate the need for, provide days off, or reduce the time spent on parenteral support.  A reduction in parenteral support is associated with improvements in the quality of life in SBS-IF patients.

reduced ability to eat. In most SBS patients, the increased fecal losses are compensated for by increasing the oral intake (hyperphagia), and pharmacological treatments may also improve remnant intestinal absorptive capacity [1]. When the body homeostasis is mildly disturbed, as may be seen in patients with intestinal insufficiency, the body composition and function may be maintained by physiological adaptation. For instance, resting energy expenditure and urinary excretions are decreased in relation to the semi-starvation and relative dehydration that follows orally incompensated malassimilation. With more severe disturbances in the body homeostasis, as is seen in intestinal failure patients, parenteral support is needed to maintain body composition and functions, and to prevent diseases caused by malnutrition, deficiencies, dehydration and electrolyte disturbances [2–4]. Consequently, the SBS encompasses a spectrum that ranges from mild malabsorption, as seen in patients with minor intestinal resections, to patients with severe malabsorption and large needs for parenteral support due to resection of virtually all of their intestines. Thus, although all patients with intestinal resections are included in the same syndrome, they are truly heterogeneous and present with a diversity of phenotypes [5 ]. The individual patients may objectively be allocated in this spectrum according to the severity of the SBS by quantifying remnant intestinal functions in metabolic balance studies and, in intestinal failure patients, also by determining their need for parenteral support [6]. &

Since the late 1960s, the use of tunneled devices for central venous access has allowed the relocation of these patients from the hospital setting to the home setting. The provision of home parenteral nutrition (HPN, consisting of both nutrition and intravenous fluids, or either of them) has revolutionized the long-term care of intestinal failure patients. HPN has saved the lives of tens of thousands of these relatively rare and unfortunate patients [7,8]. It is estimated that the current number of SBS-IF patients in the US is approximately 10–15 000 with an equal number being present in Europe [9]. Thereby, the average prevalence in developed countries is around 25 SBS-IF patients per million inhabitants. However, the large regional and national variance in the prevalence and incidence of intestinal failure patients receiving parenteral support illustrates that the organization and provision of this healthcare service still is in its infancy even in many developed countries. Although providing a lifesaving option in the home environment of the intestinal failure patient, these patients are not only challenged by the inconveniences and symptoms of their gastrointestinal disorder but also by the fear of – or the factual burden of – the potentially life-threatening complications of HPN: catheter-related bloodstream infections, bacteremia or even septicemia, central venous thrombosis and embolism [4]. Metabolic complications may develop in relation to mismanagement of parenteral support, and constituents of the parenteral solutions and chronic dehydration may contribute to progressive intestinal failure-associated liver and renal disease and, eventually, organ failure. However, given the right care, intestinal failure patients rarely die from HPN complications [10,11]. Patients with intestinal failure have impaired quality of life (QoL) due to symptoms of malassimilation and due to the need to be physically connected to their HPN for up to 16 h per day [12]. Therefore, treatments should seek to maximize remnant intestinal absorption, decrease malassimilation and accompanying symptoms, and reduce the fear, burdens or complications of the intrusive HPN, thereby ultimately improving the health-related QoL in intestinal failure patients [12,13]. Complete weaning from HPN could allow the removal of the central line, thereby eliminating the potential risks and burdens associated with the central catheter.

TREATMENT OF SHORT BOWEL SYNDROME When initiating treatments of SBS patients, it is important to evaluate and balance the benefit or clinical meaningfulness of interventions versus the inconveniences, adverse effects, risks and cost [14 ].

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It is believed that the maximal intestinal digestion and absorption is achieved by maximizing the exposure of the mucosal surface area to nutrients, fluids, electrolytes, trace elements and vitamins in the right form, concentration and composition, at the right place, in the right environment and in a timely fashion [14 ]. Thus, conventional treatments have consisted of dietary advice (e.g. hyperphagia, high carbohydrate diets, supplemental enteral nutrition and oral rehydration solutions) in conjunction with a limited pharmacological treatment armamentarium (mainly including antisecretory and antidiarrheal agents). In 2003, the US FDA approved somatropin (Zorbtive; EMD Serono Inc., Rockland, Massachusetts, USA), a recombinant version of human growth hormone, for a 4-week treatment regimen in SBS-IF patients. A number of clinical studies with small heterogeneous patient populations and a number of different doses of growth hormone in combination with glutamine had given conflicting results of the effect on intestinal absorption [15–21]. However, in a randomized, double-blind phase 3 study, treatment for 4 weeks in 16 patients with 0.1 mg/kg/day subcutaneous somatropin and a glutamine-supplemented diet significantly reduced total parenteral volume by 7.7 l/week (P < 0.001) compared to baseline in SBS patients with a preserved colon [22]. Sixteen patients receiving somatropin and an optimized nonglutamine-supplemented diet had reductions in parenteral volume of 5.9 l/week (P < 0.05), whereas this was 3.8 l/week in nine patients receiving a glutamine-supplemented diet alone. The mean reductions from baseline in total parenteral calories were significantly greater in patients receiving somatropin and glutamine-supplemented diet (5751 kcal/ week; P < 0.001) and in patients receiving somatropin and optimized nonglutamine-supplemented diet (4338 kcal/week; P < 0.01) compared with glutaminesupplemented diet alone (2633 kcal/wk). However, systemic adverse events (e.g. new-onset glucose tolerance, type 2 diabetes mellitus, carpal tunnel syndrome, tissue turgor in limbs, musculoskeletal discomfort, nightmares and insomnia) were frequently observed, and body weight decreased significantly following discontinuation of treatment suggesting a lack of long-term effects. Thus, this mode of ‘intestinal rehabilitation’ never achieved general acceptance by the SBS-IF patients nor their physicians. Instead, over the past decades, it has become increasingly clear that mucosal nerve ends and endocrine cells within the gastrointestinal tract mediate information via the enteric nervous system in response to the passing of luminal contents, thereby contributing to the highly coordinated processes of nutrient assimilation. It also appears &

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that this endogenous hormonal release is essential to the structural and functional intestinal adaptation seen in some SBS patients following intestinal resection. These ‘neuro-endocrine feedback mechanisms’ of the gastrointestinal tract often referred to as the ‘gastric, jejunal, ileal or colonic brakes’ may be disrupted by distal intestinal resections or mucosal disease [23–26]. The attenuation of the meal-stimulated secretion of hormones, such as the GLP-1 and GLP-2, and peptide YY by L cells, associated with the removal of the terminal ileum and the colon, may be associated with some of the possible pathophysiological features of SBS patients with distal bowel resections [27]: accelerated gastrointestinal motility, gastric and intestinal hypersecretion, diminished intestinal blood flow, disturbed immunological and barrier functions, impaired mucosal replacement, repair and adaptation. In SBS patients with a preserved terminal ileum or colon in continuity, an increase in the endogenous hormonal secretion may be responsible for the progressive intestinal adaptation believed to occur in these patients [28]. Consequently, these observations have instigated the pharmacological use of peptide hormones in the intestinal rehabilitation of SBS patients [29,30]. The first peptide hormone to gain marketing approval for the treatment of SBS patients is the GLP-2 agonist, teduglutide.

GLUCAGON-LIKE PEPTIDE 2 AND TEDUGLUTIDE The physiological importance of GLP-2 was first highlighted by the promotion of the expansion of the intestinal mucosa via the stimulation of crypt cell growth and the reduction of enterocyte apoptosis in relation to exogenous GLP-2 administration [31]. GLP-2 also inhibits gastric acid secretion and gastric emptying, stimulates intestinal blood flow [32–34], increases intestinal barrier function [35], opposes inflammatory insults [36,37], enhances nutrient and fluid absorption [38], and GLP-2 may also decrease bone resorption [39]. In 2001, it was demonstrated in a proof-ofconcept study that GLP-2 indeed decreased diarrhea and increased intestinal wet weight absorption in eight SBS patients with an end jejunostomy [29]. In order to prevent GLP-2 degradation by the proteolytic enzyme dipeptidyl peptidase IV, teduglutide, a GLP-2 analog, was created by a single amino acid substitution of alanine by glycine in the second position of the N-terminus. This extended the half-life from only 7 min to approximately 2–3 h [40,41]. In a publication from 2005, 17 SBS patients were allocated to five treatment groups using doses of Volume 30  Number 2  March 2014

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Short bowel syndrome-associated intestinal failure Jeppesen Table 1. Results from the phase II, metabolic balance study [42] Per protocol group (n ¼ 16)

SBS patients with end jejunostomies (n ¼ 10)

SBS patients with 50% colon in continuity (n ¼ 5)

Wet weight Diet Feces (g/day) Absolute absorption (g/day) Relative absorption (%) Urine (g/day)

33 (429)

105 (530)

271 (147)

2711 (734)

2682 (911)

2822 (341)

743 (477)

788 (551)



22 (16)

555 (485)

788 (551)



26 (16)

20 (18)





461 (200)

680 (535)

Sodium Diet (mmol/day)

5 (63)

NP

NP

25 (88)

NP

NP

Absolute absorption (mmol/day)

30 (95)

NP

NP

Relative absorption (%)

38 (70)

NP

NP

Urine (mmol/day)

53 (40)

NP

NP

Feces (mmol/day)

Energy Diet Feces (kJ/day) Absolute absorption (kJ/day) Relative absorption (%)

16 (2073)

169 (2455)

316 (297)

808 (1453)

532 (1703)

1343 (916)

792 (2279)

363 (2656)

1027 (798)

8 (17)

5 (20)

10 (7)

NP, not provided; SBS, short bowel syndrome. Changes from baseline after 21 days of teduglutide treatment.  P < 0.05.  P < 0.01.  P < 0.001 versus baseline.

0.03, 0.10 or 0.15 mg/kg teduglutide subcutaneously once daily, or 0.05 or 0.75 mg/kg twice daily in a phase 2, metabolic balance study [42]. Treatment resulted in structural adaptation evidenced by hyperplasia in the intestinal mucosa and functional adaptation evidenced by enhanced gastrointestinal fluid absorption of approximately 750 ml/day with improvements in the absorption of macronutrients and electrolytes and resulting in increased urine excretions (Table 1). Effects were similar in SBS patients with an end jejunostomy and in patients with a colon in continuity. Since metabolic balance studies are complex, difficult to perform and require inpatient admissions to a metabolic research unit, the phase 3 teduglutide studies were conducted using a more practical, but still clinically relevant, outpatient design. Study 004 [43] and study 020 [44 ] were similar in many design elements (Fig. 1). Both were 24-week prospective, randomized, doubleblind, placebo-controlled, parallel-group, multinational, and multicenter studies conducted in the US, Canada, and Europe. Both enrolled adults (18 years of age) with SBS due to diverse causes (e.g. Crohn’s disease, vascular disease, volvulus, injury and other) who were dependent on parenteral support for at least 12 months and required parenteral support at least three times per week. In both studies [43,44 ], parenteral support requirements were &&

&&

optimized and stabilized for up to 16 weeks before randomization to achieve urine output of 1–2 l per day. Patients were asked to maintain stable oral intake so that increased intestinal fluid absorption would be reflected in increased urinary output. In both studies, the investigators followed a protocoldefined weaning algorithm that allowed parenteral support volume adjustments based on 48-h urinary output and assessments of overall hydration and clinical status. The study 004 protocol limited the maximum amount by which parenteral support volume could be reduced to 10% beginning at week 4 and then monthly. By contrast, in study 020, parenteral support volume reductions began at week 2, and were as high as 30% of the baseline level. The two phase 3 studies were followed by open-label extension studies, the 004 study by a 28-week study designated the 005 study, and the 020 study by a 2-year study designated the 021 study (Fig. 1). In the first phase 3 study, published in 2011, SBS-IF patients were randomized to a 0.05 mg/kg/ day dose (n ¼ 35), a 0.10 mg/kg/day dose (n ¼ 32) or placebo (n ¼ 16) for up to 24 weeks [43]. In the primary efficacy analysis of the study, no statistically significant difference between the group on teduglutide 0.10 mg/kg/day and the placebo group was shown, whereas the proportion of patients receiving the recommended dose of 0.05 mg/kg/day achieved

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Open-label extension study

Double-bind, randomized, placebo-controlled study Teduglutide 0.05 mg/kg/d n = 27 n = 35

Teduglutide 0.05 mg/kg/d n = 25 +n=6

n = 20

Teduglutide 0.10 mg/kg/d n = 21 n = 27 +n=7

n = 23

n = 25

Urine volume 1-2 l/d

Screening

PS Optimization

PS Stabilization

Max. 7 days

Max. 8 weeks

Max. 4–8 weeks

Placebo n = 15 n = 16

n = 13

Teduglutide 0.10 mg/kg/d n = 29 n = 32

004 study, 24 weeks

Screening

Max. 7 days

n = 39

PS Optimization PS Stabilization

Max. 8 weeks

n=5

005 study, 28 weeks Placebo n = 43

Urine volume 1–2 l/d

n=6

Max. 4-8 weeks

Teduglutide 0.05 mg/kg/d n = 43

n = 37

Teduglutide 0.05 mg/kg/d n = 37 n = 39+12

n = 30 n = 35

Direct enrollment n = 12 n = 12

020 study, 24 weeks

021 study, 2 years

FIGURE 1. Design of the phase 3 placebo-controlled trials of teduglutide in adult patients with SBS-IF. SBS-IF, short bowel syndrome-associated intestinal failure.

at least a 20% reduction of parenteral support at week 20 and 24, which was significantly higher versus placebo (46 versus 6%; P < 0.01). At week 24, teduglutide treatment resulted in a 2.5 l/week reduction in parenteral support requirements from 9.6 l/week at baseline. In this study, teduglutide also induced expansion of the intestinal mucosa as illustrated in increases in villus heights and crypt depths in small bowel biopsies. Sixty-five patients opted to enter an open-label, 28-week extension study [45]. In the patients, who received 1 year of continuous teduglutide treatment, the mean reduction of weekly parenteral support volume was 4.9 l/week equivalent to a 52% reduction from baseline levels. The second phase 3 study was published in 2012 [44 ]. Forty-three SBS patients were randomized to a 0.05 mg/kg/day dose of teduglutide and 43 patients received placebo for up to 24 weeks. The proportion of teduglutide-treated patients achieving a 20– 100% reduction of parenteral support at week 20 and 24 was statistically significantly higher compared to placebo (27 out of 43 patients, 62.8% versus 13 out of 43 patients, 30.2%; P ¼ 0.002). At week 24, teduglutide treatment resulted in a 4.4 l/week (32%) reduction in parenteral support volume from a &&

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pretreatment baseline of 12.9 l/week while maintaining oral fluid intake, urine production and body weight constant throughout the study. Placebotreated patients had average parenteral support reductions of 2.3  2.7 l/week (21%) at week 24, but they significantly increased their oral fluid intake by 1.6  3.6 l/week (P < 0.009) in order to maintain urine production constant. In patients completing the study, 21 patients treated with teduglutide (54%) versus nine on placebo (23%) achieved at least a 1-day reduction in parenteral support administration (P ¼ 0.005). The long-term, 30-month results from the 021 extension study were recently published in abstract form. Treatment with teduglutide resulted in additional, clinically meaningful reductions in parenteral support volume from 12.9 l/week at baseline to 4.9 l/week after 30 months of treatment. Independence from parenteral support was achieved in 13 patients included in the 020 and 021 studies. In general, teduglutide was well tolerated with the distribution of discontinuation of treatment due to adverse events being similar between patients given teduglutide and placebo [43,44 ]. The adverse event profile was generally consistent with the underlying &&

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Short bowel syndrome-associated intestinal failure Jeppesen Table 2. Adverse reactions in at least 5% of teduglutide-treated SBS patients and more frequent than placebo in studies 004 and 020 Adverse reaction Abdominal pain Upper respiratory tract infection

Placebo (n ¼ 59) [n (%)]

Teduglutide (n ¼ 77) 0.05 mg/kg/day n (%)

16 (27)

29 (38)

8 (14)

20 (26)

12 (20)

19 (25)

Abdominal distension

1 (2)

15 (20)

Vomiting

6 (10)

9 (12)

Fluid overload

4 (7)

9 (12)

Flatulence

4 (7)

7 (9)

Hypersensitivity

3 (5)

6 (8)

Appetite disorders

2 (3)

5 (7)

Sleep disturbances

0 (0)

4 (5)

Cough

0 (0)

4 (5)

Skin hemorrhage

1 (2)

4 (5)

Nausea

Patients with stoma Gastrointestinal stoma complicationa

3 (14)a

13 (42)a

SBS, short bowel syndrome. a Percentage based on 53 patients with a stoma (n ¼ 22 placebo, and n ¼ 31 teduglutide 0.05 mg/kg/day) [46].

disease condition and the known mechanism of action of teduglutide: the most frequently reported adverse events were gastrointestinal-related (Table 2) [46]. In the 020 study, the overall parenteral support reductions were associated with increases in QoL. Teduglutide significantly improved the scores of nine of 17 individual items of the SBS-QoL scale from baseline at week 24. Effects were not significant compared to placebo [47]. According to NPS Pharmaceutical, the costs of the development program of teduglutide/Gattex have been around US$ 250 million. On 2 January 2013, NPS Pharmaceutical announced that it was pricing teduglutide/Gattex at US$ 295 000 per patient per year. The company estimated that as few as 3000 SBS-IF patients would be available for treatment in the US. According to NPS Pharmaceuticals, approximately half of the US-based patients would be on commercial insurance. Another third would be on Medicare and the rest would get Gattex for free (http://www.forbes.com/sites/mat thewherper/2013/01/03/inside-the-pricing-of-a300000-a-year-drug/). In Europe, teduglutide/Revestive has been approved for marketing, but it has not yet been launched. No information on the anticipated European pricing exists.

CONCLUSION On the basis of the acceptable benefit-to-risk ratio, the recent US FDA and EMA approval make teduglutide a welcome addition to the limited treatment armamentarium of the SBS. In conjunction

with the traditional dietary and conventional pharmacological means of promoting intestinal rehabilitation, teduglutide facilitates the structural and functional adaptation in SBS patients. Teduglutide increases intestinal absorption, diminishes fecal losses and eliminates the need for, provides days off, or reduces the time spend on parenteral support. The teduglutide development program has expanded our knowledge about the process of intestinal adaptation following intestinal resection, but it is possible that numerous other growth factors are involved. Future research should identify the key hormonal players that orchestrate the maximal adaptive response in SBS patients following intestinal resection, thereby providing their best possible QoL by alleviating the potential complications and the burden of this debilitating condition. However, the high price on the market of teduglutide has reflected the high development costs in an orphan indication which may limit the widespread development of new drugs in this indication. Acknowledgements None. Conflicts of interest Palle Bekker Jeppesen has served as a site investigator, an advisory board member, and a consultant for NPS Pharmaceuticals, Inc. (Bedminster, New Jersey, USA). Disclosure of funding for this work: The preparation of this review was not supported by any external funding.

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Volume 30  Number 2  March 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

New approaches to the treatments of short bowel syndrome-associated intestinal failure.

Teduglutide, a recombinant analog of human glucagon-like peptide 2, has recently been approved in the US and Europe (Gattex and Revestive, respectivel...
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