Clin Drug Investig DOI 10.1007/s40261-015-0286-6

ADIS DRUG CLINICAL Q&A

Teduglutide: A Guide to Its Use in Short Bowel Syndrome Kate McKeage1

 Springer International Publishing Switzerland 2015

Abstract Teduglutide (Gattex) is a recombinant analogue of human glucagon-like peptide-2 and is indicated for the treatment of adults with short bowel syndrome (SBS) dependent on parenteral support (PS). In a pivotal, 24-week clinical trial in SBS patients, subcutaneous teduglutide 0.05 mg/kg once daily increased absorption from the remnant intestine as evidenced by significant reductions in PS volume requirements versus placebo. Improvements attained in absorption in the first 6 months of therapy were maintained during the extension trial (total teduglutide treatment periods of up to 30 months), with evidence indicating that benefits accrue over time. Among patients who received teduglutide treatment for up to 30 months, 11 of 30 were able to achieve at least one additional day off PS and another ten achieved complete independence from PS. Subcutaneous teduglutide was generally well tolerated

in clinical trials, including over the long term, with most adverse events that led to study discontinuation being gastrointestinal in origin.

Adis evaluation of teduglutide in patients with short bowel syndrome (SBS) What are its key clinical benefits? First targeted long-term therapy for adults with SBS dependent on parenteral support (PS) Improves structural and functional integrity of the remnant intestine, thereby increasing fluid and nutrient absorption Reduces the volume of PS required and increases the number of infusion-free days Leads to PS independence in some patients Generally well tolerated, with most adverse events that led to discontinuation being gastrointestinal in origin What are its key clinical limitations?

The manuscript was reviewed by: R. Gilroy, Center for Transplantation, University of Kansas Medical Center, Kansas City, Kansas, USA; L. Matarese, Division of Gastroenterology, Hepatology and Nutrition, East Carolina University, Greenville, North Carolina, USA; E. Steiger, Cleveland Clinic Foundation, Nutrition Support and Vascular Access Department, Cleveland, Ohio, USA.

Because of the risk of acceleration of neoplastic growth, teduglutide should not be administered to patients with active gastrointestinal malignancy. The clinical decision to continue teduglutide in patients with non-gastrointestinal malignancy should be based on risk/benefit considerations

& Kate McKeage [email protected]

As with all SBS patients with intestinal failure, ongoing monitoring is required, including colonoscopy and laboratory assessments

1

Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand

K. McKeage

1 What is the Rationale for Developing Teduglutide? Intestinal failure associated with short bowel syndrome (SBS) usually occurs in adults as a result of major surgical resection and can lead to serious, life-threatening complications [1, 2]. The degree of intestinal failure following resection will vary between individuals, as will the postoperative level of adaption in the remnant intestine to compensate for the reduction in the absorptive surface area [3]. Because of these interindividual differences, effective management of patients with SBS requires an individualized, multidisciplinary approach [4, 5]. Patients with intestinal failure are likely to require parenteral support [PS; parenteral nutrition and/or intravenous (IV) fluids] and careful monitoring to maintain a balance of fluids, electrolytes, trace elements, nutrients and vitamins [2, 4]. While PS is important for stabilizing the nutrition and hydration of SBS patients, its long-term use is associated with several limitations, including catheter-related infection, metabolic bone disease, impaired renal function, liver disease and impaired health-related quality of life (HRQoL) [6, 7]. Therefore, a primary goal of management is to promote intestinal adaptation by improving fluid and nutrient absorption in order to reduce or eliminate PS requirements, thereby minimizing the risk of long-term complications and potentially enhancing HR-QoL [4, 7, 8]. Earlier treatment modalities focused on optimising function of the remnant intestine through diet, rehydration and antidiarrhoea and antisecretory agents, with surgery an option for some [7]. More recently, the focus switched to promoting intestinal rehabilitation and improving absorptive capacity, including the use of recombinant human growth hormone (somatotropin) and the recombinant analogue of human glucagon-like peptide-2 (GLP-2), teduglutide (Gattex) [3, 7]. Teduglutide represents the first targeted long-term medical option with the potential to reduce or eliminate the need for PS in SBS patients.

2 How does Teduglutide Work? GLP-2, a peptide secreted by L cells in the intestine, is associated with increasing intestinal and portal blood flow, inhibiting gastric acid secretion and decreasing intestinal motility [9, 10]. Compared with native GLP-2, teduglutide contains a single amino acid substitution resulting in resistance to in vivo degradation and an extended half-life [9, 11]. In SBS patients, teduglutide augments repair of the structural and functional integrity of the remnant intestine by increasing villus height and crypt depth, thereby increasing fluid and nutrient absorption [9, 11, 12]. In a study

in SBS patients (n = 16), compared with baseline, 21 days treatment with subcutaneous teduglutide (0.03–0.15 mg/ kg/day) significantly increased absolute and relative intestinal fluid (wet weight) absorption (p \ 0.001 for both) and urine weight (p \ 0.001), as well as decreasing faecal wet weight (p = 0.001) [9].

3 For Whom is Teduglutide Indicated? Subcutaneous teduglutide is indicated for the treatment of adults with SBS dependent on parenteral nutrition [12]. Table 1 provides a summary of the prescribing information for teduglutide in the treatment of SBS in the USA.

4 What is the Clinical Efficacy of Teduglutide? The approval of subcutaneous teduglutide for the treatment of patients with SBS was based on the results of a 24-week, double-blind, multinational, placebo-controlled, phase III study (STEPS) [13]; results from an open-label extension (STEPS-2) are also available (reported in an abstract and poster) [14]. Patients with intestinal failure dependent on PS at least 3 times weekly for C12 months received teduglutide 0.05 mg/kg (n = 43) or placebo (n = 43) once daily for 24 weeks. Randomization was subsequent to periods of optimization and stabilization in order to accurately establish baseline values for fluid intake (both oral and PS) and urine output (1–2 L/day), as well as ensuring adequate hydration and urine output [13]. The primary endpoint was the responder rate, defined as the proportion of patients who attained a reduction from baseline in PS fluid volume of 20–100 % at week 20 and maintained that response at week 24 [13]. PS volume reductions were based on 48-h urinary output, whereby PS was reduced by 10–30 % if the 48-h urine volume exceeded that of the previous visit by C10 %. An increase in urinary output during periods of decreased PS and stable intake is considered to reflect increased intestinal absorption [6, 13]. In the open-label extension of the STEPS trial, all patients continued (or were switched to) subcutaneous teduglutide 0.05 mg/kg once daily; some patients were included who had completed the fluid optimization and stabilization phases in STEPS, but did not receive randomized treatment [14]. 4.1 By How Much Can Parenteral Support (PS) be Reduced? Subcutaneous teduglutide once daily reduced the volume of PS required by SBS patients [13], and improvements

Teduglutide: Adis Drug Clinical Q&A Table 1 Prescribing summary of subcutaneous teduglutide (Gattex) in the treatment of short bowel syndrome (SBS) in the USA [12]. Consult local prescribing information for further details What is the approved indication for teduglutide? Treatment of adults with SBS who are dependent on parenteral support (PS) How should teduglutide be administered? Recommended dosage

0.05 mg/kg once daily

Administration

Subcutaneous injection; alternate sites on 1 of 4 quadrants of abdomen, both thighs and arms

How should teduglutide be used in patients with renal impairment? Teduglutide is cleared primarily by the kidneys; the dose should be reduced by 50 % in patients with moderate and severe renal impairment (CLCR \50 mL/min) and end-stage renal disease How should teduglutide be used in patients with hepatic impairment? No dosage adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh class B); teduglutide has not been studied in subjects with severe hepatic impairment How should teduglutide be used in the elderly (aged >65 years)? No difference in response to teduglutide was reported between older and younger patients, and no dosage adjustment is necessary in the elderly What patient monitoring is required throughout teduglutide treatment? A colonoscopy should be performed B6 months prior to starting teduglutide and after 1 year, with subsequent colonoscopies as indicated (at least every 5 years). Laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase) should be performed B6 months prior to starting teduglutide, with subsequent assessments every 6 months, and further evaluation (e.g. imaging of biliary tract, liver or pancreas) if indicated. Continued monitoring of body weight and signs of fluid retention are also recommended How should teduglutide be discontinued? Fluid and electrolyte status should be carefully monitored for potential imbalance when therapy is stopped What are the warnings and precautions? Accelerated neoplastic growth

Do not use in patients with active GI malignancy. Colonoscopy and colorectal polyp removal should be performed B6 months prior to starting teduglutide and after 1 year, with subsequent colonoscopies as indicated (at least every 5 years)

Intestinal obstruction

Discontinue teduglutide temporarily while patient is clinically managed, and restart when obstruction resolves, if indicated

Biliary and pancreatic disease

Prior to starting teduglutide, patients should undergo laboratory assessment, with subsequent testing at least every 6 months

Fluid overload Increased absorption of concomitant oral medication

Adjust PS and reassess teduglutide treatment, especially in patients with cardiovascular disease Dose adjustment of concomitant oral drugs requiring titration or with a narrow therapeutic window (e.g. benzodiazepines, phenothiazines) may be needed

CLCR creatinine clearance, GI gastrointestinal

were maintained over the long term [14]. At week 24 in the STEPS trial, there were significantly more responders in the teduglutide group than the placebo group (63 vs. 30 %; p = 0.002) [13]. Furthermore, the mean absolute reduction from baseline in PS volume at week 24 (key secondary endpoint) was significantly greater with teduglutide than placebo (4.4 vs. 2.3 L/week; p \ 0.001); baseline PS volumes were 12.9 and 13.2 L/week, respectively. Increased absorption occurred early within the first few weeks of teduglutide treatment, as demonstrated by decreases in PS volume requirements. The between group difference in the absolute decrease from baseline in PS volume favoured teduglutide from the first visit at week 4, and was statistically significant from week 8 (p = 0.011) through to week 24. Throughout treatment, more patients in the teduglutide group than the placebo group were able to reduce their PS by C1 day/week (54 vs. 23 %; p = 0.005).

During an additional 2 years of treatment in STEPS-2 (n = 88), the majority of patients achieved and/or continued clinically meaningful responses with teduglutide [14]. Among patients who received the longest teduglutide treatment duration (up to 30 months), including the placebo-controlled study and extension (n = 30), a 20–100 % reduction in PS fluid volume was attained in 93 % of patients, with a mean PS volume reduction of 7.6 L/week (66 %) from baseline [14]. Eleven of these patients were able to achieve at least one additional day off PS and ten patients achieved complete PS independence. Among all patients who received teduglutide 0.05 mg/ kg/day in phase III clinical trials (n = 134), 16 (12 %) achieved complete independence from PS (reported in an abstract plus poster) [15]. Independence from PS was achieved after 12–130 weeks of teduglutide treatment, suggesting that long-term therapy may lead to accrued benefit.

K. McKeage

4.2 Is it possible to Predict Which Patients Will Respond or Become PS Independent? No patient characteristics have been identified that predict a response or otherwise to teduglutide, with treatment benefits observed in patients with a range of disease characteristics and varying remnant bowel anatomy [15, 16]. A treatment benefit from teduglutide was achieved among SBS patients regardless of remnant bowel length and with or without colon-in-continuity, according to a recent subanalysis of 24-week STEPS trial data (n = 40) (reported in a poster) [16]. Similarly, no patient characteristics have been identified to predict which patients may become independent of PS with teduglutide treatment [14, 15]. Patients with a wide range of baseline disease characteristics and varying remnant bowel anatomy became independent of PS with teduglutide treatment in the STEPS trial and extension [14]. While patient numbers were insufficient to determine predictive factors for achieving PS independence, in an analysis of all phase III trial data (n = 134), the majority of patients who achieved PS independence had colon in continuity (12 of 16) and/or lower baseline PS requirements (\7 L/week) (11 of 16) [15]. 4.3 What are the Recommendations for Starting Teduglutide and for Monitoring Patients? The decision to start or discontinue teduglutide is based on the risks and benefits of treatment. In clinical trials and in clinical practice, optimal PS reductions are achieved when good communication between healthcare providers and patients are combined with a well-coordinated, individualized care plan [7]. The criteria for identifying patient suitability for teduglutide include: • •

• •

clinical stability a persistent need for PS despite optimized therapy with dietary modifications and pharmacological interventions nutritionally optimized and in fluid balance a desire to reduce or discontinue PS

Patient monitoring should continue throughout teduglutide therapy (Table 1), including during initiation, PS adjustments, PS weaning and maintenance [7]. In the STEPS trial, scheduled office visits occurred at weeks 2 and 4 and then every 4 weeks for the duration of treatment. Recommendations outside of the clinical trial setting include weekly collection of laboratory results, with an office visit every 4 weeks and continued monitoring of body weight, urine output, stoma or stool output, concurrent medications and PS requirements [7]. Once PS requirements are stable, the frequency of office visits can be

reduced [7]. Prescribers should follow all recommendations described in the prescribing information (Table 1). In the STEPS trial, SBS patients treated with teduglutide had been PS dependent for at least a year; however, clear evidence on the optimal timing of teduglutide therapy after surgical resection is limited [7]. Similarly, the duration of treatment effect after teduglutide is discontinued has not been determined. According to Jeppesen et al. [13], there is evidence to indicate that when teduglutide is discontinued, some patients require almost immediate increases in their PS, whereas others maintain PS reductions for up to 1 year. In a phase II, pharmacodynamic/pharmacokinetic study, improvements achieved with 21 days of teduglutide treatment (Sect. 2) were lost when the drug was discontinued, with endpoint measurements reverting towards those of baseline [9].

5 What is the Tolerability Profile of Teduglutide? Once-daily subcutaneous teduglutide was generally well tolerated in randomized clinical trials in patients with SBS, including treatment periods of up to 30 months [13, 14, 17, 18]. During the placebo-controlled studies, the most common adverse events were gastrointestinal, including abdominal pain, nausea, abdominal distension and stoma change (Fig. 1). In the 24-week STEPS trial, adverse events occurred in 83 % of patients (35 of 42) in the teduglutide group compared with 79 % of patients (34 of 43) in the placebo group [13]. In corresponding groups, serious adverse events were reported by 36 versus 28 % of patients [13]. Two of these events, acute cholecystitis and small intestinal stenosis, were considered treatment related (both in the teduglutide group) and both resolved. Treatment was discontinued due to adverse events (none were serious) in 5 versus 7 % of patients in the teduglutide and placebo groups, respectively [13]. During treatment, anti-teduglutide antibodies developed in six teduglutide-treated patients [13]. Antibodies were non-neutralizing, and there was no evidence of decreased efficacy or evidence of systemic hypersensitivity or other clinically relevant sequelae. In the STEPS trial and long-term extension, 95 % of patients (84 of 88) experienced an adverse event, which was considered treatment related in 52 % [14]. Sixty-four percent of patients experienced a serious adverse event, which was considered treatment related in 10 % [14]. The most frequently reported adverse events that occurred during up to 30 months’ treatment were abdominal pain (34 % of patients), catheter sepsis (28 %), episodes of weight loss (25 %), asthenic conditions (23 %) and febrile disorders (20 %). Ten patients (11 %) discontinued

Teduglutide: Adis Drug Clinical Q&A Fig. 1 Tolerability of oncedaily subcutaneous teduglutide 0.05 mg/kg/day in patients with short bowel syndrome. Adverse events occurring in C5 % of teduglutide-treated patients and more frequent than with placebo in two 24-week trials [12]. GI gastrointestinal, PL placebo, TED teduglutide, URTI upper respiratory tract infection, h indicates 0 %

Abdominal pain URTI

TED (n = 77)

Nausea

PL (n = 59)

Abdominal distension GI stoma change Vomiting Fluid overload Flatulence Hypersensitivity Appetite disorders Sleep disturbances

θ

Cough

θ

Skin haemorrhage 0

5

10

15

20

25

30

35

40

Incidence (% of patients)

treatment due to a treatment-related adverse event, the most frequent of which were abdominal pain (n = 4) and gastrointestinal stoma complication (n = 3). The nutritional status of patients was maintained, with mean albumin levels remaining stable, and no clinically relevant changes in mean body weight and mean serum magnesium, calcium or phosphate levels. Throughout treatment in the STEPS trial and long-term extension, there were three deaths, with one (due to metastatic adenocarcinoma) considered to be treatment related [14]. The manufacturer’s prescribing information lists the following as adverse events of special interest: malignancy, colorectal polyps, gastrointestinal obstruction, gallbladder, biliary and pancreatic disease, fluid overload and an increased absorption of concomitant oral medication (see also warnings and precautions in Table 1) [12].

6 What is the Current Positioning of Teduglutide? Teduglutide is a first-in-class (GLP-2 analogue) long-term targeted therapy for the treatment of SBS patients dependent on PS. Its action at GLP-2 receptors leads to improvement in the structural and functional integrity of the remnant intestine, thereby increasing fluid and nutrient absorption.

In the pivotal phase III STEPS trial in SBS patients, subcutaneous teduglutide 0.05 mg/kg once daily was significantly more effective than placebo, with more patients in the teduglutide group responding to treatment and requiring lower volumes of PS after 24 weeks’ treatment. The reductions in PS requirements together with improvements in other endpoints indicate that the absorptive capacity of the remnant intestine is significantly improved during teduglutide therapy. Significant improvements were evident relatively early (at week 8), and improvements attained in PS volume reductions in the first 6 months of therapy were maintained during long-term treatment, with evidence indicating that benefits accrue over time. Among patients who received 30 months’ treatment in the STEPS trial and extension, 11 of 30 were able to achieve at least one additional day off PS and ten additional patients achieved complete PS independence. Further data from clinical trials investigating the optimum time to commence teduglutide after surgical resection and the impact of treatment discontinuation would be of interest. Subcutaneous teduglutide was generally well tolerated in clinical trials, including over the long term. The most frequent adverse events were gastrointestinal in origin, which is consistent with the underlying disease condition and may also be related to the mechanism of action of teduglutide.

K. McKeage

The significant improvements in PS volume requirements with teduglutide in the STEPS trial occurred despite a higher than expected response in patients randomized to placebo [13]. Thus, good fluid management and strict adherence to the weaning algorithm, as employed in the setting of a clinical trial, appears to have an intrinsic benefit, with teduglutide able to provide a valuable additional benefit. Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Kate McKeage is a salaried employee of Adis/Springer.

References 1. O’Keefe SJ, Buchman AL, Fishbein TM, et al. Short bowel syndrome and intestinal failure: consensus definitions and overview. Clin Gastroenterol Hepatol. 2006;4(1):6–10. 2. Buchman AL. Eitiology and initial management of short bowel syndrome. Gastroenterology. 2006;130(Suppl. 2):S5–15. 3. Tappenden KA. Intestinal adaptation following resection. J Parenter Enteral Nutr. 2014;38(Suppl 1):23S–31S. 4. Matarese LE. Nutrition and fluid optimization for patients with short bowel syndrome. J Parenter Enteral Nutr. 2013. doi:10. 1177/0148607112469818. 5. Matarese LE, O’Keefe SJ, Kandil HM, et al. Short bowel syndrome: clinical guidelines for nutrition management. Nutr Clin Pract. 2005;20:493–502. 6. DiBaise JK, Matarese LE, Messing B, et al. Strategies for parenteral nutrition weaning in adult patients with short bowel syndrome. J Clin Gatroenterol. 2006;40(Suppl. 2):S94–8. 7. Seidner DL, Schwartz LK, Winkler MF, et al. Increased intestinal absorption in the era of teduglutide and its impact on management strategies in patients with short bowel syndrome-associated intestinal failure. J Parenter Enteral Nutr. 2013;37(2):201–11. 8. Buchman AL. Teduglutide and short bowel syndrome: every night without parenteral fluids is a good night. Gastroenterology. 2012;143(6):1416–20.

9. Jeppesen PB, Sanguinetti EL, Buchman A, et al. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005;54(9):1224–31. 10. Wallis K, Walters JR, Gabe S. Short bowel syndrome: the role of GLP-2 on improving outcome. Curr Opin Clin Nutr Metab Care. 2009;12(5):526–32. 11. Tappenden KA, Edelman J, Joelsson B. Teduglutide enhances structural adaptation of the small intestinal mucosa in patients with short bowel syndrome. J Clin Gastroenterol. 2013;47(7):602–7. 12. NPS Pharmaceuticals. Gattex (teduglutide): US prescribing information. 2014. http://www.gattexrems.com/Content/files/PIIFU.pdf. Accessed 16 Mar 2015. 13. Jeppesen PB, Pertkiewicz M, Messing B, et al. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology. 2012;143(6):1473–81.e1–3. 14. Jeppesen PB, Fujioka K, Nader N, et al. Long-term safety and efficacy of teduglutide treatment for intestinal failure associated with short bowel syndrome (SBS-IF): final results of a 2-year, multicenter, open-label, clinical trial [abstract no. PP101 plus poster]. In: The European Society for Clinical Nutrition and Metabolism. 2014. 15. Jeppesen PB, Boullata JI, Ziegler TR, et al. Independence from parenteral support achieved with teduglutide treatment in patients with intestinal failure associated with short bowel syndrome [abstract no. 131 plus poster]. In: The European Society for Clinical Nutrition and Metabolism. 2014. 16. Fujioka K, Schneider S, Nader NY, et al. Teduglutide reduces the need for parenteral support in patients with short bowel syndrome who have ultra-short remnant bowel and/or no colon in continuity. In: American Society for Parenteral and Enteral Nutrition: Clinical Nutrition Week [poster M-41]. 2015. 17. Jeppesen PB, Gilroy R, Pertkiewicz M, et al. Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome. Gut. 2011;60(7):902–14. 18. O’Keefe SJ, Jeppesen PB, Gilroy R, et al. Safety and efficacy of teduglutide after 52 weeks of treatment in patients with short bowel intestinal failure. Clin Gastroenterol Hepatol. 2013;11(7):815–23.e1–3.

Teduglutide: a guide to its use in short bowel syndrome.

Teduglutide (Gattex(®)) is a recombinant analogue of human glucagon-like peptide-2 and is indicated for the treatment of adults with short bowel syndr...
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