Teduglutide in Crohn’s disease
Wojciech Blonski, Anna M Buchner, Faten Aberra & Gary Lichtenstein†
†University of Pennsylvania, Gastroenterology Division, Philadelphia, PA, USA
Introduction: The currently available medications for treatment of Crohn’s disease (CD) include aminosalicylates, corticosteroids, antibiotics, immunomo- dulators and biologic agents (infliximab, certolizumab pegol, adalimumab and natalizumab). These agents target the immune and inflammatory path- ways of CD, while there is a shortage of agents that target the barrier func- tions of the gut that are impaired in CD. Glucagon-like peptide 2 is an enterogastrone with strong trophic effects on the intestinal mucosa. Teduglu- tide, the analog of glucagon-like peptide has been already approved by the US Food and Drug Administration as a treatment of short bowel syndrome. This review discusses the potential use of teduglutide in patients with CD. Areas covered: As there has been only one randomized placebo controlled trial of teduglutide in CD, there is a shortage of data regarding the efficacy of this agent in CD. The literature search was performed using Medline data- base with the use of the following key words: teduglutide, glucagon-like peptide-2, CD and inflammatory bowel disease.
Expert opinion: Based on available data, it can be concluded that this agent seems to be a promising medication in CD and further trials are required to define the place of teduglutide in treatment of CD.
Keywords: clinical trial, Crohn’s disease, inflammatory bowel disease, teduglutide
1. Introduction
Crohn’s disease (CD) is a chronic inflammatory and immune-related disorder of an unknown etiology and it is characterized by focal, asymmetric, transmural inflammation of any part of the luminal gastrointestinal tract of uncertain etiology and an unpredictable course. Current research has supported the hypotheses that genetic and environmental factors in conjunction with activation of the immune system with a subsequent heightened inflammatory response lead to development of this disease [1]. The host’s normal bacterial flora of the gut may activate constant inappropriate activation of the mucosal immune system that is sustained by defects in both the barrier function of the intestinal epithelium and the mucosal immune system [1]. One of the hypotheses was presented by Hollander et al. in 1986 who suggested that increased intestinal permeability might be the primary defect leading to development of this disease [2]. These data were further sup- ported by other researchers in subsequent studies [3,4]. The currently available medications for treatment of patients with CD include aminosalicylates, cortico- steroids, antibiotics, immunomodulators and biologic agents (infliximab, certoli- zumab pegol, adalimumab and natalizumab). Therapy with biologic agents is clinically indicated in patients with moderate to severe CD who do not respond to prior therapy with other conventional medications. It has been recently demon- strated that early combined therapy with an antiTNF (anti tumor necrosis factor — e.g., infliximab, certolizumab pegol, adalimumab) biologic agent and immune modulator leads to better outcomes when compared to sequential treat- ment with corticosteroids followed by an immune modulator and subsequently an antiTNF biologic agent with an absolute difference between treatment groups of 20% [5].
2. Overview of the market
However, the quest for the further medication with improved efficacy and limited side effects profile in patients with CD still continues. Corticosteroids, immune modulators and bio- logic agents target immune and/or inflammatory mechanism while none of the available approved agents target barrier function of the gut.
2.1 Introduction to the compound
Glucagon-like peptide-2 (GLP-2), a 33-amino acid peptide is produced by intestinal endocrine L-cells and cerebral neu- rons [6]. Research has shown that GLP-2 has enterogastrone properties with abilities to inhibit gastric motility [7], reduce gastric acid secretion [8], stimulate intestinal blood flow [9], stimulate proliferation of intestinal crypt cells and growth of the villi of the jejunum and ileum [10], inhibit apoptosis of enterocytes [11,12], stimulate the colonic growth [13], decrease intestinal permeability [14] and enhance intestinal epithelial barrier function [15].
2.2 Chemistry
Teduglutide (NPS Pharmaceuticals, Bedminster, NJ, USA) is a 33 amino acid analog of GLP-2 that is manufactured using a strain of Escherichia coli modified by recombinant DNA technology (Box 1) [16].
2.3 Pharmacodynamics
There were two open-label studies that assessed the effect of teduglutide on gastrointestinal function in patients with short bowel syndrome [17,18]. Jeppesen et al. evaluated the effect of subcutaneous administration of 400 µg of GLP-2 twice a day for 35 days in 8 patients with functional short bowel syndrome (no terminal ileum and no colon) with severe malabsorption and no postprandial secretion of GLP-2 and observed that treatment with GLP-2 resulted in statistically significant increase in the intestinal absorption of energy (53.4 vs. 49.9%, p = 0.04), wet weight (36 vs 25%, p = 0.04), and nitro- gen (52.1 vs. 47.4%, p = 0.04), increase in mean body weight (1.2 ± 1.0 kg, p = 0.01), mean lean body mass (2.9 ± 1.9 kg, p = 0.004) and mean 24-hour urine creatinine excretion (0.7 ± 0.7 mmol/day, p = 0.02) [17]. On the other hand, mean fat mass significantly decreased by 1.8 ±1.3 kg (p = 0.007) [17]. In addition, significant prolongation in time to 50% gastric emptying of solids was observed with man increase by 30 ± 16 min (p < 0.05) [17]. There was no change observed in small bowel transit time [17]. The authors also determined that GLP-2 caused increase in intestinal crypth depth (5 patients) and villus height (6 patients) [17].
Subsequently an open-label pilot study assessed the safety and efficacy of teduglutide in 16 patients with short bowel syn- drome who received this agent subcutaneously for 21 days once or twice daily [18]. Among enrolled subjects, 10 patients with an end jejunostomy received doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), 1 patient with < 50% of colon in continuity received a dose of 0.03 mg/kg/day and 5 patients with at least 50% of colon in continuity received dose 0.10 mg/kg/day [18]. The obtained pooled data showed that teduglutide increased absolute mean (+743 ± 477 g/day; p < 0.001) and relative (+22 ± 16%; p < 0.001) wet weight absorption, mean urine weight (+555 ± 485 g/day; p < 0.001), and mean urine sodium excretion (+53 ± 40 mmol/day; p < 0.001) when compared to pre-treatment values [18]. On the other hand, teduglutide decreased mean faecal wet weight (-711 ± 734 g/day; p = 0.001) and mean faecal energy excretion (-808 ± 1453 kJ/day; p = 0.040) when compared to pre- treatment values [18]. Significant increase in intestinal villus height (+38 ± 45%; p = 0.030), crypt depth (+22 ± 18%; p = 0.010), and mitotic index (+115 ± 108%); p = 0.010) was observed in patients with end jejunostomy but not in patients with colon in continuity [18].
3. Pharmacokinetics and metabolism
A single-center, randomized, double-blind, placebo controlled and ascending-dose study assessed the pharmacokinetics, safety and tolerability of teduglutide in 64 healthy subjects [19]. Study subjects were randomly assigned to receive an ascending dose of teduglutide or placebo as once-daily subcutaneous injections over 8 days [19]. Teduglutide was administered either as a 50-mg/ml (10, 15, 20, 25, 30, 50 and 80 mg) or 20-mg/ml (20 mg) formulation [19]. Blood samples were col- lected on days 1 and 8, Plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method on days 1 and 8 [19]. Peak plasma con- centrations of teduglutide 50-mg/ml formulation were observed at approximately 4 h after drug administration on days 1 and 8 [19]. Teduglutide 50-mg/ml formulation was found to have a minimal accumulation after repeated subcuta- neous administrations as demonstrated by very low levels of the mean predose plasma concentrations of teduglutide on day 8 [19].
Teduglutide 50-mg/ml formulation was character- ized by similar mean elimination half-life values on day 1 (3.17 -- 5.53 h) and day 8 (2.99 -- 4.63 h) suggesting readily absorption and rapid elimination [19]. Therefore, teduglutide 50 mg/ml formulation displayed linear pharmacokinetics because its elimination half-life remained very similar after single and multiple subcutaneous administrations across all dose ranges [19]. The values of mean apparent clearance (L/h/kg) for teduglutide 50-mg/ml formulation remained relatively constant over the dose range on days 1 and 8 without any gender-related difference in the apparent clearance of teduglutide (0.155 in men and 0.159 in women) [19]. A comparison of pharmacokinetic parameters between 20-mg/ml (1 ml) and 50-mg/ml (0.4 ml) teduglutide formu- lation showed that 20-mg/ml formulation had 15% higher peak plasma concentrations and 78% higher total exposure of teduglutide [19]. Overall, teduglutide treatment was safe and well tolerated among study subjects [19]. There were 409 adverse events (339 in teduglutide and 70 in placebo arm) observed among 86 subjects (69 teduglutide arm and 17 placebo arm) [19]. There was a similar distribution of the number of subjects experiencing adverse events and number of adverse events across all treatment groups [19]. The majority of adverse events were related to the study drug across treat- ment groups [19]. The most frequently observed adverse events in teduglutide-treated subjects were abdominal distension (29.6%), abdominal pain (16.9%), constipation (22.5%), nausea (14.1%), injection site erythema (15.5%), injection site pain (35.2%), headache (23.9%), increased ALT (18.3%) and increased AST (14.1%) [19]. The changes in liver associated chemistries were transient, similar to the frequency of patients in the placebo group and reversible at the end of the study [19]. Among all adverse events only injection site pain increased in frequency with greater teduglutide dose and injected volume [19].
In the subsequent study, Maier et al. assessed the popula- tion pharmacokinetics of teduglutide after daily subcuta- neous administrations of 2.5 -- 80 mg doses in a total of 256 patients [20]. The analyzed data were obtained from eight clinical studies, namely four Phase I studies that enrolled 159 healthy volunteers, one Phase I study that enrolled 24 patients with moderate hepatic impairment, one Phase II study that enrolled 100 patients with
moderately active CD, one Phase II and one Phase III study that enrolled 17 and 83 patients with short bowel syndrome, respectively [20]. The authors performed the population pharmacokinetics analysis in a stepwise manner using the modeling of the sparse and rich plasma concentration data that were obtained from the patients who were enrolled into eight aforementioned clinical trials and who received either single or repeated subcutaneous injections (doses from 2.5 -- 80 mg) of teduglutide [20]. An analysis showed that men had approximately 18% higher apparent clearance of teduglutide than women (12.4 vs. 10.5 L/h) [20]. In addi- tion, the volume of distribution of teduglutide was strongly influenced by the body weight with the values of 14.3 and 57.7 L/h in the subjects having weight of 50 kg and 90 kg, respectively [20]. The body weight of the subjects also influenced the elimination half-life (t½) of teduglutide [20]. Men with the weight of 50 and 90 kg had a respective t½ of teduglutide of 0.897 and 2.99 h [20]. The population pharmacokinetics was not affected by renal and hepatic function and no dose adjustments were necessary in patients with impaired kidney or liver function [20]. The authors indicated that their population pharmacokinetic model will help adequate drug labeling and determine whether an individualized dosage is required [20].
4. Clinical efficacy
4.1 Short bowel syndrome
Teduglutide was shown to reduce the requirements for paren- teral nutrition in patients with short bowel syndrome by its intestinotrophic and pro-absorptive effects [17,18,21-23]. There have been three hallmark studies that assessed the efficacy of teduglutide in patients with short bowel syndrome [21-23].
In a multicenter randomized double blind placebo controlled trial 83 patients were randomly allocated to receive subcutaneous treatment with either teduglutide 0.10 mg/kg/day (n = 32), 0.05 mg/kg/day (n = 35) or pla- cebo (n = 16) once daily during 24-week interval to assess the response defined as at least 20% reduction in parenteral support from baseline at weeks 20 and 24 in patients pre- senting with short bowel syndrome with intestinal fail- ure [21]. The authors developed the graded response score that incorporated the higher level and earlier onset of response coupled with a longer duration of response (0 points were given for < 20% reduction in parenteral volume) [21]. According to graded response score only low dose of teduglutide was significantly superior to placebo in achieving response (45.7 vs 6.3%, p = 0.007) while high dose of teduglutide did not show statistical signifi- cance over placebo (25 vs 6.3%, p = 0.16) [21]. On the other hand the reductions in parenteral volume were equal (353 ± 475 and 354 ± 334 ml/day) in high- and low-dose teduglu- tide arms and it was suggested that this discrepancy in results could have been caused by the trend towards higher baseline parenteral volume (1816 ± 1008 vs. 1374 ± 639 ml/day, p = 0.11) in the high-dose teduglutide arm versus low-dose teduglutide arm [21]. Significant increase in intestinal villus height, plasma citrulline concentration and lean body mass was observed in patients receiving teduglutide when compared with placebo [21].
There were 52 patients who completed the aforemen- tioned clinical trial in which they received teduglutide who further continued the same daily dose of teduglutide (0.05 mg/kg/day, n = 25 or 0.10 mg/kg/day, n = 27) for additional 28 weeks in a double-blind extension study [22]. The clinical efficacy was defined as clinically meaningful at least 20% reduction in weekly parenteral nutrition volume from baseline at week 52. Teduglutide has demonstrated the ability to maintain its clinical efficacy over 52 weeks in 68% of patients treated with 0.05-mg/kg/day dose and 52% patients treated with 0.10 mg/kg/day of teduglutide [22]. These data were supported Jeppesen et al. by who per- formed another large multicenter, multinational, double- blind placebo-controlled 24-week trial in which 86 patients with short bowel syndrome with intestinal failure were treated with either subcutaneous teduglutide (0.05 mg/kg/day; n = 43) or placebo (n = 43) once daily [23]. The primary effi- cacy end point was response defined as > 20% reduction in parenteral support volume from baseline at weeks 20 and 24 [23]. Overall 63% of patients treated with teduglutide responded when compared to 30% responders among placebo recipients (p = 0.002) [23]. In addition, teduglutide was supe- rior over placebo in reducing parenteral support volume at week 24 (4.4 ± 3.8 L/week from baseline 12.9 ± 7.8 L/week for teduglutide vs. 2.3 ± 2.7 L/week from baseline 13.2 ± 7.4 L/week for placebo p < 0.001) [23]. There was nearly 2.5-fold greater percentage of patients with at least 1-day reduction in the weekly need for parenteral support in the teduglutide arm than in the placebo arm (54 vs 23%, p = 0.005) [23].
4.2 Crohn’s disease
At the time of writing the manuscript there was only one randomized, placebo-controlled multicenter, multinational pilot study of teduglutide in 100 adult patients with moder- ate-to-severe CD (CD Activity Index 220 -- 450) [24]. Study subjects were allowed to be on concomitant medications that included stable dose of antiTNF monoclonal antibody therapy for at least 12 weeks, stable dose of corticosteroids for at least 30 days that was no greater than 20 mg of pred- nisone daily or 9 mg of budesonide daily, stable dose of methotrexate, cyclosporin or tacrolimus for at least 30 days, azathioprine or 6-mercaptopurine for at least 12 weeks with a stable dose for at least 8 weeks, corticosteroid or mesalamine enemas/suppositories or anti-diarrheal medications contain- ing codeine with stable dose for at least 1 week, sulfasalazine or 5-aminosalicylate containing agents at stable dose for at least 4 weeks, non-steroidal anti-inflammatory drugs and aspirin with stable dose for at least 2 days [24].
Evaluated patients were randomly assigned to receive daily subcutaneous injection for 8 weeks of either placebo (n = 25) or one of three doses of teduglutide (0.05, 0.10, 0.20 mg/kg daily in 24, 26 and 25 patients, respectively) [24]. The primary outcome was clinical response defined as 100 point decrease in CDAI or remission defined as CDAI £ 150 at week 8 [24]. After completion of 8 week induction phase all studied patients were invited to participate in an open-label phase of 12 week duration when patients received daily 0.1 mg/kg subcutaneous dose of teduglutide [24]. An open-label phase was followed by a medication-free follow-up period of 4 week duration [24].
Of 100 patients who were enrolled into the trial, 71 com- pleted the study [24]. Among teduglutide arms clinical response and remission rates were the most substantial in patients treated with the highest dose and were seen as early as week 2 [24]. The trend towards increased response rate in the highest dose of teduglutide remained consistent throughout nearly all weeks of the study [24].
Among this subgroup, 32% of patients were in remission and 44% responded to treatment with teduglutide at week 2 when compared to 20% remission and 32% response in placebo (p-value not reported) [24]. Although at week 4 the rates of remission and response in patients treated with the highest dose of teduglutide remained unchanged when compared to week 2 these rates increased among placebo recipients with remission of 28% and response of 40% [24].
Among primary outcomes measured at week 8, remission was noted in 40% of patients treated with the highest dose of teduglutide, 24% of patients treated with medium dose of teduglutide and 29% of patients treated with the low dose of teduglutide versus 28% of patients in placebo arm while response was observed in 44% of patients treated with the highest dose of teduglutide, 30% of patients treated with the medium dose of teduglutide and 42% of patients treated with the low dose of teduglutide versus 48% of placebo recipients (p-values not reported) [24].
An analysis of patients who did not achieve remission at week 8 in each arm during induction phase and were subse- quently treated with 0.10 mg/kg/day of teduglutide for 12 weeks in an open-label phase showed at completion of week 20, 50% remission rate in those previously treated with high dose of teduglutide, 29% remission rate in those previously treated with medium dose of teduglutide, 20% remission rate in those previously treated with low dose of teduglutide and 0% remission rate in those previously treated with placebo [24]. On the other hand, 37.5, 18, 20 and 18% of those who achieved remission at week 8 during induction phase with high-, medium-, low-dose of teduglutide and pla- cebo did not maintain their remission during maintenance phase, respectively [24].
Successful corticosteroid taper and elimination was observed in 71% (12/17) of patients treated with teduglutide versus 25% (1/4) rate among placebo recipients [24]. The serum level of C-reactive protein (CRP) at baseline was slightly lower in those treated with placebo when compared to active drug recipients [24]. There was a slight decrease in serum CRP level over time in all teduglutide arms and slight increase in placebo arm but the differences were not statistically signif- icant [24]. There was no difference in serum CRP between patients who either responded or achieved remission when compared to those without clinical response [24]. In addition, elevated CRP was not a predictor of a response to treatment in any treatment arm [24]. Other laboratory parameters studied included mean blood white blood cell count, platelet count and plasma citruline level [24]. The mean white blood cell count was similar between all treatment arms at baseline and during study [24]. There was a significant increase within nor- mal limits observed in platelet count among patients treated with either dose of teduglutide at 2 weeks followed by decrease towards baseline values at weeks 4 and 8 [24]. The plasma citrulline levels were similar among all patients at base- line with subsequent substantial increase over time in all patients treated with teduglutide versus placebo [24]. Plasma citrulline concentration was normal and substantially increased in patients with remission when compared with normal control subjects (43.3 ± 19.7 vs. 31.1 ± 9.4 mmol/l, p = 0.0006) [24]. However, it is unclear what normal control subjects were recruited for the measurement of plasma cirtul- line as authors did not provide this information [24]. At week 8, the mean plasma concentration of citrulline was signifi- cantly greater among all teduglutide arms when compared to placebo (p < 0.001) but no significant difference between any teduglutide arm and placebo was observed during week 12, 16, 20 and 24 when all participants received open label teduglutide at 0.10 mg/kg/day [24]. Substantial increase in plasma citrulline concentration was observed in maintenance phase in patients who received placebo in induction phase. The increase in plasma citrulline decreased in all arms at week 24 suggesting the lack of long-term efficacy of tedu- glutide in maintaining increased levels of plasma citrulline concentration [24]. The authors used plasma citrulline concen- tration as a surrogate marker for mucosal healing as significant increase in plasma citrullin concentration may indicate increase in intestinal mucosal mass [25-27].
Among patients who were not in remission at week 8 in the highest dose teduglutide arm 50% achieved remission during an open-label treatment with teduglutide given at daily dose of 0.1 mg/kg [24]. On the other hand, 37.5% of those who achieved remission in the highest dose teduglutide arm did not maintain this until week 20 [24].
5. Safety and tolerability
The withdrawal rate from the study assessing the use of tedu- glutide in CD was 29% with the main reason being adverse events [24]. The adverse events related to drug were numeri- cally more frequent in patients treated with teduglutide (63, 73, 68% for each dosing group 0.05, 0.10, 0.20 mg/kg daily,
respectively) when compared to placebo (28%) [24]. The fre- quency of adverse events was similar across study group, how- ever, there was a trend towards more adverse events resulting in withdrawal from the study among patients treated with teduglutide (17, 31 and 16% for each dosing group 0.05, 0.10, 0.20 mg/kg daily, respectively) when compared to pla- cebo (8%) [24]. There were no deaths observed during the study [24]. There were 11 serious adverse events that occurred in eight patients (1 placebo, 7 teduglutide) with majority observed in 0.1 mg/kg teduglutide dosing group [24]. None of the serious adverse events was associated with the use of teduglutide and most of them were related to worsening of CD [24]. Buchman et al. did not provide the list of serious adverse events describing in details only one, namely recur- rence of squamous cell carcinoma in patient with a prior his- tory of several squamous cell carcinomas who received teduglutide at the dose of 0.05 mg/kg/day and underwent resection of the lesion of his thigh without any complica- tions [24]. Injection site reactions were the most frequently observed adverse events (21, 38 and 42% in teduglutide dos- ing groups vs. 16% in placebo arm) [24]. The other adverse events for teduglutide 0.05, 0.10, 0.20 mg/kg daily versus placebo included abdominal distension (12.5, 11.5, 32 vs 4%), constipation (8, 19, 16 vs 0%), flatulence (4, 8, 8 vs 0%), nausea/vomiting (21, 35, 31 vs 20%), decreased appetite (0, 8, 4 vs 4%), infections (21, 15, 28 vs 16%), liver function test elevation (8, 0, 0 vs 0%), elevated amylase/lipase (8, 0, 0 vs 0%), back pain (4, 0, 12 vs 0%), dizziness (4, 11.5, 4 vs 4%), headache (17, 8, 8 vs 4%), neoplasm (4, 4, 0 vs 0%), cardiac events (0, 15.4, 4 vs 0%), blood/lymphatic abnormalities (4% with essential thrombophilia, 0, 4 vs 0%) and ocular abnormalities (4, 8, 4 vs 0%) [24]. There were no clinically significant changes in clinical chemistries, hematol- ogy and urinalysis detected from baseline values that were generally within the normal range at baseline and no specific antibodies to teduglutide were detected in any of study patients [24].
It was also reported that seven patient (four placebo recipients and six patients treated with teduglutide) had to receive rescue therapy for CD including exploratory laparo- tomy in one patient who was treated with 0.10 mg/kg per day of teduglutide and who developed a small bowel obstruction due to adhesions and a volvulus due to previous abdominal surgery without any evidence of active CD based on analysis during surgery [24]. The remaining six patients had to have their corticosteroid dose increased or had to receive additional medications (details were not provided by Buchman et al.) [24].
More safety data on teduglutide come from randomized trials that assessed its use in patients with short bowel syn- drome. Among 83 patients treated with either teduglutide 0.10 mg/kg/day (n = 32), 0.05 mg/kg/day (n = 35) or placebo (n = 16) the rates of adverse events were 97, 94 and 95%, respectively, and severe adverse events 34, 37 and 31%, respectively [21]. Overall, 79 of 83 participants of this trial (95%) developed at least one adverse event [21]. Of note, 17% of low-dose teduglutide recipients, 6% of high-dose teduglutide recipients and 6% of placebo recipients experi- enced any adverse event or serious adverse event leading to withdrawal from study [21]. The most common adverse events in patients treated with teduglutide were abdominal pain (24%), headache (24%), nausea (22%), nasopharyngitis (16%) and vomiting (15%) [21]. The most frequently ob- served serious adverse events included catheter-related complications, catheter sepsis, catheter site infection, small intestinal obstruction and fever [21]. There were no deaths reported in the active phase of the study [21]. Safety of teduglu- tide was also assessed in a double-blind 28-week extension of the aforementioned 24-week trial in which 25 patients contin- ued the same doses of teduglutide through week 52 [22]. The most frequently observed adverse events included headache (35%), nausea (31%), abdominal pain (25%), nasopharyngitis (25%), vomiting (17%), catheter sepsis (17%) and urinary
tract infection (17%) [22]. Of note, 27 of 52 patients (52%) experienced adverse event that was related to teduglutide such as gastrointestinal disturbance (19 reports), injection site complaint (26 reports) and stomal hypertrophy and injury or stroma site reaction (6 reports) [22]. The withdrawal rate was 13% due to adverse events [22]. There were 27 patients (52%) who developed serious adverse event, in 5 patients seri- ous adverse events were related to teduglutide and 2 patients withdrew from the trial due to serious adverse event [22]. No deaths were noted during the extension trial [22]. The safety analysis of 85 patients with short bowel syndrome with intestinal failure who were randomly allocated to either teduglutide 0.05 mg/kg/day, n = 42) or placebo for 24 weeks showed that treatment-emergent serious adverse events (36 vs 28%, p-value not reported), all treatment-emergent adverse events (83 vs 79%, p-value not reported) and treatment-emergent adverse events leading to withdrawal from the trial (5 vs7%, p-value not reported) were com- parable between teduglutide and placebo groups [23]. The most common adverse events included abdominal pain (31 vs 23%), nausea (29 vs 19%), gastrointestinal stoma change (24 vs 19%) and abdominal distension (21 vs 2%) in teduglutide and placebo arms, respectively [23]. Other adverse events included central line systemic infections (17 vs 16%), peripheral edema (17 vs 5%), urinary tract infection (14 vs 9%), flatulence (12 vs 7%), vomiting (12 vs 9%), fatigue (10 vs 7%), pyrexia (10 vs 9%), diarrhea (7 vs 12%), weight increase (7 vs 7%), dyspnea (7 vs 0%) and nasopharyngitis (7 vs 0%) [23].
6. Regulatory affairs
Teduglutide was approved in December 2012 by the US Food and Drug Administration for the treatment of adult patients with short bowel syndrome who require additional parenteral nutrition [28].
7. Conclusion
Buchman et al. concluded that teduglutide was potentially effective medication for inducing remission and mucosal healing in patients with moderate-to-severe CD [24]. Data from this trial does not clearly show the superiority of teduglutide over placebo in patients with CD. The remission and response rates were numerically higher in patients treated with teduglutide but failed to reach statistical significance over placebo. Patients treated with teduglutide were found to have statistically significant greater increase in plasma citrulline concentration at weeks 2, 4 and 8 when compared to placebo. Interestingly, in the maintenance phase where all patients were treated with teduglutide 0.10 mg/kg/day there was a substantial increase in plasma citrulline concentration among those who received placebo in induction part [24]. The increased citrullin plasma concentrations were observed through week 20 and at week 24 these levels substantially decreased to the levels seen at week 2 with only exception that patients who received placebo in induction phase had the same increased level of plasma citrulline level as those who received induction with 0.20 mg/kg/day of teduglu- tide [24]. It may suggest that the maintenance effect of teduglu- tide on increased citrullin plasma concentration is not long lasting. Other important finding is that 50% of patients who received 0.2 mg/kg/day dose of teduglutide in the induc- tion phase and did not achieve remission were in remission at week 20 after receiving maintenance dose of teduglutide [24]. On the other hand, 37.5% of those who achieved remission in induction phase with teduglutide lost their remission by week 20 [24]. The only clinical trial of teduglutide in CD showed rather high withdrawal rate of 28 -- 42% in teduglu- tide arms and 16% in placebo arm in induction phase and 33% in maintenance phase with adverse events being the major reason for withdrawal [24].
8. Expert opinion
At this time there are not enough data from randomized placebo controlled trials in patients with CD to determine the efficacy of teduglutide in this patient population. Based on available data from one clinical trial in patients with CD it can be concluded that this agent seems to be a promising medication in CD showing numerically higher response and remission rates when compared to placebo [24]. Recent data from a rat CD model showed that prophylactic administra- tion of GLP2-2G-XTEN; a long-acting GLP2 receptor agonist required a lower dose and less frequent dosing than teduglutide and resulted in increasing the length of small intestine and reduction of the severity of disease in a rat CD model [29]. There are not enough data to determine whether teduglutide offers any improvement over other already approved therapies in CD namely aminosalicylates, cortico- steroids, azathioprine/6-mercaptopurine, methotrexate or antiTNF related biologic agents such as infliximab, adalimu- mab or certolizumab pegol. It has to be determined whether teduglutide will have any impact on current treatment strat- egies. The key weakness of the research that was done so far in assessing the efficacy of teduglutide in CD is that only one clinical trial was done, no statistically significant superiority of teduglutide over placebo was found with respect to achieving response or remission, high withdrawal rate from the trial due to adverse events in the teduglutide arm (16 -- 31%) when compared to 8% rate in placebo arm was observed [24]. In addition, mucosal healing was not directly addressed the clinical trial. The authors used the surrogate marker, the level of plasma citrulline concentration which level was found to be increased significantly over placebo at week 2, 4 and 8 [24]. In the maintenance, open- label phase of the trial when patients received teduglutide 0.10 mg/kg/day the plasma citrulline levels were maintained through week 20 among those who received teduglutide in the induction part and substantially increased among those who received placebo during induction phase. On the other hand, the plasma citrulline levels decreased at week 24 in all treated patients suggesting the decreasing efficacy of long- term maintenance. It is necessary to assess how teduglutide affects intestinal mucosal healing that is of particular importance in patients with CD. It is important to realize that clinical trials of teduglutide administered in combina- tion with already approved agents for CD should be per- formed as teduglutide targets barrier function of the gut whereas available medications aim at immune and inflam- matory pathways of the disease. It should be determined whether administration of teduglutide would allow for corticosteroid sparing or decrease in doses or frequency of biologics.
Safety of teduglutide is a very important factor. It is con- cerning that up to 42% of patients who were treated with teduglutide in induction phase and 33% of patients receiving maintenance therapy with teduglutide discontinued study early. Therefore, the question should be asked whether tedu- glutide is a safe medication for a long-term use in patients with CD.Future randomized placebo controlled clinical trials are warranted to further assess the efficacy and safety of teduglu- tide in patients with CD. Once we have more data from clinical trials we could try to predict the place of teduglutide in treatment of CD. In 5 years, we will certainly have more available data to be able to answer this question. Let us wait what data from future clinical trials will show.
Declaration of interest
G Lichtenstein has been a consultant for Abbott, Alaven, Centocor Orthobiotech, Elan, Ferring, Millennium Phar- maceuticals, Ono Pharmaceuticals, Proctor and Gamble, Prometheus Laboratories, Inc., Salic Pharmauticals, Salix Pharmaceuticals, Schering-Plough Corp., Shire Pharmaceuti- cals, UCB, Warner Chilcotte and Wyeth; and has undertaken research for Bristol-Myers Squibb, Centocor Orthobiotech, Ferring, Proctor and Gamble, Prometheus Laboratories, Inc., Salix Pharmaceuticals, Shire Pharmaceuticals, UCB and Warner Chilcotte. None of the other authors have any com- peting interests to declare and no funding was received in preparation of this manuscript.
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