New pharmacological treatment options for chronic constipation.

Review

New pharmacological treatment options for chronic constipation

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Universitaet Zuerich on 07/01/14 For personal use only.

Maura Corsetti & Jan Tack† 1.

Introduction

University of Leuven, Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium

2.

Prucalopride

3.

Linaclotide

4.

Plecanatide

5.

Elobixibat

6.

Conclusion

7.

Expert opinion

Introduction: A number of new medications were recently demonstrated to be more effective than placebo in treating chronic constipation, including the intestinal chloride channel activator lubiprostone, the prokinetic selective 5-HT4 receptor agonist prucalopride and the guanylate cyclase-C agonist linaclotide. Recent publications have also revisited traditional laxatives like PEG. Moreover, a number of pharmacological treatments are in development and these include another guanylate cyclase-C agonist, plecanatide and an ileal bile acid transporter inhibitor, elobixibat. Areas covered: This review focuses on the pharmacology, efficacy and safety profile of prucalopride, linaclotide, plecanatide and elobixibat. Expert opinion: The possible present or future clinical application of prucalopride, linaclotide, plecanatide and elobixibat in both chronic constipation and irritable bowel syndrome with constipation is reported, and some considerations on the possible role of PEG taking into account recent literature are advanced. Keywords: 5-HT4, chronic constipation, irritable bowel syndrome with constipation, guanylate cyclase-C, ileal bile acid transporter inhibitor, PEG Expert Opin. Pharmacother. (2014) 15(7):927-941

1.

Introduction

Chronic constipation (CC) is a condition with an estimated population prevalence of 16%, characterized by infrequent bowel movements, hard stools and straining when passing stool, often in combination with abdominal discomfort, bloating, cramps and pain [1]. According to the Rome III consensus, CC is defined by the criteria reported in Table 1 [2]. CC is more prevalent in women, increases with age and lower socioeconomic status and is associated with an increased healthcare cost and an increased level of loss of work productivity and activity impairment [1]. The pathophysiology of CC is still unclear, but it has been traditionally considered to involve slow colonic transit in a subgroup of patients and/or of a pelvic floor dysfunction in a considerable number of patients that varies according to the method used to diagnose it [1,3]. The majority of subjects with CC self-manage their constipation, mainly using lifestyle (dietary) adjustments and over-the-counter laxatives [3]. In those seeking medical attention, after appropriate diagnostic workup, laxatives (over-the-counter or prescription) are recommended as initial approach [3]. However, for a large number of patients, the use of laxatives does not result in sufficient control of constipation and its associated symptoms, lacks predictability or is associated with adverse effects or poor tolerance [3]. Hence, a substantial unmet need persists in the treatment of CC. In a considerable proportion of patients, CC overlaps with irritable bowel syndrome (C-IBS). IBS is a lower functional gastrointestinal disorder affecting up to 15% of the general population in Western countries [2]. It is characterized by unexplained abdominal pain, discomfort and bloating in association with altered bowel habits, and according to Rome III consensus, is defined by criteria reported in Table 1 [2]. Studies on the pathophysiology of C-IBS have demonstrated that it 10.1517/14656566.2014.900543 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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M. Corsetti & J. Tack

Article highlights. .

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Prucalopride, a selective 5-HT4 receptors agonist, is effective and safe in treating symptoms of patients with chronic constipation (CC). Linaclotide, an agonist of guanylate cyclase-C, is effective in treating symptoms of patients with CC and its effect also on visceral sensitivity as resulted mainly by studies on animals provides an attractive pharmaceutical option for patients with irritable bowel syndrome with constipation. Only one study has compared the efficacy and safety of one of the new pharmacological options for CC (prucalopride) with the most effective osmotic laxatives (PEG). Comparative studies assessing the efficacy and safety of prucalopride, linaclotide and PEG in patients with CC are urgently requested also to evaluate the economic impact in the treatment of CC.

This box summarizes key points contained in the article.

Table 1. Rome III criteria for chronic constipation and for irritable bowel syndrome with constipation. Rome III criteria for chronic constipation*: Must include two or more of the following: Straining during at least 25% of defecations Lumpy or hard stools in at least 25% of defecations Sensation of incomplete evacuation for at least 25% of defecations Sensation of anorectal obstruction/blockage for at least 25% of defecations Manual maneuvers to facilitate at least 25% of defecations Fewer than three defecations per week Loose stools rarely present without the use of laxatives and insufficient criteria for IBS Rome III criteria for IBS with constipation*: Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with two or more of the following: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form of stool Hard or lumpy stools (Bristol Stool Scale 1 or 2) > 25% and loose or watery stools (Bristol Stool Scale 6 or 7) < 25% of bowel movements *Criteria fulfilled for the last 3 months with symptoms onset at least 6 months before diagnosis. IBS: Irritable bowel syndrome.

is multifactorial and it shares some of the mechanisms of CC including the presence of alterations in colonic transit [4], but an increased prevalence of visceral hypersensitivity seems to be the distinctive aspect of these patients when compared with CC patients [5]. Traditional C-IBS therapies are mainly directed at the relief of individual symptoms, for example, laxatives for constipation or smooth muscle relaxants for pain. They are often less efficacious in addressing the overall symptom complex [6]. 928

A number of new medications were recently demonstrated to be more effective than placebo in treating CC, including the intestinal chloride channel activator lubiprostone, the prokinetic selective 5-HT4 receptor agonist prucalopride and the guanylate cyclase-C agonist linaclotide [7]. Lubiprostone is currently approved in USA but not in Europe for treatments of both CC and C-IBS. Prucalopride has recently been approved and marketed in Europe for the treatment of female CC patients who are not satisfactorily relieved by laxatives, and it has also been introduced in several countries in different parts of the world, except for the USA. Linaclotide has recently been approved and marketed in the USA to treat CC and C-IBS, and in Europe to treat moderate and severe C-IBS patients. A number of pharmacological treatments are in development and these include another guanylate cyclaseC agonist, plecanatide and an ileal bile acid transporter inhibitor, elobixibat. Recent publications have also revisited traditional laxatives like PEG, showing efficacy superior to placebo in treating CC [7], and also constipation symptoms in C-IBS [8]. This review focuses on the pharmacology, efficacy and safety profile of prucalopride, linaclotide, plecanatide and elobixibat as well as on their possible present or future clinical application. In the expert opinion session also, some considerations will be advanced on the possible role of PEG taking into account recent literature. We conducted a search of literature on prucalopride, linaclotide, PEG, plecanatide and elobixibat using PubMed, ISI web of knowledge and clinical trial registries available on the Internet. 2.

Prucalopride

Pharmacology Prucalopride (R093877) is a 5-HT4 receptor agonist that was developed by Janssen pharmaceuticals in the 1990s. Prucalopride is a benzofuran carboxamide derivative, and thus, belongs to a different chemical class than other 5-HT4 receptor agonists such as cisapride, renzapride and mosapride (substituted benzamides) or tegaserod (a 5-OH-indole derivative) [9,10]. However, unlike these other 5-HT4 receptor agonists, prucalopride is highly selective and is devoid of measurable affinity for other receptors [9]. Prucalopride is well absorbed from the gastrointestinal tract, with an absolute bioavailability of more than 90% after oral administration [11]. The oral bioavailability is not affected by simultaneous food intake [12]. The plasma terminal half-life is estimated to be 30 h. Plasma protein binding is low at 28 -- 33% [13]. The main route of elimination is via the urine (60 -- 70% excreted unchanged in the urine), and this leads to higher area under the curve of plasma levels in the elderly [13,14]. As prucalopride has a low level of metabolism by the liver, hepatic impairment is unlikely to alter its pharmacokinetics and no CYP3A4 drug interactions are anticipated [13]. The pharmacokinetics of a single intake of an oral solution (0.03 mg/kg) of prucalopride were 2.1

Expert Opin. Pharmacother. (2014) 15(7)

New treatments for chronic constipation

Excitatory motor neuron Ach SP +++

Sensory neuron

Inhibitory motor NO neuron VIP


5-HT

5-HT4 receptor

Prucalopride

Figure 1. Schematic representation of the localization of 5-HT4 receptors at the level of the gut intrinsic nervous system as site of action of prucalopride. Ach: Acetylcholine; No: Nitric oxide; Sp: Substance P; VIP: Vasoactive intestinal peptide.

evaluated in children, showing comparable kinetics to adults (at doses of 1.5 -- 2 mg) but with lower systemic exposure [15].

radiopaque markers, and also increased rectal sensitivity to distension and electrical stimulation [25]. Phase III studies in CC Three pivotal studies of similar design evaluated the efficacy of prucalopride at 2 and 4 mg doses compared to placebo in patients with CC. More than 80% of these reported that they failed to be adequately relieved by preceding laxative treatments [26-28]. Responders for the primary end point were patients with ‡ 3 complete spontaneous bowel movements (CSBM) per week, a stringent end point that restores stool pattern to within the normal range. Secondary end points included the proportion of patients with an increase of ‡ 1 CSBM/week, as well as the number of bowel movements, stool consistency and severity of straining on daily diaries, as well as symptom severity and quality-of-life questionnaires [29,30]. All three studies showed efficacy of both doses of prucalopride over placebo in achieving the primary end point (average of ‡ 3 CSBM per week over 12 weeks) with a number need to treat (NNT) of 6, while no significant difference was found between the 2 and 4 mg doses (Figure 2). Similar results were obtained for the secondary end points of increase of ‡ 1 CSBM/week. Both doses of prucalopride were superior to placebo in improving patient’s assessment of constipation symptoms (PAC-SYM) and patient’s assessment of constipation quality-of-life (PACQOL) scores with all domains significantly better compared to placebo. At a subsequent integrated analysis of the data from three double-blind Phase III trials, it has been demonstrated that the efficacy and safety profile of prucalopride did not differ between patients who had or had not obtained adequate relief from laxatives in the past and that early response (weeks 1 -- 4) predicted ultimate response over 2.3

2.2

Pharmacodynamic studies

Results from animal studies demonstrated that prucalopride activates both cholinergic and nitrergic pathways (Figure 1) [16] and facilitates colonic propulsion through a combination of inhibition of circumferential resistance and enhancement of longitudinal muscle contractility [17-19]. In man, studies conducted in healthy subjects [20-22] consistently showed that 1-week treatments with 1 and 2 mg of prucalopride significantly enhanced overall colonic transit, while anorectal manometry and sensitivity to rectal balloon distention were not altered. In one study, 0.5 and 2 mg doses induced significant accelerations in overall colonic transit and proximal colon emptying half time compared to placebo, while the 4 mg dose did not seem to provide significant incremental benefit [21]. The effect of prucalopride on gastrointestinal and colonic transit was also evaluated in patients with CC [23-25]. In 40 patients with CC and without rectal evacuation disorder, 2 or 4 mg prucalopride daily for 7 days accelerated overall gastric emptying and small bowel transit assessed by scintigraphy and the 4 mg dose significantly enhanced overall colonic transit and ascending colon emptying [23]. In 28 patients with CC, 1 mg prucalopride daily for 2 weeks significantly increased in the number of bowel movements while both the 1 and 2 mg did not change anorectal function and sensitivity [24]. In 74 patients with CC, prucalopride 1 mg daily during 4 weeks significantly increased the number of bowel movements, accelerated both orocecal transit, measured by lactulose breath test, and colonic transit, measured by


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Quigley et al

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Pooled data

Prucalopride 4 mg

Figure 2. Response rates to placebo and two doses of prucalopride in the three pivotal Phase III trials in patients with chronic constipation. *p < 0.01 vs. placebo. z p 1 nM. The concentration of guanylate cyclase-C receptor agonist that produces 50% of the maximal activity (EC50) of linaclotide at pH 7 (99 ± 17.5 nM) is 8 -- 10-fold more potent than that of guanylin and uroguanylin at the same pH (970 ± 236 and 798 ± 217 nM). Pharmacokinetic analysis in rats in vivo has demonstrated that linaclotide is only minimally absorbed after 10 mg/kg oral dosing and < 1% of the orally administered dose is recovered in the feces in the first 24 h. Linaclotide has been demonstrated to resist after 3 h of incubation in simulated gastric fluid (pH 1). The first part of degradation involves the proteolytic removal of its C-terminal tyrosine, which is not protected by the disulphide bonds by carboxypeptidase A in the duodenum and in the jejunum, resulting in the formation of a 13-amino acid metabolite, MM-419447 (Des-Tyr14). The second part of degradation takes part in the intestine where both linaclotide that escaped the first proteolytic process and the active metabolite undergo reduction of disulphide bonds. This process leaves both linaclotide and MM-419447 highly susceptible to proteolytic degradation that converts them to small fragment non-active peptides and amino acids which are then absorbed through the intestine. More than 95% of the quantity of active peptide


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Linaclotide plecanatide

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Guanylin or uroguanylin

E. Coli or Yersinia enterotoxin -

CI


EC cell

GC

CFTR

GTP cGMP

PKG II K+

ATP

K+ Na+

Na+ K+ 2CI- CI

Sensory neuron

Active extracellular transporter of cGMP

Figure 3. Schematic representation of the action mechanism of linaclotide and of other ligands through guanylate cyclase C receptors on enterocytes and through the active transmembrane transport of cyclic guanosine 3¢,5¢-monophosphate on sensory neurones. cGMP: Cyclic guanosine 3¢,5¢-monophosphate; CFTR: Cystic fibrosis trans-membrane conductance regulator; EC: Entero-endocrine cell; GC: Guanylate cyclase C; GTP: Guanosine triphosphate; PKGII: cGMP-dependent protein kinase II.

recovered in the feces is represented by MM-419447, which has the same pharmacological and pharmacokinetics properties as linaclotide. In humans, after oral dosing, systemic exposure to linaclotide and MM-419447 is minimal, and the majority of the plasma has concentrations of these substances that are below the quantitation limits of 1 ng/ml (linaclotide) and 2 ng/ml (MM-419447). The amount of total recovered active peptide in the stool samples is similar in fed and fasted conditions. Pharmacodynamic studies in animal models Results from animal studies demonstrated a stimulatory effect of linaclotide on gastrointestinal secretion and transit [45], and also revealed a role for guanylate cyclase-C agonism in the modulation of visceral sensitivity [46,47]. In a first study, the effect of guanylate cyclase-C activation on visceral hyperalgesia was tested in three different rodent models including colonic hyperalgesia after the induction of inflammatory colitis by intracolonic administration of trinitrobenzenesulfonic acid (TNBS), and stress-induced colonic hyperalgesia induced by acute restraint and by water avoidance stress (WAS) [46]. In addition, the role of guanylate cyclase-C receptor activation in the modulation of sensory response to distension was evaluated in the model of TNBS-induced visceral hyperalgesia in male wild type (wt) and in guanylate cyclase-C null mice [46]. The results of this in vivo study demonstrate that linaclotide did not affect the response to colorectal distension under basal conditions, but reduced hypersensitivity to distension in 3.2

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the different experimental conditions. The effect of linaclotide was evident only at low doses (£ 3 µg/kg), while at higher doses (‡ 10 µg/kg) it either did not affect the sensory response to distension or, in the WAS model, it even increased the colorectal hypersensitivity. Under basal conditions, colorectal sensitivity to distension was lower in guanylate cyclase-C null mice than in wt mice, while after TNBS instillation both wt and null mice developed hypersensitivity to colorectal distension, but linaclotide only reversed the sensory response in wt mice and not in guanylate cyclase-C null mice [46]. The results after administration of linaclotide suggested that guanylate cyclase-C activation was involved in the modulation of sensory response to distension only in presence of hypersensitivity. However, these results were in contrast with those of null mice for guanylate cyclase-C, which suggested that ctivation of the guanylate cyclase-C receptor may play a role in mechanosensitivity under basal conditions but was not involved in the development of colorectal hypersensitivity. Recent studies have further investigated the effect of guanylate cyclase-C activation in the modulation of visceral sensitivity suggesting that the different results under basal conditions and in models of hypersensitivity may be related to the actions of guanylate cyclase-C agonists on different types of mechanoreceptors [47,48]. The effect of cGMP (0.3 -- 30 mg/kg), the primary downstream effector of guanylate cyclase C-activation, has been assessed in rats in vivo, on the response to colorectal distension in both TNBS- and acute partial restrain stress-induced hypersensitivity, and, in vitro,




on pelvic afferent firing in response to colorectal distension before and after TNBS-induced sensitization [47]. In this study, both in vivo under basal conditions (sham stress) and in vitro before and after TNBS-induced sensitization, respectively, in distension range of 10 -- 40 and 10 -- 20 mmHg, cGMP did not affect sensitivity to colorectal distension. In contrast, cGMP had an analgesic effect in vivo after TNBSinduced sensitization (0.3 -- 30 mg/kg, dose-dependently) and after stress (3 mg/kg) and in vitro (3 mg/kg) before and after TNBS-induced sensitization, respectively, in distension range of 50 -- 60 mmHg before and of 30 -- 60 mmHg after [47]. Similarly, uroguanylin (30 -- 300 µg/kg) was shown to have an in vivo analgesic effect on sensitization induced by TNBS and this inhibition was mediated by cGMP, which was actively transported from the epithelial cell in the submucosal space (Figure 3). Another study has demonstrated that in vitro linaclotide (100 -- 1000) and uroguanylin (30 -- 3000) dosedependently inhibit colonic splanchnic high-threshold nociceptors with a greater efficacy in TNBS-induced hypersensitivity, and through a mechanism involving guanylate cyclase-C receptors located in the colonic mucosa [48]. Moreover, high-threshold nociceptor responses under basal conditions are similar in guanylate cyclase-C null and wt mice, but linaclotide inhibits the response only in wt [48]. Taken together these data demonstrate that linaclotide and uroguanylin dose-dependently inhibit high-threshold splanchnic afferents in both basal and sensitized conditions, and this is mediated through cGMP. In contrast, linaclotide and cGMP produce inhibition of afferents responding in vivo to distension range up to 60 mmHg only in sensitized conditions. It remains to be clarified whether this is confined to a specific dose range of guanylate cyclase-C activators [46]. Moreover, whether linaclotide and cGMP also affect basal mechanosensitivity of these afferents in vivo, as recently suggested by in vitro studies [49], needs to be further evaluated.

Pharmacodynamic studies in humans and in patients with CC

3.3

In humans, one placebo-controlled, double-blind, randomized, Phase I study in 48 healthy subjects, studying the effect of oral multiple ascending doses (30, 100, 300, 1000 µg), demonstrated that all doses of linaclotide increased the stool frequency and the stool weight, while only the highest dose decreased the stool consistency, and improved the ease of stool passage. In this study, all linaclotide doses were well tolerated [50]. Similar results were observed in a multicenter, randomized, double-blind, placebo-controlled pilot study testing the safety, tolerability and exploratory efficacy of 100, 300 and 1000 µg linaclotide once daily for 2 weeks in 42 CC patients without a history of pelvic floor dysfunction, the majority of whom were females [51]. In this study, linaclotide 100 µg was significantly more effective than placebo in increasing bowel frequency, while linaclotide 1000 µg significantly decreased stool consistency and improved straining. Linaclotide also

had a significant favorable effect on abdominal discomfort compared to placebo. Diarrhea was the more common adverse event reported by patients treated with linaclotide compared to those treated with placebo. Only in 1 patient diarrhea, scored as moderate intensity, lead to discontinuation of linaclotide. In a subsequent multicenter, double-blind, placebocontrolled, parallel group, dose range-finding Phase II study, the effect of 75, 150, 300 and 600 µg of oral linaclotide for 4 weeks was tested in 310 CC patients without a history of pelvic floor dysfunction [52]. The majority of patients were females. All doses of linaclotide increased the frequency of spontaneous bowel movements (SBM) and of CSBM, improved stool consistency, straining, abdominal discomfort, bloating, global assessment and quality of life. The efficacy of linaclotide generally increased with increasing dose, except for abdominal discomfort and bloating, and for straining at the dose of 75 µg. Again, the only more commonly observed adverse event with linaclotide was diarrhea with six patients discontinuing the treatment for diarrhea (rated as severe by two) during linaclotide treatment at 600 µg. Phase III studies in CC The 150 and 300 µg doses were selected for further development, but corrected to 145 and 290 µg, reflecting improved methods used to measure linaclotide content in the capsules. Two multicenter, double-blind, placebo-controlled, parallel group, dual-dose, Phase III studies finally evaluated the effect of oral linaclotide 145 and 290 µg for 12 weeks in 1276 CC patients without pelvic floor dysfunction (trial 303 and trial 01) [53]. At the end of the 12-week treatment period, the patients in the trial 303 entered a 4-week, double-blind period of randomized withdrawal to a once-daily regimen to assess the possible rebound effect and the sustained response. The primary end point (> 3 CSBM and an increase of ‡ 1 complete SBM per week during at least 9 or 12 weeks) was reached by 21 and 16% of patients treated with linaclotide 145 µg and by 19 and 21% of patients treated with linaclotide 290 µg as compared to 3 and 6% with placebo respectively in trials 303 and 01, with an NNT of 6. Improvement in all secondary end points, including straining, stool consistency, abdominal discomfort, bloating and constipation severity, and in PAC-QOL was significantly superior with linaclotide than placebo. No rebound effect was observed, and the effect of linaclotide was observed within the first 24 h and was sustained through 16 weeks. 3.4

Phase II studies in patients with C-IBS The effect of oral linaclotide 100 and 1000 µg once daily on colonic transit was first evaluated in a randomized, doubleblind, placebo-controlled Phase IIa study in 36 women with Rome II C-IBS, without evidence of evacuation disorders [54]. Scintigraphy-assessed colonic transit was normal in more than half of patients. After 5 days of treatment, linaclotide resulted in a significant stimulatory effect on ascending colon emptying half time and overall colon transit at 48 h as compared 3.5


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5 Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Universitaet Zuerich on 07/01/14 For personal use only.

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Placebo

Study 303

Linaclotide 145 µg

Linaclotide 290 µg

Figure 4. Response rates to placebo and two doses of linaclotide in the two Phase III trials in patients with irritable bowel syndrome with constipation.

to placebo, with a statistically significant effect for 1000 µg but not 100 µg. Linaclotide was also more effective than placebo in improving stool frequency, stool consistency and ease of passage, with a clearer dose-response effect for stool consistency. In a subsequent randomized, multicenter, double-blind, placebo-controlled Phase II study, the effect of oral 75, 150, 300 and 600 µg linaclotide for 12 weeks was assessed in 420 Rome II C-IBS patients [55]. In addition, during a 2-week baseline period, patients were required to report a mean score of 2 or more for daily assessment of abdominal pain or discomfort on a 1 -- 5 scale, a mean of < 3 CSBM/ week and £ 6 SBM/week. All doses of linaclotide significantly improved the frequency of CSBM (the primary end point), severity of straining, stool consistency, abdominal pain, bloating and abdominal discomfort. The effect of linaclotide on both bowel function and abdominal symptoms was maximal at the dose of 300 µg. Particularly on abdominal symptoms of pain, discomfort and bloating, the efficacy did not increase with dose increment from 300 to 600 µg. Phase III studies in C-IBS The two multicenter Phase III, placebo-controlled, randomized studies, which were the basis for the FDA approval of linaclotide in C-IBS, investigated the effect of oral once-daily linaclotide (290 µg) for 12 weeks (trial 31) and for 26 weeks (trial 302) in, respectively, 800 and 804 patients C-IBS Figure 4 [56,57]. To be eligible, patients had to fulfill the Rome II criteria for C-IBS and in the trial 31 they were asked not to report a history of pelvic floor dysfunction. In trial 31, patients who completed all the 12 weeks period were eligible to enter the double-blind 4-week randomized withdrawal period to assess the sustained effect and the possible rebound 3.6

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effect of linaclotide. In both trials, the effect of linaclotide was assessed according to the FDA interim primary end points for IBS-C (Table 2) [58]. In both trials, three additional primary end points were also assessed, which required patients to meet the following weekly responder criteria for at least 9 out of the first 12 weeks of treatment period: an improvement of ‡ 30% from baseline in the average of daily worst abdominal pain scores; ‡ 3 CSBM and an increase of ‡ 1 CSBM from baseline; or a combination of the two criteria. As secondary end points, the 12-week change-from-baseline of worst abdominal pain, abdominal discomfort, abdominal bloating, stool frequency, stool consistency, severity of straining, constipation severity, IBS severity, adequate relief and degree of relief were considered. In trial 31, a greater percentage of patients treated with linaclotide compared to those treated with placebo were responders for FDA primary end points (Figure 4) and for the other three primary end points and for the secondary end points. During the randomized withdrawal period, patients remaining on linaclotide showed sustained improvement, those who were re-randomized from linaclotide to placebo showed a return of symptoms but without worsening of symptoms relative to baseline. Similar results were reported in trial 302, and the differences from placebo were continuous over the 26 weeks of treatment (Figure 4). The results of the two Phase III studies on C-IBS have been also evaluated according to pre-specified primary end points by the European Medicines Agency (EMA) and the efficacy was also confirmed according to these EMA end points (Table 2) [59,60]. In this evaluation, compared to placebo, linaclotide was associated with significant improvement of all the secondary end points, including bloating severity and health outcomes assessments (IBS-Qol, Irritable Bowel Syndrome




Table 2. FDA and European Medicines Agency end points for clinical trials in irritable bowel syndrome with constipation. FDA end points for IBS-C: A responder is defined as a patient who meets both of the following criteria in the same week for at least 6 of the 12 weeks of the treatment period: An improvement of ‡ 30% from baseline in the mean rating of daily worst abdominal pain scores An increase of ‡ 1 complete SBM from baseline EMA end points for C-IBS: A responder is defined as a patient who meets both of the following criteria in the same week for at least 6 of the 12 weeks of the treatment period: An improvement of ‡ 30% from baseline in either mean abdominal pain score or mean abdominal discomfort for that week, with neither of these scores worsening from baseline for that week IBS degree-of-relief responders (symptoms ‘considerably’ or ‘completely’ relieved) C-IBS: Irritable bowel syndrome with constipation; EMA: European Medicines Agency; SBM: Spontaneous bowel movements.

Quality of Life; and EQ-5D, Euro Quality of life 5 dimensions) [59]. In a recent paper, it has been demonstrated that 22 -- 44% of the C-IBS patients included in the Phase III linaclotide trials scored symptoms of pain, discomfort, bloating and fullness as severe at baseline (‡ 7 on the 11-point numerical rating scale). In this subpopulation of patients, linaclotide was effective in improving all the symptoms and also the global measure of symptom relief and quality of life (IBS-Qol), with a greater efficacy than in patients with milder symptoms at baseline [61].

Safety and tolerability As reported in a recent meta-analysis including all the Phase III trials in CC and in C-IBS, the only most common adverse event occurring more frequently in linaclotide than in placebo-treated patients was diarrhea. The calculated relative risk of diarrhea is 2.19 for 145 µg and 2.84 for 290 µg in CC and 4.72 for 290 µg in C-IBS, and is higher in C-IBS when data are pooled by diagnosis (6.63 in C-IBS vs 2.84 in CC) [62]. Members of the European regulatory body, EMA, have recently published a paper with recommendations for the use of linaclotide in specific patient groups. They state that linaclotide should not be used in children and in adolescents, as the drug has not been tested in this population where guanylate cyclase-C seems to be overexpressed. The risk/benefit balance should be considered in patients at major risk of diarrhea or of complications of diarrhea, such as patients with cardiovascular disease and those older than 65 years (who represented only 5% of patients in the Phase III clinical trials and seemed to have more diarrhea) [63]. 3.7

4.

Plecanatide

Plecanatide is a guanylate cyclase-C activator with a structure identical to uroguanylin except for a replacement of an amino acid on N-terminus. Plecanatide is therefore supposed to act as the endogenous agonist of guanylate cyclase-C receptors in the intestinal tract and with the same dependency by pH, which gives uroguanylin a major activity in the acidic environment of the duodenum. At present, only one Phase I study evaluating the safety and tolerability of plecanatide in humans has been published [64]. In this single-site double-blind, randomized, single ascending dose study, 72 healthy subjects were enrolled in nine cohorts to receive a single dose 0.1 -- 48.6 mg of placebo or plecanatide to assess pharmacokinetics. Time to first stool, stool frequency and stool consistency were also measured as pharmacodynamic parameters. All the outcome parameters were evaluated for 48 h after the administration. No measurable systemic absorption of oral plecanatide was observed at any of the doses studied, using an assay that was sensitive to 1 ng/ml concentrations. Diarrhea was the most prevalent side effect, even if its frequency did not differ statistically significantly between placebo and plecanatide and appeared not to be dose-related in the plecanatide-treated subjects. Additional gastrointestinal events reported in the plecanatide subjects were nausea, abdominal discomfort and pain, and vomiting, all but one occurring at the two highest doses of 24.3 and 48.6 mg. Overall plecanatide was safe and well-tolerated up to the highest dose administered. As regard to pharmacodynamics, the time for first bowel movement was within the 24 h with all doses except 5.1 mg, and with a dose-related response. The stool consistency was reduced both at 24 and 48 h. The stool frequency did not differ significantly between placebo and plecanatide. Three studies with plecanatide are ongoing: one evaluating three different doses (0.3, 1 and 3 mg) of plecanatide in patients with CC over 12-week treatment period, one longterm safety and tolerability study with the 3 mg dose in CC, and one with four different doses (0.3, 1, 3 and 9 mg) of plecanatide in C-IBS over 12-week treatment period [65]. 5.

Elobixibat

Elobixibat (A3309) is a specific first-in-class ileal bile acid transporter inhibitor, developed for the treatment of CC [66]. After synthesis in the liver, bile acids are excreted into the biliary tract and are mixed with food in the small intestine to facilitate lipid digestion and absorption [66]. Approximately 95% of the bile acids are reabsorbed in the terminal ileum, to reach the liver again through the portal vein, for re-use in the so-called enterohepatic recirculation of bile acids. In vivo studies using bile acid perfusion confirmed that bile acids stimulate fluid and electrolyte secretion and also contractions in the human colon [66]. Diarrhea is a well-known


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LDL

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C4 +++

7a-hydroxylase Bile acids Liver

LBAT


Portal vein IBAT Elobixibat +++

Intestine

Bile acids

Figure 5. Schematic representation of the action mechanism of elobixibat. C4: 7 a-hydroxy-4-cholesten-3-one; IBAT: Ileal Bible Acid Transporter; LBAT: Liver Bible Acid Transporter.

consequence in patients with impaired bile acid absorption from the terminal ileum [67] as well as of treatment with bile acids [66]. Recently, an increased bile acids biosynthesis and fecal presence has been involved in the pathogenesis of symptoms in patients with IBS and diarrhea [67,68]. Based on these observations, inhibition of ileal bile acid malabsorption constitutes a potential target for the pharmacotherapy of CC (Figure 5). Pharmacology [66] Elobixibat (A3309) is a stereochemically pure enantiomer of a substituted benzothiazepine and has a molecular weight of 695.9 g/mol. It targets the ileal bile acid transporter, a brush border membrane glycoprotein expressed in the ileum. In transfected HEK293 cells expressing various bile acid transporters, A3309 dose-dependently inhibited the accumulation of 30 µM of radiolabelled glycocholic acid. A3309 had an estimated IC50 of 0.53 ± 0.17 nM for the human ileal bile acid transporter inhibitor (IBAT), and 0.13 ± 0.03 and 5.8 ± 1.6 nM for the mouse and canine transporters, respectively. The selectivity of A3309 was demonstrated by the compound’s IC50 of 0.24 ± 0.02 µM for the human hepatic sodium/bile acid co-transporter (400-fold higher than for IBAT inhibition) and by an at least 1000-fold lower affinity for intestinal amino acid transporters. Animal experiments showed that A3309 has a minimal systemic exposure and a high protein binding (> 99%). In humans, no detectable concentrations of A3309 were found with the 0.1 and 0.3 mg/day doses [69]. Analyses of the 1 -- 10 mg/day doses showed A3309 plasma levels in the picomolar range, with a maximum concentration within 4 h after intake and elimination within 24 h, but the route of elimination was not specified [69]. No metabolites for elobixibat have been reported. 5.1

936

Biochemical aspects [66] The enterohepatic circulation of bile acids drives feedback inhibition of hepatic bile acid synthesis, and bile acid synthesis can be measured through plasma levels of C4 (7a-hydroxy4-cholesten-3-one), one of the intermediate metabolites in the generation of bile acids. In addition, Fibroblast Growth Factor 19 (FGF19), whose plasma level is determined by the intracellular concentration of bile acids in ileal enterocyte, is also a marker of the intestinal feedback regulation of hepatic bile acid synthesis. Anticipated effects following pharmacological inhibition of ileal bile acid reabsorption with elobixibat therefore are reductions in the plasma levels of FGF19 and increases in plasma levels of C4. 5.2

Pharmacodynamic studies Studies in a constipated dog model provided the rationale for the subsequent clinical application in patients with CC [66]. Two studies evaluated the effects of elobixibat on gastrointestinal transit in patients with CC [69,70]. In a pilot study, 30 patients were randomized to 14 days treatment with placebo or one of five dose levels (0.1, 0.3, 1.0, 3.0 and 10 mg once daily) of elobixibat [69]. A significant effect of the drug was observed on colonic transit time measured by radio-opaque markers, and transit times were reduced from 4.4 ± 1.2 to 3.6 ± 1.2 days with the 3 mg dose, and from 3.0 ± 2.1 to 1.9 ± 1.0 days with the 10 mg dose [69]. C4 plasma levels were increased and FGF plasma levels decreased in a dose-dependent fashion during treatment with A3309. Also, total cholesterol and LDL cholesterol decreased dose-dependently [69]. No significant effects on the frequency of CSBM were observed, but the highest dose was associated with a significant increase in the total number of 5.3




SBM and with more liquid stool consistency [69]. No significant differences occurred in associated symptoms such as abdominal discomfort or bloating. In a second study, a total of 36 females with CC without pelvic floor dysfunction were randomized to placebo or A3309 15 or 20 mg daily for 14 days [70]. A3309 accelerated overall colonic transit, as measured by colonic transit scintigraphy [71], at 24 and 48 h in comparison to placebo [70]. The effects of 15 mg were more pronounced than those of 20 mg and seem to involve the proximal colon. No significant effects on gastric and small bowel transit were observed, but there was a tendency toward prolonged gastric half emptying time with both doses [70]. Serum C4 increased dose-dependently with A3309 15 and 20 mg, while no change was observed during placebo treatment [70]. A3309 treatment was associated with significant favorable effects on stool consistency, ease of passage and straining. No significant effect on stool frequency was obtained. Patients reported superior improvement of constipation severity and treatment effectiveness ratings, but not for associated symptoms of abdominal pain, discomfort or bloating [70]. A significant correlation was found between serum C4 and colonic transit times as well as mean stool consistency, during A3309 treatment. Pretreatment C4 and baseline colonic transit at 24 h were also significantly correlated [70]. Clinical studies In a dose-finding Phase IIb study with A3309 after a 2-week baseline assessment, 190 patients with CC (modified Rome III criteria) were randomized to 8 weeks of treatment with placebo, 5, 10 or 15 mg A3309 daily [72]. The primary end point was the change in SBM during week 1 of treatment, compared to baseline. Secondary end points included weekly rates of SBM and CSBM, daily assessments of stool consistency and straining, and abdominal symptoms (pain, discomfort, bloating). In the first week of the double-blind treatment phase, the 10 and 15 mg doses of A3309 were associated with a significantly higher increase in SBM over baseline compared to placebo. The effect of A3309 on SBM was dose-dependent and persisted during the entire treatment period of 8 weeks. After the initial dose of 10 and 15 mg, the time to the first SBM was significantly shorter than after placebo. Both the 10 and 15 mg were associated with significant improvements in stool consistency and straining throughout the treatment period, and the 15 mg was associated with significant improvement in bloating severity. Severity of pain and discomfort did not differ between the treatment arms, but the highest dose was associated with a significantly better improvement of bloating compared to placebo [72]. Plasma C4 was significantly increased for all active A3309 dose levels. Significant decreases in serum cholesterol levels occurred in the 10 and 15 mg doses, and this was associated with decreases in LDL cholesterol and LDL/HDL ratio [72]. Severe abdominal pain/cramping or diarrhea was reported by 5 patients in the 15 mg group, and discontinuation rates in this group were higher (12.5 -- 12.8% with placebo and 5 or 10 mg, vs 5.4

22.9% with 15 mg). Three serious adverse events occurred in each treatment arm but were considered unrelated to treatment. No significant changes in vital signs, laboratory results or other safety evaluations occurred [72]. Three studies with elobixibat are ongoing [73]: one assessing the efficacy and safety of two different doses (5 and 10 mg) of elobixibat over a 12-week period followed by a 4-week withdrawal period in CC; another is a Phase III study assessing the efficacy and safety of two different doses (5 and 10 mg) of elobixibat in CC over a 26-week period; the last one is a multicenter, open-label study assessing the safety and tolerability of two different doses (5 and 10 mg) of elobixibat in CC over a 52-week period. 6.

Conclusion

Prucalopride, a highly selective 5-HT4 agonist, is an effective treatment for CC with a good safety profile, reported in extensive clinical and cardiovascular trials to date. Its efficacy and safety has also been documented in elderly patients with cardiovascular comorbidity. Moreover, the drug may have potential for the treatment of other gastrointestinal motility disorders. Linaclotide is a poorly absorbed guanylate cyclase-C agonist and is effective in the treatment of both CC and C-IBS. Its effect on visceral sensitivity, as demonstrated in studies in animals, and on pain, as observed in clinical trials, provides an attractive therapeutic option for the treatment of C-IBS. The drug showed a favorable safety profile in the clinical trial program, with a low incidence of serious adverse events. However, the relatively high incidence of diarrhea needs to be considered upon application in populations with a potentially higher risk of complications by diarrhea such as the elderly and patients with cardiovascular disease. Plecanatide is another guanylate cyclase-C agonist under development for the same indications and is suggested to be mainly active in the proximal part of the small bowel. Its efficacy and tolerability profile is under further evaluation in ongoing clinical studies. Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. Phase II studies have demonstrated that it is effective in enhancing colonic transit, increasing bowel frequency, reducing stool consistency and straining in patients with CC. 7.

Expert opinion

Over the last years, the pharmacological treatment options for CC have changed dramatically. Systematic reviews and meta-analysis have confirmed that some of the traditionally used treatments like PEG, bisacodyl and picosulfate are more effective than placebo [7,74]. In addition, several drugs with novel modes of action such as the secretagogue lubiprostone, prucalopride and linaclotide have emerged. PEG is an osmotic laxative, extensively used in clinical practice and available worldwide, demonstrated to be more effective than placebo in both the short and the long term and also more


937



effective than lactulose (the only other osmotic laxative with sufficient evidence-based data demonstrated to be more effective than placebo in a systematic review) [75]. Diarrhea was the only symptom leading to treatment discontinuation in only 0.4% of cases [76]. Bisacodyl and sodium picosulfate are stimulant laxatives with anti-absorptive and secretory effects that have been demonstrated to be more effective than placebo only in the short term, with diarrhea and abdominal pain as their most frequent side effects [7]. Lubiprostone is a lipophilic prostanoid compound that activates the type 2 chloride channel on the luminal surface, which has been demonstrated to be more effective than placebo in treatments of both CC and C-IBS in the short term. The drug is not currently approved in Europe, and the main side effect nausea is often mild and transient leading to withdrawal in 5% of patients [7]. However, also in presence of these new or established pharmacological options the optimal treatment of patients with CC is hampered by the lack of comparative trials that quantify the gain of the newly developed versus the traditional treatments. Moreover, a considerable part of patients with CC seem not to respond both to traditional and to novel treatments. Recently, a double-blind, single-center study has compared the efficacy of 26 gm of PEG with that of 2 mg prucalopride for 28 days in 240 females with CC in whom laxatives had failed to provide adequate relief. The study was conducted in the highly controlled environment setting of a Phase I unit in Romania [77]. The study showed non-inferiority of PEG versus prucalopride in achieving the primary end point of 3 or more CSBM and a greater efficacy of PEG in a number of secondary end points including severity of straining and fecal consistency [77]. Besides the clinical setting in a Phase I unit, the fact that PEG is not available on the market in Romania adds another important difference compared to the prucalopride clinical trials [31,77]. However, these results prompt some considerations. In the past, PEG was also reported to be more effective in CC than tegaserod, a 5HT4 partial agonist that is less selective than prucalopride [78]. As these drugs have different mechanisms of action (PEG an osmotic laxative and prucalopride a prokinetic), the findings suggest that both mechanisms have similar relevance in the studied population and open possibilities for combination therapy in patients not responding to either therapies alone. In addition, studies evaluating the effect of PEG on colonic transit showed accelerated transit mainly in the left colon [79], while prucalopride mainly enhances transit in the right colon [21,23]. To date, no such comparisons are available for linaclotide, and none are currently planned for plecanatide and elobixibat. Nevertheless, comparison studies are urgently needed to better establish the optimal use of traditional and novel drugs for the treatment of CC, and to identify clinical predictors of increased or decreased likelihood of response to specific drug categories. On the same line, specific studies comparing the economic impact of each of these drugs

938

in the management of CC are necessary. Taking into account only the costs of drug acquisition, in UK where PEG, prucalopride and linaclotide are available in the market, the cost of a day of treatment with PEG is about £ 0.86, with prucalopride about £2 and with linaclotide £1.32. However, as demonstrated in a previous study comparing the economic impact of PEG and lactulose in the management of CC, the true cost of managing CC is impacted by a range of different resources and not only the drug acquisition cost [80]; therefore, cost-effectiveness studies are awaited. With regard to treatment of C-IBS, the studies with linaclotide reported symptom relief that seems higher than previously observed with older drugs [6]. However, here also comparator studies, for instance with spasmolytics or laxatives, would be welcome. Furthermore, it should be noted that the inclusion criteria of the C-IBS clinical trials with linaclotide favored the enrolment of patients with relatively high symptom severity, and the risk of diarrhea was higher in C-IBS trials compared to CC trials with linaclotide [62]. The use in clinical practice will further clarify the efficacy and tolerability profile in C-IBS patients with a more diverse level of symptom severity. In conclusion, at the moment, considering the efficacy and safety profile in the short and long term of PEG, this should be the first-line choice in the treatment of patients with CC. In patients not responding to the osmotic laxative, also elderly people and people with cardiovascular comorbidities, in countries where available, prucalopride should be considered as second-line choice, with an initial treatment period of 4 weeks followed in the responders by long-term administration (up to 3 months as from approval but safe for up to 18 months considering the open studies). In the same population of patients, where available, linaclotide should also be considered as second choice in the treatment of CC but not in elderly people, in people with comorbidities or in children, with an initial treatment period of 4 weeks followed, in responders, by long-term administration up to 12 weeks considering its approval. In patients with C-IBS, linaclotide should be considered as first choice mainly in patients with moderate or severe IBS with the same precautions of the use in CC and with a long-term administration up to 26 weeks considering its approval.

Declaration of interests J Tack has received research grants or support from Abbott and Shire; he has been part of speakers bureau’s for Abbott, Almirall, AstraZeneca, Danone, Janssen, Menarini, Novartis, Shire, Takeda and Zeria; and has scientifically advised Almirall, AstraZeneca, Cosucra, Danone, Ferring, GI Dynamics, GlaxoSmithKline, Ironwood, Janssen, Menarini, Novartis, Rhythm, Shire, Takeda, Theravance, Tranzyme, Tsumura, Will pharma and Zeria. M Corsetti has no competing interests to disclose.



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Affiliation

Maura Corsetti MD PhD & Jan Tack† MD PhD † Author for correspondence University of Leuven, Translational Research Center for Gastrointestinal Disorders, Herestraat 49, 3000 Leuven, Belgium

941

Chronic constipation and treatment options (Review).

New Options in Constipation Management.

Chronic migraine - new treatment options.

Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation.

New treatment option for irritable bowel syndrome with constipation and chronic idiopathic constipation.

Novel pharmacological therapies for management of chronic constipation.

Safety and efficacy of the vibrating capsule, an innovative non-pharmacological treatment modality for chronic constipation.

Treatment options for chronic pancreatitis.

Linaclotide: a new option for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

New treatment options for alcoholic hepatitis.

New treatment options for hearing loss.

[New treatment options for metastatic melanoma].

Multiple myeloma. New treatment options.

Constipation in palliative care: treatment options and considerations for individual patient management.

Whole gut irrigation: a new treatment for constipation.

Current options for treatment of chronic coronary artery disease.

Therapeutic options for the treatment of chronic pain in dogs.

[Which treatment options are validated for chronic viral hepatitis?].

Update and insights into treatment options for chronic spontaneous urticaria.

Resisting resistance: Establishing new treatment options for CRPC patients.

Etiology and new treatment options for patients with plastic bronchitis.

Functional constipation in children: non-pharmacological approach.

New and Emerging Treatment Options for Irritable Bowel Syndrome.

New options for the adjuvant treatment of cutaneous melanoma?