Resultados a largo plazo del tratamiento con linaclotida en el síndrome de intestino irritable tipo estreñimiento / Long-term results of linaclotide in the treatment of constipation-type irritable bowel syndrome

Antecedentes: el síndrome de intestino irritable tipo estreñimiento (SII-E) es una patología prevalente, compleja y multifactorial que representa un desafío tanto desde el punto de vista diagnóstico como terapéutico. Objetivo: evaluar la efectividad, seguridad y satisfacción de linaclotida en pacientes con SII-E. Métodos: estudio prospectivo, unicéntrico y observacional realizado en pacientes con diagnóstico de SII-E. Los pacientes recibieron tratamiento con linaclotida (Constella(r), Allergan Inc., Irvine, CA), 290 microgramos/24 horas, una cápsula 30 minutos antes del desayuno. La variable primaria de efectividad fue el número de deposiciones por semana. Las variables secundarias incluían el grado de satisfacción y el registro de la frecuencia e intensidad de los síntomas (dolor e hinchazón), medidos mediante una escala visual analógica (EVA) de once niveles (0-10), y recogidas mediante un diario que se entregó al paciente. Resultados: treinta pacientes, todas mujeres, fueron incluidas consecutivamente. La mediana del tiempo de seguimiento fue de 18 meses. La media (deviación estándar [DE]) de deposiciones por semana aumentó desde 0,9 (0,6) al inicio del estudio hasta 4,7 (3,7) al final del mismo (p < 0,0001). Resultados similares fueron observados con el dolor (5,7 [2,3] frente a 3,1 [2,8] al inicio y al final del estudio, respectivamente, p < 0,0001) y con la hinchazón (6,8 [1,6] frente a 2,9 [2,5] al inicio y final del estudio, respectivamente, p < 0,0001). El grado medio (DE) de satisfacción al final del estudio fue 6,7 (3,0). Conclusiones: el tratamiento con linaclotida en pacientes con SII-E en el entorno de la práctica clínica se ha mostrado eficaz y seguro a largo plazo

Background: constipation-predominant irritable bowel syndrome (C-IBS) is a prevalent, complex and multifactorial disorder that represents a challenge in terms of diagnosis and therapeutic management. Objective: to evaluate the effectiveness, safety and treatment satisfaction of linaclotide in C-IBS patients. Methods: prospective, single-center and observational study conducted in patients diagnosed with C-IBS. The patients were treated with linaclotide (Constella(r), Allergan Inc., Irvine, CA), once-daily via an oral capsule of 290-µg, 30 minutes before breakfast. The primary effectiveness endpoint was the number of bowel movements per week. The secondary endpoints included treatment satisfaction and changes from baseline in frequency and severity of symptoms (abdominal pain and bloating). This was assessed via an 11-point visual analog scale (VAS) reported by the patients in a daily register. Results: thirty female patients were consecutively included. The median follow-up time was 18 months. The mean (standard deviation [SD]) number of weekly bowel movements significantly increased from 0.9 (0.6) at baseline to 4.7 (3.9) at the end of follow-up, p < 0.0001. Abdominal pain significantly decreased from 5.7 (2.3) at baseline to 3.1 (2.8) at the end of the follow-up period, p < 0.0001. Similarly, bloating significantly decreased from 6.8 (1.6) to 2.9 (2.5) at the beginning and end of the treatment period, respectively, p < 0.0001. The mean (SD) degree of satisfaction at the end of the study was 6.7 (3.0). Conclusions: long-term linaclotide treatment in patients with C-IBS is effective and safe in the clinical setting

Treatment Algorithm for Chronic Idiopathic Constipation and Constipation-Predominant Irritable Bowel Syndrome Derived from a Canadian National Survey and Needs Assessment on Choices of Therapeutic Agents.

Background. Chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) are common functional lower gastrointestinal disorders that impair patients' quality of life. In a national survey, we aimed to evaluate (1) Canadian physician practice patterns in the utilization of therapeutic agents listed in the new ACG and AGA guidelines; (2) physicians satisfaction with these agents for their CIC and IBS-C patients; and (3) the usefulness of these new guidelines in their clinical practice. Methods. A 9-item questionnaire was sent to 350 Canadian specialists to evaluate their clinical practice for the management of CIC and IBS-C. Results. The response rate to the survey was 16% (n = 55). Almost all (96%) respondents followed a standard, stepwise approach for management while they believed that only 24% of referring physicians followed the same approach. Respondents found guanylyl cyclase C (GCC) agonist most satisfying when treating their patients. Among the 69% of respondents who were aware of published guidelines, only 50% found them helpful in prioritizing treatment choices and 69% of respondents indicated that a treatment algorithm, applicable to Canadian practice, would be valuable. Conclusion. Based on this needs assessment, a treatment algorithm was developed to provide clinical guidance in the management of IBS-C and CIC in Canada.

Clinical relevance of cyclic GMP modulators: A translational success story of network pharmacology.

Therapies that modulate cyclic guanosine-3'-5'-monophosphate (cGMP) have emerged as one of the most successful areas in recent drug discovery and clinical pharmacology. Historically, their focus has been on cardiovascular disease phenotypes; however, cGMP's relevance is likely to go beyond this rather limited organ-based set of indications. Moreover, the multitude of targets and their apparent interchangeability is a proof-of-concept of network pharmacology.

Guanylin-Guanylyl cyclase-C signaling in macrophages regulates mesenteric fat inflammation induced by high-fat diet.

Guanylin (Gn), a bioactive peptide, and its receptor, guanylyl cyclase-C (GC-C), are primarily present in the intestine and maintain homeostasis in body fluids. Recently, rats whose macrophages overexpress Gn and GC-C were found to be resistant to diet-induced obesity. Considering that obesity is strongly related to a chronic inflammatory state in white adipose tissues, it is possible that Gn-GC-C macrophages contribute to the regulation of inflammation. In the present study, we investigated the inflammatory state of mesenteric fat in rats transgenic for both Gn and GC-C (double-transgenic [dTg] rats) by evaluating the levels of cyclic guanosine monophosphate (cGMP), a second messenger of Gn-GC-C, cGMP-dependent protein kinase (PKG), and phosphorylated vasodilator-stimulated phosphoprotein (VASP), a target protein of PKG. The levels of cGMP in dTg rats was higher than in WT rats fed the same diet. Although there were no significant differences in levels of PKG and phosphorylated VASP between WT and dTg rats fed a standard diet (STD), these levels in dTg rats fed a high fat diet (HFD) were markedly increased compared with levels in HFD WT rats. Furthermore, mRNA levels of proinflammatory factors in mesenteric fat were lower in HFD dTg rats than in HFD WT rats and were similar to levels in STD WT and dTg rats. These results indicate that the Gn-GC-C system in macrophages regulates the cGMP-PKG-VASP pathway and controls obesity through the downregulation of proinflammatory factors.

Emerging treatments in Neurogastroenterology: Perspectives of guanylyl cyclase C agonists use in functional gastrointestinal disorders and inflammatory bowel diseases.

BACKGROUND: Functional gastrointestinal disorders (FGID) and inflammatory bowel diseases (IBD) are the most frequent pathologic conditions affecting the gastrointestinal (GI) tract and both significantly reduce patients' quality of life. Recent studies suggest that guanylyl cyclase C (GC-C) expressed in the GI tract constitutes a novel pharmacological target in the treatment of FGID and IBD. Endogenous GC-C agonists - guanylin peptides: guanylin and uroguanylin, by the regulation of water and electrolyte transport, are involved in the maintenance of homeostasis in the intestines and integrity of the intestinal mucosa. Linaclotide, a synthetic agonist of GC-C was approved by Food and Drug Administration and European Medicines Agency as a therapeutic in constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). Lately, several preclinical and clinical trials focused on assessment of therapeutic properties of synthetic agonists of uroguanylin, plecanatide, and SP-333. Plecanatide is currently tested as a potential therapeutic in diseases related to constipation and SP-333 is a promising drug in ulcerative colitis treatment. PURPOSE: Here, we discuss the most recent findings and future trends on the development of GC-C agonists and their use in clinical trials.

Translating colorectal cancer prevention through the guanylyl cyclase C signaling axis.

Colorectal cancer (CRC) is a major public health concern, ranking among the leading causes of cancer death in both men and women. Because of this continued burden there is a clear need for improved treatment, and more importantly prevention of this disease. In recent years there is significant evidence to support the hypothesis that guanylyl cyclase C (GCY2C) is a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor is an important step in the disease process. Thus, ligand replacement therapy has been proposed as a strategy to prevent CRC. Until recently this strategy was not clinically plausible; however, the recent regulatory approval of linaclotide (LINZESS™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.), an oral GUCY2C ligand, has raised the possibility of utilizing this strategy clinically to prevent CRC.

Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis.

Agonists of the transmembrane intestinal receptor guanylyl cyclase C (GCC) have recently attracted interest as promising human therapeutics. Peptide ligands that can specifically induce GCC signaling in the intestine include endogenous hormones guanylin and uroguanylin, diarrheagenic bacterial enterotoxins (ST), and synthetic drugs linaclotide, plecanatide, and SP-333. These agonists bind to GCC at intestinal epithelial surfaces and activate the receptor's intracellular catalytic domain, an event initiating discrete biological responses upon conversion of guanosine-5'-triphosphate to cyclic guanosine monophosphate. A principal action of GCC agonists in the colon is the promotion of mucosal homeostasis and its dependent barrier function. Herein, GCC agonists are being developed as new medications to treat inflammatory bowel diseases, pathological conditions characterized by mucosal barrier hyperpermeability, abnormal immune reactions, and chronic local inflammation. This review will present important concepts underlying the pharmacology and therapeutic utility of GCC agonists for patients with ulcerative colitis, one of the most prevalent inflammatory bowel disease disorders.

Constella™(EU)-Linzess™(USA): the last milestone in the long journey of the peptide linaclotide and its implications for the future of peptide drugs.

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are highly prevalent gastrointestinal disorders associated with health, economical and social problems. Recently, after a long journey of preclinical studies and clinical trials, linaclotide, a first-in-class GC-C receptor peptide agonist, has received the approval in the USA and Europe for the treatment of IBS-C and CIC. This article provides an overview of clinical, economic and biological aspects of IBS-C and CIC and covers the current and emerging therapeutic agents for treating these conditions. Particularly, the pharmacodynamic and pharmacokinetic properties of linaclotide, a small, disulfide-rich peptide, and its implications in the future of peptide drug discovery and development are discussed.

CD-NP: a novel engineered dual guanylyl cyclase activator with anti-fibrotic actions in the heart.

Natriuretic peptides (NPs) are cardioprotective through the activation of guanylyl cyclase (GC) receptors A and B. CD-NP, also known as cenderitide, is a novel engineered NP that was designed to uniquely serve as a first-in-class dual GC receptor agonist. Recognizing the aldosterone suppressing actions of GC-A activation and the potent inhibitory actions on collagen synthesis and fibroblast proliferation through GC-B activation, the current study was designed to establish the anti-fibrotic actions of CD-NP, administered subcutaneously, in an experimental rat model of early cardiac fibrosis induced by unilateral nephrectomy (UNX). Our results demonstrate that a two week subcutaneous infusion of CD-NP significantly suppresses left ventricular fibrosis and circulating aldosterone, while preserving both systolic and diastolic function, in UNX rats compared to vehicle treated UNX rats. Additionally we also confirmed, in vitro, that CD-NP significantly generates the second messenger, cGMP, through both the GC-A and GC-B receptors. Taken together, this novel dual GC receptor activator may represent an innovative anti-fibrotic therapeutic agent.

Linaclotide: first global approval.

Linaclotide is a once-daily, orally administered, first-in-class agonist of guanylate cyclase-C that is minimally absorbed. It is being developed to treat gastrointestinal disorders by Ironwood Pharmaceuticals and its partners, Forest Laboratories (North America), Almirall (Europe) and Astellas Pharma (Asia-Pacific). Linaclotide has received its first global approval in the US for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC), and a marketing submission has been filed in the EU for IBS-C. This article summarizes the milestones in the development of linaclotide leading to this first approval for IBS-C and CIC. This profile has been extracted and modified from the Adis R&D Insight drug pipeline database. Adis R&D Insight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch.

Two randomized trials of linaclotide for chronic constipation.

BACKGROUND: Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase C receptor. In two trials, we aimed to determine the efficacy and safety of linaclotide in patients with chronic constipation. METHODS: We conducted two randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials (Trials 303 and 01) involving 1276 patients with chronic constipation. Patients received either placebo or linaclotide, 145 µg or 290 µg, once daily for 12 weeks. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. Adverse events were also monitored. RESULTS: For Trials 303 and 01, respectively, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 µg of linaclotide and by 19.4% and 21.3% of the patients who received 290 µg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide with placebo). Improvements in all secondary end points were significantly greater in both linaclotide groups than in the placebo groups. The incidence of adverse events was similar among all study groups, with the exception of diarrhea, which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups. CONCLUSIONS: In these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation. Additional studies are needed to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation. (Funded by Ironwood Pharmaceuticals and Forest Research Institute; ClinicalTrials.gov numbers, NCT00765882 and NCT00730015.).

Linaclotide, a synthetic guanylate cyclase C agonist, for the treatment of functional gastrointestinal disorders associated with constipation.

Chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C) are two functional gastrointestinal disorders that are associated with constipation. CC and IBS-C affect approximately 20% of the general population including the elderly, impairing quality of life. Patients not responding to over-the-counter treatments require effective and safe long-term therapies. Some treatments introduced in the last decade have been associated with side effects that led to withdrawal from the US market (e.g., tegaserod) or intolerance to treatment (e.g., nausea in patients treated with lubiprostone). Linaclotide is a novel drug, with a unique mechanism of action, low bioavailability and local action in the intestinal epithelial cells. It is currently being developed for patients with CC and IBS-C. From animal studies to human pharmacodynamic Phase Ib trials, and a comprehensive program of Phase IIb and III trials in health and disease, linaclotide demonstrates long-term efficacy and safety in CC and IBS-C.

A guanosine 3',5'-cyclic monophosphate (cGMP) reporter system based on the G-kinase/CREB/CRE signal transduction pathway.

Guanylate cyclases constitute a gene family of enzymes that synthesize the second messenger guanosine 3',5'-cyclic monophosphate (cGMP) and play important roles in diverse physiological functions. Here we report a novel, simple and highly sensitive method for measurement intracellular cGMP concentrations using a cAMP-responsive element (CRE) and cGMP-dependent protein kinase (cGK). Transient transfection of the CRE reporter plasmid, encoding a luciferase reporter gene under the control of a modified promoter containing a CRE, and a cGK expression vector into HEK293 cells followed by treatment with 8-bromo-cGMP showed a dose dependent increase in luciferase activity. Moreover, HEK293 cells expressing GC-A or GC-B natriuretic peptide receptors and harboring this reporter system responded to specific ligands in a dose dependent manner. Our results indicate that this reporter gene method enables high throughput screening of receptor-type GC selective agonists in the treatment of cardiovascular diseases and homeostatic dysfunctions.

Emerging pharmacological therapies for the irritable bowel syndrome.

The irritable bowel syndrome (IBS) is a symptom-based disorder defined by the presence of abdominal pain and altered bowel habits. Clinical presentations of IBS are diverse, with some patients reporting diarrhea, some constipation, and others a mixture of both. Like the varied clinical phenotypes, the pathogenesis of IBS is also diverse. IBS is not a single disease entity, but rather likely consists of several different disease states. This fact has important implications for the choices and efficacy of IBS treatment. This article reviews the IBS drugs that have reached phase II or III clinical trials.

Investigational agents for the irritable bowel syndrome.

IMPORTANCE OF THE FIELD: Irritable bowel syndrome (IBS) is a common disorder with significant health and economic consequences. The etiology of IBS is complex and appears to be multifactorial. Traditional IBS therapies have been directed primarily at the relief of individual symptoms but have been largely disappointing. This has triggered the search for newer treatment strategies with improved patient outcomes. AREAS COVERED IN THIS REVIEW: Enhanced knowledge about the putative pathophysiology of IBS has allowed the identification of new mechanistic targets for treatment. Our aim is to review emerging and promising drugs in the treatment of IBS based on disease pathophysiology. Data were extracted using Medline and PubMed search engines until January 2010. Abstracts were identified through 'Web of Science' and abstract supplements of major gastrointestinal scientific meetings. Drugs were classified according to mechanism of action and those with efficacy in trials involving human subjects examined. WHAT THE READER WILL GAIN: Additional insight into the pathophysiology as well as current and prospective treatments of IBS. TAKE HOME MESSAGE: A multitude of putative drug targets have been identified and some novel treatments have progressed through to human clinical trials, but very few will be approved for the market in the near future. Moreover, and in keeping with the complex and multifactorial nature of this syndrome, it is unlikely that there will be one dominant and universally effective form of therapy for all IBS patients.

Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit.

Linaclotide is a first-in-class, orally administered 14-amino acid peptide that is in development for the treatment of irritable bowel syndrome with constipation and chronic constipation. We have characterized the solution structure of linaclotide, the in vitro binding and agonist activity to guanylate cyclase C receptors, the stability of linaclotide under conditions mimicking the gastric environment, oral bioavailability, and the pharmacodynamic effects in rat models of gastrointestinal transit and intestinal secretion. Nuclear magnetic resonance spectroscopy analysis determined that the molecular structure of linaclotide is stabilized by three intramolecular disulfide bridges. Linaclotide exhibited high affinity and pH-independent binding (K(i): 1.23-1.64 nM) to guanylate cyclase C receptors on human colon carcinoma T84 cells and concomitantly, linaclotide binding resulted in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3', 5'-monophosphate (cGMP) (EC50:99 nM). Linaclotide was stable after 3 h incubation in simulated gastric fluid (pH 1) and similarly, was completely resistant to hydrolysis by pepsin. Pharmacokinetic analysis of linaclotide showed very low oral bioavailability (0.1%). Orally administered linaclotide elicited a significant, dose-dependent increase in gastrointestinal transit rates in rats at doses of ≥5 µg/kg. Exposure of surgically ligated small intestinal loops to linaclotide induced a significant increase in fluid secretion, accompanied by a significant increase in intraluminal cGMP levels. These results suggest that the guanylate cyclase C agonist linaclotide elicits potent pharmacological responses locally in the gastrointestinal tract, and that orally administered guanylate cyclase C agonists may be capable of improving bowel habits in patients suffering from irritable bowel syndrome with constipation and chronic constipation.

[New drugs for the treatment of constipation]. / Neue medikamente zur behandlung der obstipation.

This review introduces new therapeutic options in the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. Therefore, prucalopride and lubiprostone are discussed including their mechanisms and side effects. In addition, other substances that are currently under evaluation such as renzapride and linaclotide are described, since recent results showed a significant effect in patients with constipation. Thus, after the withdrawal of tegaserod due to cardiac side effects, new potent drugs are now available for the treatment of constipation.