Pharmacologic Properties, Metabolism, and Disposition of Linaclotide, a Novel Therapeutic Peptide Approved for the Treatment of Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation

Busby, Robert; Kessler, Marco M.; Bartolini, Wilmin; Bryant, Alexander P.; Hannig, Gerhard; Higgins, Carolyn S.; Solinga, Robert; Tobin, Jenny; Wakefield, James; Kurtz, Caroline B.; Currie, Mark G.

doi:10.1124/jpet.112.199430

Cited by 112 publications

(161 citation statements)

References 33 publications

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“…In its current formulation, only ~1–3% of orally administered linaclotide or its active metabolite is recovered in stool. (16) The present study examined whether sufficient concentrations of the orally administered peptide can successfully engage GUCY2C in epithelial cells of the colon and rectum, key targets for chemoprevention. The study comprised three stages (Fig.…”

Section: Methodsmentioning

confidence: 99%

Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention

Weinberg

Lin

Foster

et al. 2017

Cancer Prevention Research

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Guanylate cyclase C (GUCY2C) is a tumor suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of 0.87 milligrams of oral linaclotide daily for 7 days to healthy volunteers, after oral colon preparation with polyethylene glycol solution (MoviPrep), activates GUCY2C, resulting in accumulation of its product cyclic (c)GMP in epithelial cells of the cecum, transverse colon, and distal rectum. GUCY2C activation by oral linaclotide was associated with homeostatic signaling, including phosphorylation of vasodilator-stimulated phosphoprotein and inhibition of proliferation quantified by reduced Ki67-positive epithelial cells. In the absence of the complete oral colonoscopy preparation, linaclotide did not alter cGMP production in epithelial cells of the colorectum, demonstrating that there was an effect related to the laxative preparation. These data show that the current FDA-approved formulation of oral linaclotide developed for small bowel delivery to treat chronic idiopathic constipation is inadequate for reliably regulating GUCY2C in the colorectum to prevent tumorigenesis. The study results highlight the importance of developing a novel GUCY2C agonist formulated for release and activity targeted to the large intestine for colorectal cancer prevention.

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Section: Methodsmentioning

confidence: 99%

Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention

Weinberg

Lin

Foster

et al. 2017

Cancer Prevention Research

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“…In that regard, linaclotide is activated in the acidic environment of the stomach and has its primary effect on secretion in the duodenum. Indeed, ,3% of oral linaclotide can be recovered in evacuated stool (Busby et al, 2013), suggesting that exposure in the colorectum might be limited. Thus, proof-of-concept trials have been initiated to define the ability of once daily oral linaclotide to activate GUCY2C, induce cGMP signaling, and regulate homeostatic pathways, including epithelial cell proliferation, across the rostral-caudal axis of the colorectum in normal healthy volunteers (ClinicalTrials.gov Identifier: NCT01950403).…”

Section: Translation Of Gucy2c-targeted Chemoprevention For Colorectamentioning

confidence: 99%

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

et al. 2016

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Obesity has emerged as a principal cause of mortality worldwide, reflecting comorbidities including cancer risk, particularly in colorectum. Although this relationship is established epidemiologically, molecular mechanisms linking colorectal cancer and obesity continue to be refined. Guanylyl cyclase C (GUCY2C), a membrane-bound guanylyl cyclase expressed in intestinal epithelial cells, binds the paracrine hormones guanylin and uroguanylin, inducing cGMP signaling in colorectum and small intestine, respectively. Guanylin is the most commonly lost gene product in sporadic colorectal cancer, and its universal loss early in transformation silences GUCY2C, a tumor suppressor, disrupting epithelial homeostasis underlying tumorigenesis. In small intestine, eating induces endocrine secretion of uroguanylin, the afferent limb of a novel gut-brain axis that activates hypothalamic GUCY2C-cGMP signaling mediating satiety opposing obesity. Recent studies revealed that dietinduced obesity suppressed guanylin and uroguanylin expression in mice and humans. Hormone loss reflects reversible calorieinduced endoplasmic reticulum stress and the associated unfolded protein response, rather than the endocrine, adipokine, or inflammatory milieu of obesity. Loss of intestinal uroguanylin secretion silences the hypothalamic GUCY2C endocrine axis, creating a feed-forward loop contributing to hyperphagia in obesity. Importantly, calorie-induced guanylin loss silences the GUCY2C-cGMP paracrine axis underlying obesity-induced epithelial dysfunction and colorectal tumorigenesis. Indeed, genetically enforced guanylin replacement eliminated diet-induced intestinal tumorigenesis in mice. Taken together, these observations suggest that GUCY2C hormone axes are at the intersection of obesity and colorectal cancer. Moreover, they suggest that hormone replacement that restores GUCY2C signaling may be a novel therapeutic paradigm to prevent both hyperphagia and intestinal tumorigenesis in obesity.

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“…Several examples exist where disulfide bonded peptides have increased stability to proteolysis and are stable enough for oral delivery including linaclotide, cyclosporine, and desmopressin (56)(57)(58).…”

Section: Proteolytic Degradation and Hydrolysismentioning

confidence: 99%

Early Engineering Approaches to Improve Peptide Developability and Manufacturability

Furman

Chiu

Hunter

2014

AAPS J

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Abstract. Downstream success in Pharmaceutical Development requires thoughtful molecule design early in the lifetime of any potential therapeutic. Most therapeutic monoclonal antibodies are quite similar with respect to their developability properties. However, the properties of therapeutic peptides tend to be as diverse as the molecules themselves. Analysis of the primary sequence reveals sites of potential adverse posttranslational modifications including asparagine deamidation, aspartic acid isomerization, methionine, tryptophan, and cysteine oxidation and, potentially, chemical and proteolytic degradation liabilities that can impact the developability and manufacturability of a potential therapeutic peptide. Assessing these liabilities, both biophysically and functionally, early in a molecule's lifetime can drive a more effective path forward in the drug discovery process. In addition to these potential liabilities, more complex peptides that contain multiple disulfide bonds can pose particular challenges with respect to production and manufacturability. Approaches to reducing the disulfide bond complexity of these peptides are often explored with mixed success. Proteolytic degradation is a major contributor to decreased half-life and efficacy. Addressing this aspect of peptide stability early in the discovery process increases downstream success. We will address aspects of peptide sequence analysis, molecule complexity, developability analysis, and manufacturing routes that drive the decision making processes during peptide therapeutic development.

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Pharmacologic Properties, Metabolism, and Disposition of Linaclotide, a Novel Therapeutic Peptide Approved for the Treatment of Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation

Cited by 112 publications

References 33 publications

Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention

Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

Early Engineering Approaches to Improve Peptide Developability and Manufacturability

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