Original ResearchClinical—Alimentary TractThe Tryptophan Hydroxylase Inhibitor LX1031 Shows Clinical Benefit in Patients With Nonconstipating Irritable Bowel Syndrome
Section snippets
Study Design
This phase 2 clinical trial was conducted as a multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study. Male and female patients 18 to 70 years of age with an established history of nonconstipating IBS (IBS-D and mixed-subtype IBS) based on ROME III criteria were recruited across 36 centers in the United States. Diagnostic criteria for nonconstipating IBS included symptom onset 6 months or more before study enrollment, with presence of abdominal pain or discomfort in
Study Population
Between December 2008 and September 2009 a total of 227 patients were screened for inclusion in the protocol; 155 met enrollment criteria and were randomized to study medication. Of these, 142 completed the study with 134 meeting the predefined requirements for inclusion in the per-protocol population (Figure 2). All sites were given the opportunity to participate in the biomarker substudy; 76 patients at 19 of 34 sites participated. Patients enrolled in the biomarker substudy were
Discussion
LX1031 was developed as an oral TPH inhibitor that acts locally on the GI mucosa, gaining access primarily to TPH in the intestinal lining and thereby inhibiting 5-HT synthesis in the GI epithelium. The favorable safety profile observed in this study may be related, in part, to its local site of action in the GI tract, ability to inhibit 5-HT synthesis at the level of the EC cell, and low degree of oral bioavailability and systemic exposure. This exploratory phase 2 study shows that LX1031 may
Conclusions
LX1031, a locally acting TPH inhibitor, appeared safe and well tolerated in this exploratory phase 2 study over 4 weeks in patients with symptomatic, nonconstipating IBS. Results suggest that reduction of mucosally derived 5-HT may positively influence symptoms common to nonconstipating IBS. Importantly, a relationship was observed between improvement in symptoms and a reduction in 24-hour urinary 5-HIAA, a biomarker that corresponds to the rate of 5-HT synthesis and the mechanism of action of
Acknowledgments
The authors thank Kristi A. Boehm, MS, from Lexicon Pharmaceuticals, Inc, for writing assistance.
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2020, Handbook of Behavioral NeuroscienceCitation Excerpt :These compounds decrease peripheral 5-HT via inhibition of TPH1 and they have been shown to oppose chemically-induced gut inflammation in mice (Margolis et al., 2016). They also provide gastrointestinal symptom relief in nonconstipating irritable bowel syndrome (Brown et al., 2011) as well as in carcinoid syndrome (Kulke et al., 2017; Pavel et al., 2015). A set of ursolic acid derivatives was synthesized by Fu et al. (2015) and these compounds significantly inhibited TPH1 mRNA and protein expression in RBL-2H3 cells.
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2020, Pharmacology and TherapeuticsCitation Excerpt :However, TPH inhibitors are not only effective in animals but also in patients. LX-1031 relieved the symptoms of diarrhea-predominant irritable bowel disease in patients in a phase-II clinical trial (Table 2) (Brown et al., 2011; Camilleri, 2011). Therefore, isoform-unspecific TPH inhibitors may be promising drugs for gastrointestinal diseases with an inflammatory component.
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2018, Trends in Pharmacological SciencesCitation Excerpt :Accordingly, Tph1−/− mice and animals treated with LP-920540 or telotristat ethyl are protected in several different colitis models, including necrotizing enterocolitis and colitis induced by oral dextran sulfate sodium administration or trinitrobenzene sulfate, as well as in an infection-induced intestinal inflammation model [68–72] (Table 1). Based on these results, a Phase II clinical trial with LX-1031 was performed in diarrhea-predominant IBS, and slight but significant symptom relief was achieved in the patients (Supplemental information online) [39,73]. Thus, TPH inhibitors may be promising drugs for the treatment of inflammatory bowel diseases.
Conflicts of interest These authors disclose the following: Phil Brown was an employee and is a stockholder of Lexicon Pharmaceuticals, Inc. Doug Drossman is a consultant to Prometheus, Lexicon, Takeda, and Astra Zeneca. Alastair Wood is a partner, investor, and shareholder in Symphony Capital, LLC. Gary Cline is an independent contractor with the Department of Biostatistics at Icon Clinical Research and provided statistical analysis of the clinical data discussed in this article. Kenny Frazier, Jessica Jackson, Johanna Bronner, Joel Freiman, Brian Zambrowicz, and Arthur Sands are employees and stockholders of Lexicon Pharmaceuticals, Inc. Michael Gershon is a consultant to Lexicon Pharmaceuticals, Inc.
Funding Lexicon Pharmaceuticals, Inc, and Symphony Icon provided the funding for the LX1031 clinical studies. The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and major secondary efficacy end points) and safety (specifically, serious adverse events as defined in federal guidelines) have been confirmed independently by a biostatistician who is not employed by the corporate entity.
The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis.