Gastroenterology

Gastroenterology

Volume 141, Issue 2, August 2011, Pages 507-516
Gastroenterology

Original Research
Clinical—Alimentary Tract
The Tryptophan Hydroxylase Inhibitor LX1031 Shows Clinical Benefit in Patients With Nonconstipating Irritable Bowel Syndrome

https://doi.org/10.1053/j.gastro.2011.05.005Get rights and content

Background & Aims

Serotonin (5-hydroxytryptamine [5-HT]) has an important role in gastrointestinal function. LX1031 is an oral, locally acting, small molecule inhibitor of tryptophan hydroxylase (TPH). Local inhibition of TPH in the gastrointestinal tract might reduce mucosal production of serotonin (5-HT) and be used to treat patients with nonconstipating irritable bowel syndrome (IBS).

Methods

We evaluated 2 dose levels of LX1031 (250 mg or 1000 mg, given 4 times/day) in a 28-day, multicenter, randomized, double-blind, placebo-controlled study of 155 patients with nonconstipating IBS. 5-hydroxyindoleacetic acid (5-HIAA), a biomarker of pharmacodynamic activity, was measured in urine samples at baseline (24 hours after LX1031 administration), and at weeks 4 and 6 (n = 76).

Results

Each dose of LX1031 was safe and well-tolerated. The primary efficacy end point, relief of IBS pain and discomfort, improved significantly in patients given 1000 mg LX1031 (25.5%), compared with those given placebo, at week 1 (P = .018); with nonsignificant improvements at weeks 2, 3, and 4 (17.9%, 16.3%, and 11.6%, respectively). Symptom improvement correlated with a dose-dependent reduction in 5-HIAA, a marker for TPH inhibition, from baseline until week 4. This suggests the efficacy of LX1031 is related to the extent of inhibition of 5-HT biosynthesis. Stool consistency significantly improved, compared with the group given placebo, at weeks 1 and 4 (P < .01) and at week 2 (P < .001).

Conclusions

In a phase 2 study, LX1031 was well tolerated, relieving symptoms and increasing stool consistency in patients with nonconstipating IBS. Symptom relief was associated with reduced levels of 5-HIAA in urine samples. This marker might be used to identify patients with nonconstipating IBS who respond to inhibitors of 5-HT synthesis.

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.

References (60)

  • S.P. Dunlop et al.

    Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome

    Clin Gastroenterol Hepatol

    (2005)
  • M.D. Coates et al.

    Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and IBS

    Gastroenterology

    (2004)
  • M. Camilleri et al.

    Alterations in expression of p11 and SERT in mucosal biopsy specimens of subjects with irritable bowel syndrome

    Gastroenterology

    (2007)
  • R. Rahimi et al.

    Efficacy and tolerability of alosetron for the treatment of irritable bowel syndrome in women and men: a meta-analysis of eight randomized, placebo-controlled, 12-week trials

    Clin Ther

    (2008)
  • T. Lembo et al.

    Alosetron controls bowel urgency and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome

    Am J Gastroenterol

    (2001)
  • O. Grundmann et al.

    Irritable bowel syndrome: epidemiology, diagnosis and treatment: an update for health-care practitioners

    J Gastroenterol Hepatol

    (2010)
  • M. Camilleri

    Evolving concepts of the pathogenesis of irritable bowel syndrome: to treat the brain or the gut?

    J Pediatr Gastroenterol Nutr

    (2009)
  • B.M. Spiegel

    The burden of IBS: looking at metrics

    Curr Gastroenterol Rep

    (2009)
  • S. Maxion-Bergemann et al.

    Costs of irritable bowel syndrome in the UK and US

    Pharmacoeconomics

    (2006)
  • M.J. Ten Berg et al.

    Quality of life of subjects with irritable bowel syndrome is low compared to others with chronic diseases

    Eur J Gastroenterol Hepatol

    (2006)
  • D.A. Drossman et al.

    International survey of patients with IBS: symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit

    J Clin Gastroenterol

    (2009)
  • E. Corazziari et al.

    The functional gastrointestinal disorders and the Rome III process

  • D.A. Drossman

    IntroductionThe Rome foundation and Rome III

    Neurogastroenterol Motil

    (2007)
  • S.D. Dorn et al.

    Irritable bowel syndrome subtypes defined by Rome II and Rome III criteria are similar

    J Clin Gastroenterol

    (2009)
  • H. Hasegawa et al.

    Intracellular metabolism of biogenic amines in paraneurons

    Arch Histol Cytol

    (1989)
  • V. Erspamer

    Occurrence of indolealkylamines in nature

  • M. Vialli

    Histology of the enterochromaffin cell system

  • M.D. Gershon

    Enteric serotonergic neurones…finally!

    J Physiol

    (2009)
  • K.B. Neal et al.

    Strain-specific genetics, anatomy and function of enteric neural serotonergic pathways in inbred mice

    J Physiol

    (2009)
  • B.K. Koe et al.

    p-Chlorophenylalanine: a specific depletor of brain serotonin

    J Pharmacol Exp Ther

    (1966)
  • Cited by (88)

    • The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis

      2021, The Lancet Gastroenterology and Hepatology
      Citation Excerpt :

      The risk of bias was assessed for each study and 11 articles21–31 were excluded because of a high risk for bias. 73 randomised controlled trials, described in 70 articles,32–101 were included in the meta-analysis. Detailed characteristics of individual trials are provided in the appendix (pp 2–4).

    • The role of serotonin and its pathways in gastrointestinal disorders

      2021, The Complex Interplay Between Gut-Brain, Gut-Liver, and Liver-Brain Axes
    • Tryptophan hydroxylase and serotonin synthesis regulation

      2020, Handbook of Behavioral Neuroscience
      Citation 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.

    • Inhibition of serotonin synthesis: A novel therapeutic paradigm

      2020, Pharmacology and Therapeutics
      Citation 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.

    • Peripheral Serotonin Synthesis as a New Drug Target

      2018, Trends in Pharmacological Sciences
      Citation 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.

    View all citing articles on Scopus

    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.

    View full text