title: The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome.
abstract: OBJECTIVE
  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.
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, Texas 77381, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Brown
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Drossman
authors.forename: Alastair J J
authors.initials: AJ
authors.lastname: Wood
authors.forename: Gary A
authors.initials: GA
authors.lastname: Cline
authors.forename: Kenny S
authors.initials: KS
authors.lastname: Frazier
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Jackson
authors.forename: Johanna
authors.initials: J
authors.lastname: Bronner
authors.forename: Joel
authors.initials: J
authors.lastname: Freiman
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.forename: Arthur
authors.initials: A
authors.lastname: Sands
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gershon
mesh_terms: D015746:Abdominal Pain / Q000209:etiology; D000328:Adult; D015415:Biomarkers / Q000652:urine; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003248:Constipation; D004311:Double-Blind Method; D005243:Feces; D005260:Female; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000652:urine*; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D010649:Phenylalanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012701:Serotonin / Q000096:biosynthesis*; D012720:Severity of Illness Index; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: C557875:2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3'-methoxybiphenyl-4-yl)ethoxy)-pyrimidin-4-yl)phenyl)propionic acid; D015415:Biomarkers; D001713:Biphenyl Compounds; D012701:Serotonin; D010649:Phenylalanine; D006897:Hydroxyindoleacetic Acid; D014365:Tryptophan Hydroxylase