Major Finding: LX1031 is a novel, orally administered serotonin synthesis inhibitor that produced a statistically significant improvement in IBS symptoms over a 4-week period in patients with nonconstipating IBS. There was a significant correlation between percent reduction in urinary 5-HIAA and global response, with the best responders to high-dose LX1031 showing at least a 15% reduction in 5-HIAA.
Data Source: A randomized, double-blind, placebo-controlled trial of 134 patients.
Disclosures: Lexicon Pharmaceuticals Inc. supported the study.
BOSTON – LX1031, a novel, orally administered serotonin synthesis inhibitor, significantly improved overall irritable bowel syndrome symptoms in patients with nonconstipating IBS during a 4-week treatment period.
LX1031 is an investigational agent. The global response and improvement in stool form were significantly correlated with serotonergic inhibition, as indicated by the reduction of urinary levels of the serotonin metabolite 5-HIAA. Symptom improvement was greatest for those receiving high-dose LX1031 who had at least a 15% reduction in 5-HIAA levels, according to Dr. Joel P. Freiman, who presented the findings at the meeting.
“LX1031 acts locally on enterochromaffin cells in the GI tract to inhibit tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin,” explained Dr. Freiman, senior medical director of drug safety for Lexicon Pharmaceuticals Inc., manufacturer of LX1031.
“Reducing enteric 5-HT production via inhibition of TPH represents a mechanistically novel approach to the management of IBS symptoms,” he said.
In a randomized, double-blind, placebo-controlled trial, patients with nonconstipating IBS were treated with low-dose LX1031 (250 mg q.i.d., 44 patients), high-dose LX1031 (1,000 mg q.i.d., 43 patients), or placebo (47 patients) for 28 days. The average age of participants was 48 years, and 84% were female.
At the 1,000-mg dose, patients reported “adequate relief from pain and discomfort” within 2 weeks at significantly greater levels than those reported by patients who received placebo, and this benefit was sustained through the fourth week of treatment (P = .046).
After 4 weeks of treatment, the urinary 5-HIAA level was reduced 31.4%, compared with those receiving placebo. The percentage change in urinary 5-HIAA over the 4-week treatment period was significantly correlated with the global response.
To further explore the link between response to LX1031 and serotonin inhibition, the researchers conducted a post hoc subset analysis on data from 24 patients who had received high-dose LX1031. The investigators used a 15% reduction from baseline in urinary 5-HIAA levels as the cut-off and found that 15 patients had a greater than 15% reduction while 9 patients had a smaller than 15% reduction.
The investigators also found that 73% of those in the greater than 15% reduction group reported adequate symptom relief (the high-responder group), compared with 11% of those who had a less than 15% reduction (the low-responder group).
The high responders reported significantly better scores regarding stool consistency and global improvement and trends toward better outcomes regarding measures such as pain, urgency, and bloating than did the low responders.
“Urinary 5-HIAA levels may be a biomarker that will serve as a potential guide to IBS therapy,” Dr. Freiman commented.
He added that studies are planned to prospectively determine whether measuring changes in urinary 5-HIAA can predict which patients will respond best to LX1031.
Regarding safety and tolerability, most adverse events were mild, self-limited, and equally distributed among all the groups, Dr. Freiman said at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.
The most common adverse events were nausea, diarrhea, vomiting, and headache. There was one serious adverse event, supraventricular tachycardia, that was thought to be unrelated to the study medication. Thirteen patients discontinued the medication, and of those, seven discontinued because of adverse events (one in the placebo group, four in the low-dose group, and two in the high-dose group).