By Schonfeld, Amy
Clinical Psychiatry News , Vol. 38, No. 12
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 mgq.i.d., 44 patients), high-dose LX1031 (1,000 mgq.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. …