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Salix unveils encouraging results from Phase III trial of Xifaxan 550 mg in irritable bowel syndrome with diarrhoea
22 October 2014 - 22 October 2014 - US Salix Pharmaceuticals (NASDAQ:SLXP) disclosed Tuesday that Dr. Anthony Lembo of Beth Israel Deaconess Medical Center will present positive results from a Phase III trial of Xifaxan (rifaximin) 550 mg in patients with irritable bowel syndrome with diarrhoea (IBS-D) at the American College of Gastroenterology meeting.

The trial, dubbed TARGET 3 (T–Targeted, nonsystemic; A–Antibiotic; R–Rifaximin; G–Gut–selective; E–Evaluation of; T–Treatment for non–C IBS) recruited patients with IBS-D (Rome III criteria) who presented with severity scores of ≥ 3 for IBS-related abdominal pain (scale 0-10) and severity score of ≥ 3 for IBS-related bloating (scale 0-6), and experienced ≥ two days of stools with Bristol Stool Scale (BSS) Type 6 (loose) or 7 (watery) during the seven-day baseline before the open-label phase of the trial.

The trial was designed with both an open-label and a double-blind phase.

During the first phase of the trial, all patients were treated with rifaximin 550 mg three times a day for two weeks, followed by a four-week treatment-free follow-up period to evaluate response to treatment. Adequate relief was defined as the proportion of patients who responded during ≥ two of four weeks for both abdominal pain (≥30% decrease from baseline in mean weekly pain score) and stool consistency (≥50% decrease from baseline in number of days/week with BSS Type 6 or 7).

Patients responding to therapy during the initial phase of the trial were subsequently followed until they experienced recurrence of symptoms (up to 18 additional weeks). Participants in the trial who experienced recurrence (based on abdominal pain or stool consistency) were randomised to a double-blind, placebo-controlled, repeat treatments phase. Patients were retreated with rifaximin 550 mg three times a day or placebo for two weeks, followed by a four-week treatment-free follow-up evaluation period. Patients received an additional course of double-blind treatment 10 weeks after the first double-blind treatment.

A total of 42% (n=1074 of 2579) of IBS-D patients were considered responders from a two week treatment course of rifaximin 550 mg at the end of the four-week treatment free follow-up period following the open-label phase. Of the 1074 patients who responded to rifaximin 550 mg, 36% (n=382) did not experience recurrent IBS-D symptoms when followed for up to 18 weeks following the initial two week treatment.

Of 692 patients who experienced recurrent IBS-D symptoms, 636 (mean age 46.8 years, 69% female) were randomised to receive rifaximin 550 mg TID (n=328) or placebo (n=308). Notably, the 636 patients entered into the double-blind phase presented with a lesser degree of symptom severity than at study entry for both abdominal pain and stool consistency.

The trial's primary goal, based on abdominal pain or stool consistency, compared the proportion of responders between the rifaximin 550 mg repeat treatment and placebo group and significantly favoured rifaximin 550 mg repeat treatment (33% versus 25%, p=0.02). Throughout the second double-blind repeat treatment phase, the percentage of responders was again statistically significant for rifaximin 550 mg against placebo-treated patients (37% versus 29%, p=0.04). Side effects were reported in 43% and 46% of patients treated with rifaximin 550 mg and placebo, respectively.

Two methods were used to assess the effects of rifaximin 550 mg on the gut microbiota in TARGET 3: traditional culture techniques and next-generation gene sequencing of stool samples collected from about 100 randomly selected particiants in the study. The analysis of the effects of rifaximin 550 mg on the microbiome, culture and susceptibility on the gut microbiota showed no evidence of bacterial sensitivity to other antibiotic classes, significant effects on pathogen emergence, pathogen susceptibility, or the general microbial population when compared to a single course of rifaximin 550 mg.

As Dr. Anthony Lembo, lead investigator of the study, explained, IBS-D is a chronic condition which can significantly affect patients' overall health and daily activities. Reliable symptom management may help patients return to a more normal lifestyle, he noted. The TARGET 3 trial results are promising because they demonstrate that repeat treatment courses of rifaximin 550 mg are efficacious and provide durability in symptom relief, Lembo added.

Dr. William Forbes, executive vice president, Medical, Research and Development, and chief development officer of Salix Pharmaceuticals, voiced the company's belief that TARGET 3 provides compelling data about the reproducibility and durability of the symptomatic relief provided by a short-course of therapy with rifaximin 550 mg. Forbes added that Salix trusts that TARGET 3 should provide adequate information for the basis of the product labelling used to guide patients and their health care providers on how to administer repeat courses of rifaximin in patients with recurrence of their symptoms.

Rifaximin 550 mg is a nonsystemic antibiotic which does not enter the bloodstream. It works locally in the gut. Rifaximin is currently not cleared for use in IBS-D. The therapy is being reviewed by the US FDA. A prescription drug user fee goal date (PDUFA) of February 28, 2015 has been designated following Salix's August 29, 2014 response to the FDA's March 7, 2011 Complete Response Letter.
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