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Company Responds to FDA’s Concerns About Rifaximin (Xifaxan) for Repeat Treatment of IBS With Diarrhea

Phase III trial finds significantly greater symptom relief versus placebo

Salix Pharmaceuticals, Ltd., has responded to a complete response letter (CRL) from the FDA regarding the company’s supplemental new drug application for rifaximin (Xifaxan) 550-mg tablets for the proposed indication of the treatment of irritable bowel syndrome with diarrhea (IBS-D).

During its original review, the FDA determined that it was important in a chronic condition such as IBS to have information about how a product that is intended for short-course administration should be administered beyond the first cycle of use once symptoms reappear. In addition, the FDA determined that patients and their health care providers should have information on the safety and effectiveness of the retreatment.

The FDA conveyed this information to Salix in a CRL issued on March 7, 2011. Over the subsequent years, Salix worked with the agency to develop a study protocol (TARGET 3) intended to collect prospective controlled data to support repeat treatment with rifaximin in order to obtain adequate information for product labeling to guide patients and their health care providers on how to safely and most effectively administer repeat treatment of rifaximin in patients with IBS. This collaboration with the FDA included a public meeting with the agency’s Gastrointestinal Drugs Advisory Committee on November 16, 2011.

In February 2012, Salix initiated the phase III TARGET 3 study to evaluate the efficacy and safety of repeat treatment with rifaximin 550 mg three times daily (TID) for 14 days in subjects with IBS-D who had responded to an initial treatment course with rifaximin 550 mg TID for 14 days.

The study screened subjects with IBS-D; treated them with rifaximin; and followed those who responded to this initial course of therapy until their symptoms recurred, at which time they underwent double-blind randomization to either another course of rifaximin 550 mg TID for 14 days or matching placebo. In addition, the subjects continued to be followed to assess the durability of their response and underwent an additional course of previously assigned double-blind therapy.

The study’s primary endpoint was the proportion of subjects who responded to repeat treatment in both IBS-related abdominal pain and stool consistency during the 4-week treatment-free follow-up period (the primary evaluation period) in the double-blind repeat treatment phase compared with the placebo-treated group. Safety assessments included an evaluation for resistance and changes in the gut microbiome.

Enrollment in the double-blind portion of the TARGET 3 trial was completed in January 2014. The study randomly assigned 636 adults with IBS-D to the double-blind retreatment phase.

On August 11, 2014, Salix reported that a significantly greater proportion of rifaximin- treated subjects (compared with placebo-treated subjects) experienced symptom relief during the primary evaluation period in the first repeat treatment phase. They also avoided subsequent symptom recurrence (in subjects with symptom relief) during the study’s double-blind phase (a key secondary efficacy endpoint) and during the first double-blind repeat treatment and follow-up (another key secondary efficacy endpoint).

An analysis of the effects of rifaximin on the microbiome found no disturbance of fecal microbiota in subjects taking repeat courses of rifaximin compared with subjects taking a single course of rifaximin followed by placebo for the remainder of the trial. In addition, results of culture and susceptibility testing demonstrated no evidence of cross-resistance to non-rifamycin antibiotics in isolates grown from either stool or skin-swab cultures. Importantly, repeat treatment courses of rifaximin did not appear to predispose patients to the emergence of potentially pathogenic bacteria in the stool or on the skin.

Xifaxan (rifaximin) is currently indicated to reduce the risk of overt hepatic encephalopathy recurrence in adults (18 years of age or older).

Source: Salix Pharmaceuticals; September 2, 2014.

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