FDA may be in a position in 2015 to approve two new treatments for diarrhea-predominant irritable bowel syndrome, potentially tripling the number of drugs indicated for the condition.

On Sept. 2, both Salix Pharmaceuticals Ltd. and Allergan PLC announced they have applications pending at FDA for drugs intended to treat irritable bowel syndrome with diarrhea (IBS-D).

Salix is making a second bid to add an IBS-D treatment claim for its antibacterial Xifaxan (rifaximin). On Aug. 29 it resubmitted an sNDA with data from the Phase III TARGET 3 trial that was conducted at FDA’s request to evaluate the efficacy and safety of repeated courses of treatment with rifaximin.

Salix is expecting a six-month review of the supplemental application, which would place it roughly in line with the estimated user fee date for Actavis’ eluxadoline.

Actavis announced that FDA had accepted the eluxadoline NDA and designated it for priority review, which translates into a six-month review following the two-month filing period for the new molecular entity. However, Actavis is expecting the timeline to be extended by three months, which would appear to put its PDUFA data behind that of rifaximin.

The IBS-D category represents an area of unmet need but has been a challenging space for drug development Also see "IBS-D Lead May Go To Tioga With Salix Required To Run Another Trial" - Pink Sheet, 22 August, 2011..

IBS-D affects approximately 15 million patients in the U.S., according to Actavis.

The only prescription drug currently approved for IBS-D is Prometheus Laboratories Inc.Lotronex (alosetron), a selective serotonin 5-HT3 antagonist. However, the drug’s availability is highly restricted under a Risk Evaluation and Mitigation Strategy due to the risks of ischemic colitis and constipation-related complications ([A#14130710010]).

‘Complete Response’ Leads To TARGET 3

Xifaxan was first approved in 2004 for treatment of patients 12 years and older with travelers' diarrhea caused by noninvasive strains of Escherichia coli. In March 2010 FDA approved a higher dose (550 mg) for reduction in the risk of overt hepatic encephalopathy recurrence in patients 18 years and older.

Salix’s original sNDA for treatment of non-constipation IBS and IBS-related bloating was based on data from two identically designed, double-blind, placebo-controlled trials that examined efficacy of a 14-day course of Xifaxan 550 mg taken three times daily. Patients were followed for 10 weeks after treatment.

FDA issued a “complete response” letter in March 2011 which Salix attributed to the agency’s “newly expressed need for retreatment information” Also see "Salix Tumbles With Expected "Complete Response" Letter On Xifaxan In IBS" - Pink Sheet, 24 February, 2011..

The agency’s letter cited inadequate data to support repeated courses of treatment in a chronic condition. FDA also raised questions about the patient population most likely to benefit and the potential for bacterial resistance Also see "Panel To Help Define Target Population For Xifaxan Reuse In IBS-D" - Pink Sheet, 14 November, 2011..

In August 2011, Salix announced that it would conduct an additional Phase III trial. FDA convened its Gastrointestinal Drugs Advisory Committee in November 2011 to discuss Salix’ proposed design for a trial to assess short-term treatment of symptomatic recurrence of IBS-D.

The majority of committee members said Salix’s proposed trial was capable of assessing the effects of repeated courses of treatment ([A#14111116009]). Some committee members also recommended that a new study include data collection on duration of symptom relief Also see "Data On Length Of Symptom Relief Could Improve Xifaxan Trial, Panel Members Suggest" - Pink Sheet, 28 November, 2011..

In a June 2012 final guidance, FDA said IBS clinical trials should be designed to demonstrate short-term benefit as well as efficacy in the maintenance and retreatment settings Also see "IBS Trials Should Gauge Efficacy In Maintenance And Retreatment, FDA Says" - Pink Sheet, 11 June, 2012..

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

IBS-D subjects who responded to initial treatment were followed until symptom recurrence, at which time they underwent double-blind randomization to either another 14-day course of rifaximin or placebo. Subjects continued to be followed to assess durability of response and underwent an additional course of previously assigned double-blind therapy.

The primary endpoint was the proportion of subjects who responded to repeat treatment in both IBS-related abdominal pain and stool consistency during the four-week, treatment-free follow-up period in the double-blind repeat treatment phase.

In total, 636 subjects were randomized into the study’s double-blind retreatment phase.

On July 1, Salix announced that a statistically significant greater proportion of rifaximin-treated subjects compared to placebo subjects responded to repeat treatment as assessed by the composite primary endpoint. The press release announcing the top-line results for the primary endpoint did not provide any specifics in terms of response rates or p-values.

On Aug. 11, Salix announced statistically significant results for two key secondary endpoints that evaluated symptom relief and avoidance of symptom recurrence.

“Overall, the data demonstrate that efficacy is maintained following repeat treatment with rifaximin for up to three treatment cycles in subjects with IBS-D, with no evidence of significant effects on pathogen emergence, pathogen susceptibility or the general microbial population in stool or skin swab samples,” the company said.

A Dual Opioid Receptor Approach

Eluxadoline is a combined mu opioid receptor agonist and delta opioid receptor antagonist that acts locally in the GI tract and has low systemic absorption and bioavailability. The dual opioid activity is designed to treat IBS-D symptoms while reducing the incidence of constipation that can occur with unopposed mu opioid receptor agonists, according to Actavis.

The drug was developed by Furiex Pharmaceuticals Inc.,which was acquired by Actavis through the latter’s merger with Forest Laboratories Inc. ([A#14140429003]).

The eluxadoline NDA submission is based on two Phase III trials in which efficacy of both the 75 mg and 100 mg doses was demonstrated over placebo on the composite endpoint of simultaneous improvement in pain and diarrhea over 12 weeks Also see "Furiex Makes Inroads In Tough-To-Treat IBS-d With Positive Phase III Eluxadoline Data" - Pink Sheet, 4 February, 2014..

Actavis said that pursuant to pre-NDA discussions with the agency, it is planning to submit an amendment with additional data from a study that was ongoing at the time of submission. This is expected to result in a three-month extension that will push the user fee date into the second quarter of 2015.

Irritable Bowel Drugs From Salix, Actavis Await FDA Action In 2015

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