COMMENTARY

Rifaximin for IBS: Where Do We Stand?

David A. Johnson, MD

Disclosures

May 27, 2015

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Rifaximin for Diarrhea-Predominant Irritable Bowel Syndrome

I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. A new treatment was recently approved by the US Food and Drug Administration (FDA) for irritable bowel syndrome (IBS). The diagnosis of IBS is something we wrestle with in clinical practice on a regular basis. It's an extremely common disorder. The pathophysiology is heterogeneous, but a lot of attention has been focused on bacteria and microflora playing a significant role in the pathogenesis of many of the symptoms—abdominal pain, diarrhea, and bloating.

TARGET 1 and 2

The idea of changing the gut microbiome with antibiotics has been very attractive, with the initial studies looking at the use of a nonsystemic antibiotic, rifaximin (Xifaxan®). Several studies have looked at this. There were three randomized controlled trials, two of which were combined in a very pivotal study that was reported by Mark Pimentel and his colleagues[1] in 2011 in the New England Journal of Medicine.

These were the TARGET (Targeted non-systemic Antibiotic Rifaximin Gut selective Evaluation Treatment of non-constipated IBS) 1 and 2 studies, in which approximately 1200 patients were randomly assigned to receive rifaximin 550 mg three times daily vs placebo.

TARGET 1 and 2 showed very promising results after a 2-week course of rifaximin 550 mg three times daily. The 10-week follow-up showed a global risk reduction of about 9% and a number-needed-to-treat (NNT) of 9-10. These findings have been remarkably consistent with the results of other rifaximin trials.[2,3,4] Another randomized controlled phase 2 trial was published earlier.[5]

TARGET 3: Addressing FDA Concerns

Nonetheless, the FDA had concerns about a drug, especially an antibiotic, being used in patients with longstanding clinical profiles that are subject to multiple relapses. Certainly the safety and efficacy were interesting in the short term, but the long-term follow-up, the durability of effect, and the implications of using an antibiotic caused the FDA to not approve rifaximin in 2011.

The company then met with the FDA and put together a third trial, called TARGET 3. This was reported by Tony Lembo and colleagues[6] at the American College of Gastroenterology (ACG) meeting in 2014. TARGET 3 looked at approximately 2579 patients who were first treated with an open-label course of rifaximin for 2 weeks. The FDA required a composite end score in this study that was different from the preceding studies. This included the ROME III criteria, and stools were evaluated by the Bristol stool scale. The composite endpoint was a 30% or greater reduction in abdominal pain and at least a 50% improvement in the number of days per week in which the Bristol stool scale was type 6 or 7 (loose or watery stools).

During the open-label phase, 1074 patients (42%) responded to therapy and met the composite endpoint. Another 30% of patients improved but were ineligible to continue because they did not meet the composite endpoint. Approximately 73% of the patients had at least some response to open-label therapy with rifaximin.

The 42% who met the composite endpoint were followed for 18 weeks. If they relapsed, they were eligible to be randomly assigned to a 2-week course of rifaximin or placebo. Of this group, 36% did not relapse. The patients who relapsed received either rifaximin 550 mg three times daily or placebo for 2 weeks, followed by a 4-week treatment-free period. If the patients relapsed a second time, they were treated again.

In the first relapse re-evaluation, 33% (rifaximin) vs 25% (placebo) improved, for an 8% therapeutic benefit. If patients relapsed again they were eligible for re-treatment and followed for 6 weeks. At that time, the composite endpoint was met in 37% of the rifaximin group and 29% of the placebo group.

A few of the secondary endpoints were also important. The prevention of recurrence was in favor of rifaximin (13.2% vs 7.1% for placebo). The duration of response was higher in the rifaximin group (17% vs 11.7% for placebo).

To assess the FDA's durability and safety concerns, they looked at 100 randomly selected stool specimens on which they performed elaborate gene sequencing, culture and sensitivity, and found no predisposition to select out resistant organisms.

One patient developed Clostridium difficile infection (CDI). That patient had also received ciprofloxacin and was in the rifaximin group. Rifaximin has a very good effect on C difficile, and the minimum inhibitory concentration is impressive, although it is not indicated for the treatment of CDI.

Approximately one third of the patients went 22 weeks without relapsing. When we talk about the durability of effect with this drug, it seems to be quite promising. The safety and efficacy are what we would expect. The therapeutic gain is 8%-9%, with a NNT of approximately 10. It's not huge, but it's reasonable nonetheless compared with the other therapies we have in the IBS-with-diarrhea arena—which are very few. Alosetron (Lotronex®) is very problematic to use. Many doctors and other healthcare providers are afraid to use this drug. Although the safety data are great, there is lingering doubt about ischemic colitis. It requires more monitoring than some people are willing to take on. In the therapeutic arena of IBS with diarrhea, we don't have a lot of good options. Rifaximin gives us a nice option.

Guideline Recommendations for Rifaximin

Where do the national societies weigh in on this? Both the American Gastroenterological Association guideline which came out in 2014[7] and the ACG monograph guideline from 2014[8] looked at the data on the randomized controlled trials for rifaximin, and came to the conclusion that there was moderate evidence that it was effective. The ACG gave it a weak recommendation. The national societies weighed in on the preceding TARGET 1, TARGET 2, and the other phase 2b study, but not on the data from TARGET 3, which are not yet published. We will wait for those data as we look for other ways to dissect the information and apply it to our patients.

Concern about cost persists, because when we talk about a relapsing disease, and IBS in particular, treatment with a fairly expensive medication may be somewhat cost-prohibitive for some insurance plans. Nonetheless, it is a viable option and one that we can be comfortable saying is a safe and effective option.

Why rifaximin works is not entirely understood. Small intestinal bacterial overgrowth is probably not the cause of IBS. When these studies were done initially, they were done with a lactulose breath test, which is subject to false-positive results. When the gold-standard jejunal cultures of patients with IBS are done, the numbers are quite small. They are consistently in the 3%-5% range for intestinal overgrowth in the small bowel. So it is probably more at the colonic level, and whether the colonic microbiome changes more predominantly in IBS is not known. Whether it is a shift in the bacterial load or a change in the microflora that changes the host response to the toxins or secretions from these bacteria, food processing, and sensitization, is not well known. Nonetheless, the drug works. It seems to have an adjunct advantage, and it may be something that you can now put in your quiver for patients with IBS with diarrhea.

We will await the publication of TARGET 3, but at present time we are glad that the FDA has given us another option for a difficult disease to manage, with many clinical implications. I'm Dr David Johnson. Thanks for listening.

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