Rifaximin's Role in Managing IBS-D

Mark Pimentel, MD: We’ll stick with you, Tony, because you were involved in some of the pivotal studies, as we move to the next drug, which is rifaximin. What is the mechanism of action? How do you think it works? What’s your thought on that product?

Anthony J. Lembo, MD: Sure. Rifaximin, of course, is a broad spectrum antibiotic, but it’s different from a lot of other antibiotics. I think it’s worth just taking a step back. One of the risk factors for developing IBS [irritable bowel syndrome] in our clinic is seen in patients who have taken recurrent antibiotics. And so it requires a little bit of discussion. Some patients will say, “Well, I think I might have gotten IBS because I took antibiotics for a year in response to rosacea,” or whatever, beforehand. And so, we have to discuss that rifaximin is not bactericidal. It doesn’t actually kill the bacteria, so it’s not going to change your flora, which is the good news. It’s not going to increase your risk of developing Clostridium difficile. The bad news is, we don’t actually know exactly how it works because it doesn’t change the flora. It probably changes the way the bacteria bind to or interact with the mucosa.

But the data are quite compelling in IBS, particularly IBS with diarrhea [IBS-D]. It improves symptoms. It improves abdominal pain. We had a poster at this meeting on its effect on abdominal pain. It improves bloating and global IBS symptoms. The dosing is typically 550 mg, 3 times a day, for 14 days. That’s the FDA-approved dosing for it. And it works in men and women. It doesn’t seem to be long-lasting though. It’s not a permanent fix. So patients often need to be re-treated. There were a lot of questions around that, which led to TARGET3, which was the third pivotal trial done with rifaximin. And that was a re-treatment trial. It’s a little complicated because it wasn’t your standard, just placebo or drug. In this case, patients who took rifaximin—and knew they were getting rifaximin—and improved and had a recurrence within 4 or 5 months were able to be randomized into either rifaximin or placebo and show that there was still an improvement in symptoms. So you could re-treat patients. In fact, in that study, patients got up to 3 doses of rifaximin, and it did seem to improve symptoms more than placebo. It looks safe. It’s effective. It’s not effective in everybody, but in a subset of patients it can work.

Mark Pimentel, MD: You use it in your practice. What’s your pattern of practice, in terms of re-treatment? How do you gauge when the time is right to re-treat?

Brennan Spiegel, MD: I do use rifaximin in my practice, but not in everybody. As I sort of mentioned earlier, I kind of have combinations depending on the unique patient profile. But when I use it, I typically wait to see if somebody has a response at all. If somebody doesn’t have a response, there’s no point in talking about re-treatment. But when it works, in my experience, it really works. When it works, it works. You can clearly see [that] people benefited. Bloating, discomfort, diarrhea [get] better and they feel completely better. But the key is, it’s not necessarily a cure. For some people, it really can be. It’s almost as if they’ve been reset somehow and they do well. For others, they come back. Personally, I will re-treat once. After that, I’m going to send them to you, because we work in the same clinic. But quite honestly, I just want to make sure that there’s something else we need to think about before I go down 6 re-treatment courses. But I also am cognizant of the data, and I think you’ve published some of this work: that re-treatments are successful. It’s not like there’s a diminishing-return curve, where people no longer respond at all or become resistant to the medicine.

Mark Pimentel, MD: But 1 of the things that we see in practice is the patient will call us and say, “I think I need re-treatment.” How do you handle that? What’s your threshold to say to go again? Do you wait for them to have a regression of 50% of their symptoms? What’s your thermometer for re-treatment?

William D. Chey, MD: I don’t know that we have great guidance on that, and I just say that I’ve been recalibrating that over time. I initially would just rely on what the patient told me. What I have found are a couple of things. The first thing has been that there have been some patients who would have so much anticipatory anxiety about their symptoms coming back that they would be pulling the trigger with really minimal symptoms. That worries me. We do have data for up to 3 re-treatments. It works, and I’m super excited about that. But we don’t have data where people are treated 10, 20 times. And really, when you’re talking about a disease that primarily affects young women, that’s what we’re potentially looking at with long-term use of rifaximin.

I’ve become more circumspect over time. In other words, now I actually query the patients carefully about what symptoms they’re experiencing and how close their experience is to where they were when they started. The good news is, the data [were] suggesting my clinical practice would definitely reflect that the patients don’t seem to get back to the level of severity that they were suffering with before they started treatment. I’m not requiring people to go back to that, but I just want to make sure that they’re symptomatic enough to justify another course of antibiotics. And particularly rifaximin is an expensive medication that many patients have to pay out of pocket for.

Mark Pimentel, MD: Brennan alluded to the fact that when they do respond, they really respond.

William D. Chey, MD: Oh, yeah, the magnitude of response is fantastic.

Mark Pimentel, MD: In the TARGET3 trial, and maybe I’ll ask Dr. Rezaie about that—his clinical experience. Do you see the TARGET3 data? It was almost a true-to-life trial because everybody gets rifaximin in the beginning, and you see what happens. In your practice, do you see that 33% who are just 1 and done, or at least they go for prolonged periods of time without re-treatment? Because that was what was seen there—6 months, no relapse.

Ali Rezaie, MD: At the beginning of TARGET3, everybody got open-label Xifaxan, and 44% responded. And out of those, 36% did not have a flare for 18-plus-4 weeks, which is 22 weeks after the open-label therapy. So there is definitely that group of super-responders to rifaximin. When you treat them, they come back and say, “The bloating is gone. The bowel movements have dramatically improved.” And then, yes, there’s that group who do respond and then have a flare for which they require re-treatment. And yes, there is a group of patients who don’t respond to therapy as well. I think that reflects the heterogeneity of the underlying pathophysiology of irritable bowel syndrome. I understand the rifaximin mechanism of action is not completely understood, but clearly, it works on microbiome, and not every IBS patient’s symptoms are driven by microbiome. So they’re a different pathophysiology. I think the lesson that you’re learning from the treatment of patients is that we have to go back and probably find those buckets of patients with different pathophysiology and target them with precision medicine.

Transcript edited for clarity.