At the 2025 North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), held in Chicago, Illinois, investigators presented new interim safety findings from the phase 3 R-ALLY trial and its open-label extension evaluating tenapanor in pediatric patients with irritable bowel syndrome with constipation (IBS-C). Preliminary data demonstrated that tenapanor, a first-in-class sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor, was safe and well-tolerated among adolescents, with no serious treatment-related adverse events reported.

The phase 3 R-ALLY study randomized 77 patients aged 12 to <18 years to receive tenapanor 25 mg twice daily, 50 mg twice daily, or placebo for 12 weeks. Fifty-six participants who completed the randomized treatment period entered a 40-week open-label extension. According to the study abstract, the authors noted that "In the OLE, no serious TEAEs were reported, all TEAEs were considered unrelated to study drug except diarrhea, and all TEAEs were resolved except 2 mild events: 1 overflow incontinence and 1 diarrhea."

In this Q&A, Thomas Wallach, MD, chief, Pediatric Gastroenterology, SUNY Downstate Health Sciences University, New York, New York, explains the safety and tolerability of tenapanor for pediatric IBS-C.

Q&A

Contemporary Pediatrics: Can you talk about the study tenapanor in pediatric patients with IBS-C, and your analysis of its blinded safety as part of the phase 3 open-label extension?

Thomas Wallach, MD:

Tenapanor is a novel laxative that is generally thought to have some additional support for the intestinal barrier function, and it works by blocking something called NHE3. Basically, what ends up happening is it just has the colon secrete more liquid into the intestine. So instead of classical laxatives, which often use the main ones we call as osmotic laxatives, it's like polyethylene glycol, MiraLAX, that kind of stuff, what they do is you drink water or liquid and it holds it in your intestine.

What this would be doing instead, and some other medications use a similar approach is encouraging your intestine to secrete more water into so that you're you're it's looser or softer, easier to go, and can reduce some of the symptoms that are associated with constipation or IBS. It has been studied in adults and found to be effective, as well as very safe, with pretty good outcomes in the adult trial with irritable bowel syndrome, regular bowel syndrome type C or constipation, and this is part of a reported aspect of an ongoing trial to demonstrate its efficacy in kids. This is the 12 to 18 year old range, although they have a another study that will be starting soon, which is looking at it in younger children.

Contemporary Pediatrics: What were some of the specific outcomes of your study presented at NASPGHAN 2025?

Wallach:

So, whenever you're adapting a drug from a adult population to a pediatric population, there's 2 really big questions. One, does the disease work the same, so will the mechanism work? And 2, is there a safety issue that we don't anticipate in adults and kids? Because kids are different, right? What we commonly say in pediatrics is children are not little adults. At different points in our lives, organs have different maturations, different functions, different things can be dangerous or not dangerous. And so there are things that are worthwhile in adults that maybe aren't safe enough for use in kids. And so these are sort of the 2 big questions we want to address with any of these studies. Does it work the same way it works in adults? And so do we see the same effect, and do we see any new or concerning safety signals?

So what this abstract represents is essentially the safety signals from the pediatric trial, which is close to conclusion, where we've looked at 12 to 18 year olds taking tenapanor at standard doses, as well as to control cohort, to look and see if there's any difference in safety related events. And what we were very happy to report is that, with the exception of minor ones, like things like loose stool, which is not surprising with the laxative, there was really nothing that was an adverse event that was jumping out, which is again, consistent with the adult study. So we really are just looking at problems with laxatives, right? If you get someone to poop, maybe sometimes it works too well. So it's a highly reassuring and again, makes me comfortable as a preliminary report in using tenapanor in a pediatric population, because there is data now on safety, but also helps speak to the likelihood that you know, this will also be nicely reported when the trial is complete, and we expect to see a very high safety rate in pediatrics as well as we've seen some nice preliminary stuff that we previously reported, suggesting that the efficacy should be about the same.

This study does not in any way, shape or form, speak to whether or not you should feel comfortable, because what we are reporting is not efficacy. So what I would say the 2 keys to using the drug in a patient population is efficacy and safety. Now what I do think this does allow is, if you are considering use because you are having a difficult situation and you want to consider additional options, I would feel comfortable using it based off this safety record. What I can't speak to is that I would say, oh, people should do this now, because we haven't proven yet that it works. But I do think that this is highly reassuring and highly suggestive. And what often ends up happening when we're treating pediatric constipation is that there are sort of 2 main options that are easy to get, which is the stool softening agents and the bulking agents, which is things like fiber, MiraLAX, polyethylene glycol, lactulose, and then the pro kinetic or irritant agents, which is things like Senna or Ex-lax and stuff like that. They both have side effects people don't necessarily like. The big one for the the fiber is that it makes gas. The problem with MiraLAX is this, the volume to get to effective sizes, you have to drink a lot and well, it doesn't have much of a taste. There is a textural component that some people find difficult. And the other part of the problem in pediatrics in particular is that a high percentage of children who have severe constipation, are also neurodivergent and have severe issues with sensory integration.

So when you have something that's a large volume of unpalatable to them, I take MiraLAX, and I think it's great, but unpalatable to them options, it can be very hard to get compliance, and so that can lead to secondary problems. There are other medications that do exist that are pills or maybe liquids, that are small volumes that we could get people to take. They are somewhat effective, but not as well studied. A lot of them do not have indications in pediatrics and can be quite expensive to access for maybe not and impressive return. So there is a huge need for volume constrained, effective laxative therapy, because if we use large volumes, people with IBS-C have issues. There are children who have volume constraints on their stomach because they're chronically ill and they have issues.

There are a lot of different reasons why a large volume treatment won't work. And there's also reasons why a irritant laxative would be counterproductive or create secondary problems. And so while they are both great options and great treatments, and they work quite effectively, there are patients for whom they just don't work for either physical or like tolerance effects, and there is a clear need for this. Constipation is a huge, huge issue in this country. It drives a huge amount of abdominal pain. And the abdominal pain things that go into adulthood. It drives secondary complications, like things that you can have in your colon, like diverticula when you're older. It is a major problem.

We estimate, you know, half of people basically, are essentially constipated, and it's very difficult to address, and one of the best times to address it is in childhood. If we fix it in childhood, the colon is kind of like a muscle, right? So it is muscle. As we all know, as we get older, our injuries take longer to fix. So, connective tissue and muscle tissue does better at getting back to normal in an early age. If we fix it in childhood, we might not need it in adulthood. So I think this is a very important thing to add, even though, you know, it seems like, oh, it's constipation, but constipation causes a lot of health care issues and a lot of discomfort. So this is a great thing to add to the armamentarium.

Reference

Williams N, Wallach T, Ringheanu M, et al. SAFETY AND TOLERABILITY OF TENAPANOR IN PEDIATRIC PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH CONSTIPATION: AN ANALYSIS OF BLINDED SAFETY DATA FROM A PHASE 3 STUDY AND ITS OPEN-LABEL EXTENSION. Abstract. Presented at: 2025 NASPGHAN Annual Meeting. November 5-9, 2025. Chicago, Illinois.