How do NHE3 inhibitors work?
There’s only one NHE3 inhibitor right now on the market, and that’s tenapanor. It is FDA approved for the treatment of IBS-C. That’s the intended use of this medication. This is a unique mechanism of action.
There are three mechanisms of action identified with tenapanor. I think the first and most relevant for patients with IBS-C is the mechanism by which tenapanor blocks dietary sodium absorption. It does that by inhibiting the sodium hydrogen exchanger, isoform type three, so that’s the NHE3. This is basically a channel that moves, transports, and exchanges hydrogen and sodium; sodium in the lumen moves into the cell when this transporter is working as it should.
Tenapanor blocks that transport of sodium from the gut lumen through the cell and then eventually into the blood, so it prevents that reabsorption. That’s how it works with regard to constipation, because if you trap sodium in the gut lumen, then you also trap other ions.
If you trap other ions and sodium, you create an osmotic gradient, essentially, so there’s more ions in that space, and the body likes balance, so it will hold onto fluid. So you basically cause fluid to be retained in the GI tract. Our bodies see about 10 liters of fluid a day.
About 1.5-2 liters are what we take in orally. The other 7.5-9 or 8-9 are secretions. There’s plenty of fluid to be retained, if you will, in the gut, and that’s how it works for constipation.
Two other mechanisms have been shown in animal models. Tenapanor appears to decrease intestinal permeability. The theory behind irritable bowel syndrome is that intestinal permeability may be impaired, which allows translocation of possible organisms, viruses, bacteria, fungi, or inflammatory cells and cytokines, which then leads, we believe, to some of the kind of underpinnings of IBS, like visceral hypersensitivity and microinflammation.
It may even be changing the microbiome.
The third mechanism, which speaks to that concept of visceral hypersensitivity—which many people with IBS have—is hard to measure, but this is basically the origins of abdominal pain.
These patients have nerves in their gut that fire at a lower threshold and they perceive that firing or activation of those nerves as painful experiences, so it’s a lower threshold for pain if you will, and tenapanor has been shown in animal models to decrease that visceral hypersensitivity. So, it helps treat constipation through its activity on dietary sodium, nut it may also be helping dramatically with abdominal pain through its action on enteric neurons.
How do those mechanisms of action differ from those of other treatments for IBS-C?
Other FDA-approved therapies for IBS-C are classified as secretagogues. These agents bind to certain receptors in the gut and cause active secretion of fluid into the GI tract, whereas tenapanor is causing retention of fluid in the GI tract.
These various agents have slightly different mechanisms. We don’t know for sure whether all of those other FDA-approved medications have similar mechanisms with regard to modulating the nerve activity; there is some evidence that several of them do. The primary differences between tenapanor and those other FDA-approved agents is the active secretion with those other agents versus the fluid retention with tenapanor. I view them as complementary therapies.
Many over-the-counter therapies are uses for IBS-C. None of them are FDA approved for that indication, but that includes lifestyle modifications, which is not a medical therapy per se but can help some patients, and then the general typical laxative therapies, which includes osmotic laxatives that retain fluid, and then stimulant laxatives, which cause increased motility.
Those are also reasonable first-line therapies for people. Many therapies for Irritable Bowel Syndrome have very different mechanisms and not as good an evidence base. It doesn’t mean they don’t work, but there is not as good an evidence base as our FDA-approved therapies.
What makes NHE3s particularly useful in treating IBS-C, considering the condition’s multifactorial pathophysiology?
Several large-scale phase 3 trials show that this agent works compared with placebo. We have no comparative data with regard to other medications, so we cannot say that it’s superior to other medications, but I think its benefit is that it’s an additional rigorously proven therapy that is effective in some patients with IBS-C.
Some agents are not as well tolerated by some patients as others. We do see some side effects with the secretagogues, primarily diarrhea, which is also the most common side effect with tenapanor.
Every patient with IBS-C is different. There is no single cause of IBS, so symptom manifestations are often different from patient to patient. Different patients respond to different therapies, and so having an additional therapy that is different from the over-the-counter therapies or perhaps the other FDA–approved therapies for IBS-C allows us to potentially reach another group of patients who have tried those other things and they were either ineffective or perhaps they were not well tolerated. Having more choices, especially when it’s a well-tolerated and effective therapy, is always beneficial.
What evidence is there to support the use of NHE3 inhibitors in treating IBS-C?
Two large-scale trials—TEMPO 1 and TEMPO 2—were both published in the American Journal of Gastroenterology in 2021 and 2022. These studies looked at patients with IBS-C who were randomized to receive either tenapanor at 50 milligrams twice a day, which is the FDA-approved dose, or placebo twice a day.
They did this for either 12 weeks in one of the studies, or 26 weeks in another one of the studies. They showed that tenapanor, compared with placebo, was significantly better for improving the symptoms of abdominal pain as well as enabling patients to have a complete spontaneous bowel movement. The FDA requires simultaneous improvement of both of those symptoms for a specific number of weeks out of a 12-week trial. Tenapanor did demonstrate superiority over placebo for that simultaneous improvement of both abdominal pain and constipation for at least 6 out of those 12 weeks simultaneously.
I like that these studies looked at a whole host of secondary symptoms as well. This is relatively intuitive from the primary results, but they actually measured improvement in abdominal pain and timing as well as bowel movement frequency and completeness and symptoms like bloating and distention and QOL. All of those were significantly improved with tenapanor compared with placebo. That gives me some other endpoints to look at when I’m seeing patients and asking how they’re doing. I’m not just asking them about their two cardinal symptoms of IBS, but also about these other symptoms.
It means having an additional agent that has shown efficacy. It’s a nice option for us because that’s what we really want with these patients. We want to improve their QOL.
I encourage clinicians to become familiar with this agent. As we get more use with it, we’ll be able to hopefully figure out which patients seem to respond better to this than to other therapies, but I think it’s really just about raising awareness that we have another option that it’s slightly different in terms of its mechanism and may offer some benefit over other things that some patients may have tried.
I’m excited that we do have another agent in this field, because about 15 years ago, we didn’t really have much. Now we’ve got multiple agents that potentially have the ability to really improve our patient’s symptoms and QOL. Now, making sure that people understand this medication and that it is well tolerated and showed good efficacy in those studies is important.
