The Phase 3 T3MPO-2 Study: A Gastroenterologist’s Perspective

Physician’s Weekly recently spoke with Brian E. Lacy, MD, PhD,  a board-certified gastroenterologist, about the phase 3 T3MPO-2 study—which assessed the efficacy of tenapanor in treating patients with irritable bowel syndrome with constipation (IBS-C)—and what the study results mean to patients with IBS-C and those who treat this population.

PW: What was the purpose of the phase 3 T3MPO-2 study?

Dr. Lacy: This study was initiated in December 2015, prior to FDA approval of tenapanor in 2019. The goal was to evaluate the efficacy and safety of tenapanor for the treatment of adult patients with IBS and constipation over 26 weeks. The FDA requires IBS studies to be at least 12 weeks in duration, which was the length of the study in the T3MPO-1 study. However, both safety and efficacy can be better evaluated with a longer study (eg, 26 weeks), recognizing that it is more difficult to keep subjects enrolled (and of course, more expensive). Of note, the European Medicines Agency generally requests 26-week studies.

Can you explain more about the study?

This study was performed in the United States. It was a large study (620 adults, men and women, aged 18-75) diagnosed with IBS-C using the Rome III criteria (recall that Rome IV was not released until 2016, and thus this study used the most current Rome guidelines at the time). The study involved 92 centers, which means there was a diverse group of patients, more representative of the general IBS population in the US. This study was randomized, double-blinded, and placebo-controlled, and thus the most rigorous design for a new medication. Patients had to meet the strict FDA endpoint of reporting both an improvement in abdominal pain and bowel habits to be considered a responder.

What are the most important findings?

If I were to give a quick “elevator” speech to fellow providers, I would note the following:

1. This study confirmed the prior earlier findings from T3MPO-1, which is reassuring (especially for a medication with a novel method of action).
2. This study demonstrates that tenapanor is safe for long-term use (26 weeks; and most FDA-approved medications have not been studied for that long, so this sets this medication apart). No new safety signals were identified (diarrhea was typically mild and transient).
3. Efficacy persisted during the 26-week study. Benefits do not wear off.

What are the implications of these findings?

1. Tenapanor has a novel mechanism of action (MOA), which means that we have another option for our patients with IBS-C, which is great. No single IBS-C medication helps all patients, likely due to innate differences in receptor profiles (type, location, density, responsiveness).
2. Physicians typically prescribe other agents first, as they are more familiar with them because they were FDA-approved earlier (eg, linaclotide in 2012). However, not all patients respond to one agent or another (eg, lubiprostone or linaclotide or plecanatide—all good medications), and thus, with a novel MOA, prescribers now have another choice.
3. Prescribers should not think that this has to be the last choice, the last-ditch effort. Since there are no head-to-head comparisons, this could easily be started first, prior to other FDA-approved medications.

How does the side-effect profile of tenapanor compare with that of other IBS-C treatments?

In a word: comparable. The most common side effect of all IBS-C medications is diarrhea. Fortunately, in both large studies, this was rated as mild and often transient. The dropout rate due to diarrhea was low. Similar side effects have been noted with all other FDA-approved medications: lubiprostone, linaclotide, plecanatide, and tegaserod (approved, but due to a business decision, not widely available). However, in contrast to lubiprostone, nausea was not a major side effect. Of note, when cautioned about possible side effects, such as diarrhea, most patients do well with this, as typically it occurs only in the first few days.

What do the study findings mean for patients with IBS-C?

What this means to me is that we have one more treatment option for our IBS patients with IBS-C, which is wonderful. What it means for patients is that another option is available with a novel MOA. Thus, if they failed lubiprostone (a type 2 chloride channel activator), and if they failed both guanylate cyclase-C agonists (linaclotide, three doses; plecanatide, one dose available), then they have a new treatment option that works differently. To me that’s really good news. It also highlights that the field is continuing to evolve and that we are learning new things every day, which means even more therapeutic options in the future.