Shubham Pant, MD: Larry, tell me, what kind of treatments have you had? I know you’re a professor yourself. I’m sure you’ve looked into it. Tell me about your treatments, what you’ve had for this, for the carcinoid syndrome.
Larry Pleasant: Well, I’ve had the monthly injections of…
Shubham Pant, MD: That’s octreotide, the somatostatin analogs.
Larry Pleasant: Right, I’ve had those. I continue to use the subcutaneous injections of octreotide, short-acting, occasionally, for breakthrough flushing. I take a drug called Creon to help with digestion. Shubham Pant, MD: Pancreatic enzymes.
Larry Pleasant: Right, exactly. And most recently, I began to take a drug called Xermelo, or telotristat, in March.
Shubham Pant, MD: And what was that drug for?
Larry Pleasant: That drug is to control the diarrhea.
Shubham Pant, MD: And did the octreotide control the diarrhea?
Larry Pleasant: The octreotide helped, but it did not control the diarrhea adequately.
Shubham Pant, MD: And when did you start taking this new drug?
Larry Pleasant: I started taking it this past March, very soon after it was approved by the FDA.
Shubham Pant, MD: And what was it approved for, Dr. Morse? What does this drug do?
Michael A. Morse, MD: It was FDA approved for people with inadequately controlled diarrhea, when people had previously had somatostatin analogs. The way the drug works is actually very interesting because we can separate what it does from what the somatostatin analogs do. And they’re given together for a good reason. So, somatostatin analogs bind to receptors on neuroendocrine tumors.
Shubham Pant, MD: On the surface?
Michael A. Morse, MD: On the surface. They’re delivered as a form that can be slowly released so it gets into the bloodstream, circulates throughout the body, and binds to the outside of neuroendocrine cell and stops it from secreting serotonin, for example. And that works fine in many people for a long period of time. Different people will have different experiences. Some people will be controlled for much of the month on a somatostatin analog and then right before they’re due, they’ll get a lot more symptoms. Some people are just moderately controlled throughout the period of time. Some people are controlled initially and then after months or years, their symptoms will become worse. Traditionally, our options were basically to increase the dose of the somatostatin analog, use short-acting when people had more severe episodes. Lots and lots of adjunctive medications…
Shubham Pant, MD: Like you’re saying anti-diarrheal, the Imodium and such?
Michael A. Morse, MD: Large quantities of those. And sometimes diet modifications. But eventually, that’s just not enough and the diarrhea becomes uncontrollable despite having been on the somatostatin analogs. Now telotristat, or Xermelo is the trade name for it, was designed to interfere with the enzyme, tryptophan hydroxylase, or TPH, which is what people call it. The enzyme converts the building block, tryptophan, through a series of steps into serotonin.
Shubham Pant, MD: And serotonin is the hormone that is being secreted, which causes a lot of the syndromes.
Michael A. Morse, MD: That’s right. The symptoms, particularly the diarrhea, are very highly linked to the serotonin production. So, if you can stop the production of the serotonin from the inside of the cell now, there’s less serotonin to even be released. It was tested in people who were already taking somatostatin analogs, and that’s why we give them together.
Shubham Pant, MD: Give them both together?
Michael A. Morse, MD: Correct.
Shubham Pant, MD: And Larry, has it helped with your diarrhea?
Larry Pleasant: It has been remarkable.
Shubham Pant, MD: So, have you just thrown away that app that you had…?
Larry Pleasant: I don’t use it any more. I still carry the bag, but I don’t use it any more. It really has been a game-changer for me. From the initial dosage, it has been remarkable. I almost never have an episode of diarrhea now.
Shubham Pant, MD: But you have regular bowel movements?
Larry Pleasant: Yes. I’ve gone back to regular bowel movements—once a day, something like that. No unexpected diarrhea, nothing. And it has made a tremendous difference in the way that I live.
Shubham Pant, MD: Have you started teaching in more universities after that?
Larry Pleasant: Actually, I have.
Shubham Pant, MD: You can go to different universities. Do you take any midnight lectures now?
Larry Pleasant: Sometimes I get home well after midnight, but no, no more midnight lectures.
Shubham Pant, MD: No more midnight lectures.
Michael A. Morse, MD: One thing I want to point out is, you definitely had a remarkable effect from it. As I mentioned earlier, the diarrhea can be for different causes in people who have neuroendocrine tumors. The predominant cause would be carcinoid syndrome. But sometimes, people have had extensive surgery on their bowel and they have what’s called short gut syndrome. Food transits very rapidly through their…
Shubham Pant, MD: And you can absorb the water in, so just kind of think of diarrhea.
Michael A. Morse, MD: That’s right, you can’t absorb enough of the liquid and you have loose stools. There are people who have what’s called bacterial overgrowth, areas of the bowel that just don’t move effectively. Bacteria grow in those areas and basically ferment the food into something that can lead to diarrhea. Sometimes the somatostatin analogs can cause fat malabsorption, and that can cause diarrhea.
Shubham Pant, MD: And that’s what you may need the Creon for because you have to break down the fat.
Michael A. Morse, MD: So, it’s important to set expectations that there are many different causes. We’re going to try to tackle one of the main causes. For some people, that’s all they need. In other people, they still do need some of the other components, but they’re overall better. The other thing that’s important for people to realize is that it doesn’t necessarily work instantaneously. I think you actually had significant benefit right away.
Larry Pleasant: I did.
Michael A. Morse, MD: But the way the studies were done, people were followed out to at least 12 weeks and there was continuing benefit. So, people that started and don’t immediately notice dramatic benefits should be encouraged to continue to take it because they may see those benefits over time.
Shubham Pant, MD: So, when did the majority see the benefit? Like where were the curves? When you see the study, there are all these curves that went all over the place.
Michael A. Morse, MD: It’s interesting that the benefits start early, but the benefits become greater and greater and greater out to the twelfth-week mark, which is where the study was intended to look at the benefit between the people taking the Xermelo, or telotristat, and the people who weren’t. But what we see is every day or every week along that path, there are more people who are having fewer diarrheal stools.
Shubham Pant, MD: What about other side effects like flushing? How can you control the flushing? What are different ways to control the flushing?
Michael A. Morse, MD: This is a challenge because we don’t think the flushing is driven by serotonin in most cases. There are other hormones—substance P, tachykinins, bradykinins—that may be the cause of it. And while the somatostatin analogs reduce the secretion of those as well, tryptophan hydroxylase-targeting with Xermelo only deals with serotonin. So, we continue to need to use, as in your case, octreotide to control those. And obviously, there’s a lot of research going on in the field trying to identify why the flushing occurs and other ways of controlling it. I would point out that the Xermelo pivotal trial that led to its approval did not have that many people with significant flushing on it. So, we actually don’t know the answer to what impact it’s going to have. We suspect we may need other therapies for that in the future.