Salk Scientists Discover New Diet Pill

Maureen Cavanaugh: This is KPBS midday edition. I’m Maureen Cavanaugh. Imagine just taking a pill to lose weight, that quest is the holy grail of obesity research. So far the miracle diet pills produced by science have been largely ineffective or downright dangerous. But now scientist at Salk say they think they’ve come closer than ever before to cracking the diet pill puzzle. They say this pill is like an imaginary meal. And joining me to explain what that means is Dr. Ronald Evans who is Director of Salk’s Gene Expression Laboratory and senior author of the new paper on the pill published this month in Nature Medicine. And Ron, welcome to the program. Dr. Ronald Evans: Thank you. Maureen Cavanaugh: And joining me is Dr. Mark Jabro. He is Director of the Weight Management Program and Sharp Rees-Stealy Medical Center. Dr. Jabro welcome. Dr. Mark Jabro: Thank you. Maureen Cavanaugh: Now Ronald Evans, as I understand it you’ve been researching the protein that triggers the body to prepare for digestion. How does that play a role in weight loss? Dr. Ronald Evans: Well, as soon as you begin to eat food the body has a very rapid response which is the release of a food called bile acid. Bile acid aids in the digestion of food normally, but it also is a signal to the body that’s something has happened, food is coming into your system. And we devised a pill that triggers the same response flips the switch as if bile acid had been released but the pill is doing it, so instead of having a meal that starts this process we do it with a pill. So that’s why we call it an imaginary meal, there are no calories, there’s no bile acid, it’s just the pill. And that begins a cascade of events that ultimately has all of these effects that we talk about in the paper. Maureen Cavanaugh: And the effects it says that this response that the body normally goes into when it’s preparing for a meal sort of clears out the system for a meal. How does that help burn fat or help you lose weight? Dr. Ronald Evans: One of the first things that happens as you begin to normally digest food is increase blood flow to your intestine, series of signals from the gut to the liver to the fat, to the brain, so that the body knows what’s happen. It turns out that there is a little bit of like a baton in a race where one tissue hands the baton off to the next. Once you get that cascade going we find that the body takes over and so we get the liver activated, we get the blood system activated, we get the adipose tissue activated, you wind up opening up the adipose depot, triggering a response that we call thermogenesis or burning of fat and creates heat that also helps make room for some of the new energies coming in but there are no calories in this process, and so you actually wind up losing weight. Maureen Cavanaugh: So how does this pill trick the body into thinking that it’s going to get a meal? Dr. Ronald Evans: It tricks you by giving the body the impression that this digestive fluid had been released, that normally in your body every meal gets released and sends this response throughout your body. This pill is a chemical trigger. It actually controls a big network of genes and that’s really how it works, it controls your genome in your gut and that activates a boat load of responses that help to lower insulin, that help to lower glucose, that help to reduce inflammation, and in people that are overweight or diabetic like the mice that we use in our study it also improves their liver functioning in a very dramatic way. Maureen Cavanaugh: You have used this, you call it fex? Dr. Ronald Evans: Yes, fex. Maureen Cavanaugh: What is that for? Dr. Ronald Evans: The target of the drug is a molecule called the receptor for bile acid and the receptor is called FXR and we call the drug fexaramine or fex, it’s really named after the target to which we built the drug. Maureen Cavanaugh: Now, let’s talk about the mice who were given this pill so to speak who are given this particular substance. They were fed high calorie meals basically they were fed a lot. Dr. Ronald Evans: Right. Maureen Cavanaugh: And you gave them this substance. What happened? Dr. Ronald Evans: So the interesting thing about this approach, there are two interesting things – one the drug never actually gets into the body, never was it absorbed into the bloodstream. You take it, it passes right through, as it is going through the intestine to be eliminated it tickles the switches that need to be turned on and then it goes out. So that’s one thing. So never it gets into the body, so that’s a very interesting safety feature for the whole process. The other thing about the drug is once it gets that whole process kick-started, the rest of the body takes over and this taking over is really dramatic and for people who are obese like our mice are obese they’re obese, we tested this in three different kinds of mouse models of diabetes and obesity. And in all of these models, we begin with high insulin levels, high glucose levels in something called fatty liver disease the insulin levels dropped, the glucose levels dropped and the fatty liver resolves. It’s very much similar to a surgical procedure called vascular sleeve gastrectomy that causes rapid benefits by altering the intestine in the stomach and so we think the pill may actually be a chemical way to actually achieve some of the benefits of that kind of surgery. Maureen Cavanaugh: And despite eating this high calorie high fat diet, they stopped gain weight? Dr. Ronald Evans: That’s a great point. They don’t’ have to stop eating the high calorie diet. Our mice don’t change their eating behaviors. So they continued to eat their normal diet, but they lose weight. They eat their normal diet and their insulin is improved and so many diet pills, and I think we’ll hear a little bit more about this, try to act on the brain to change your appetite which is not an easy thing to do because we’re geared to eat. This one just triggers a normal response but in doing that it does not change your appetite and so it allows the mice to eat these normal big high caloric meals, it still improve. And for us that’s the holy grail because you can’t depend on people in the long run to change their behavior, it just is not the way that most people are. Maureen Cavanaugh: Let me go to Dr. Mark Jabro, he is Director as I said of the Weight Management Program at Sharp Rees-Steley. And let’s take a step back if we would because you deal with people in a clinical setting who want to lose weight every single day. If we had a genuine diet pill that really helped people lose weight without bad side effects how significant a breakthrough do you think that would be? Dr. Mark Jabro: It almost sounds too good to be true, I would think that it would be wildly popular. My patients are struggling with the desire to lose weight, are having difficulty making those behavioral modifications and I think if we had a non-systemic approach of a pill that you could take that would basically increase your metabolism it sounds like without affecting the amount of food you eat and cause weight loss I think you would have a lot of people in line to try this particular medication. We do have a lot of medicines already available, there are three medications that we can write by prescription currently and the fourth was recently approved. So sometimes when you are talking about basic clinical research especially in a mice model that doesn’t translate to human drugs for quite some time if ever, I’d been involved in clinical research and I can you that a lot of the compounds I work on never make it past the early human stages. We tend to find things out in humans that we don’t really see in the animal models. So while I’m optimistic I think there is a lot of work to be done with this particular model. And another thing to remember is that the human body has evolved over the millennia to conserve, by our conservative system to make sure that we get in appropriate nutrition and that we survive and be able to pass on our genes and our eating behaviors are essential to this. So any time you try to alter something that’s highly conserved unexpected problems can pop up and sometimes we’ll see that later in the human trials, but I think it’s very exciting and hopefully something like this will come to fruition. Maureen Cavanaugh: Just a question of one more if I could Dr. Jabro, when you are dealing with patients and you say you have a couple of prescription drugs that you can give them now not totally effective but helpful, how you determine whether one of your patients might benefit from an aid like that, a prescription weight loss pill, something like that? Dr. Mark Jabro: When we try to look at what’s happening underneath that, basically is the patient following a proper diet, are they exercising, do they have the right behaviors to lose weight, and I think if that piece that behavioral piece in that diet and exercise piece were there then and it’s still struggling, they’re coming across hunger or just that inability to get that food out of their mind, I think at that point you can think about kind of adding on therapy. And previously we didn’t really have much in the medication category, we immediately would have to go after they failed diet go right to surgical options but as you know over the past few years we now have three and now four medications coming where we can kind of fit those in before someone would have to go to surgery and I think if you have a highly motivated patient you want to add it on if their hunger is just out of control. Maureen Cavanaugh: Ronald Evans, speaking about fex one thing intrigues me – if this pill would try to trick your body to get prepared to eat a meal wouldn’t it then therefore leave your body very hungry when all I got was this pill? Dr. Ronald Evans: It’s a great question but in fact it doesn’t really change the hunger system, the pill doesn’t get in and it’s not a modifier of the central part that drives your interest in eating food. The nature of the process that we trigger is really metabolic. As I said it is very similar to what happens when you do a medical procedure called vascular sleeve gastrectomy which is a structural alteration of some of the same tissue that are actual pill hits which is the intestine and it’s believed that there are series of events that occur in that surgery that depend on our molecular switch and so in a way the surgical procedure is achieving a benefit that almost seems miraculous in its own fashion but we could mimic that benefit with this pill. And so if it does play out then we might be able to use a pill to basically replace the surgery and it has an advantage of when people who are obese and diabetic are not the best candidates for surgery, it’s tricky, it doesn’t always work and with the pill you can always stop giving it or you change the dosing. So if we can generate a pill that is safe, it does not get in body that achieves these metabolic benefits that we are seeing in the mouse models I think that we will have a big advance both conceptually and practically. Maureen Cavanaugh: Ron, you used that word safe and any one of a certain age is going to remember the introduction of Fen-Phen that was the diet pill in the 1990s that was widely popular for a while. It also turned out to be very dangerous. It caused pulmonary hypertension in a lot of people, heart fail problem. How are you going to avoid another Fen-Phen? Dr. Ronald Evans: That’s a good question, and safety has to be at the top of the list. One major advantage of our pill is that it does not get into the body. Fen-Phen and all the other drugs that have these side effects do get in the body and then they have a chance to do things that you don’t want them to do like touch the heart. Maureen Cavanaugh: What do you mean is it goes to the intestines and it stays there? Dr. Ronald Evans: Stays there. It doesn’t into the blood stream. Maureen Cavanaugh: Right. Dr. Ronald Evans: So it doesn’t circulate. So it doesn’t have the opportunity to interact and cause the kind of side effects that you see. Really it triggers the internal part by the way natural food would trigger that part. So it’s a series of gut hormones, they’re being activated, stimulated, released along with some other properties that lead to increased thermogenesis that is burning of fat that has very rapid effects and are sustained as long as you take the drug. And so one of the other safety features is if you want you can stop it or you can change the dosing, but not getting into the body is a major conceptual advance in trying to treat systemic disease like obesity and diabetes and so we’re very excited by the concept, number one. But number two we do know that there are other types of gut or intestinal hormones that have great effects on metabolic activity that are already in use and we think that this pathway is another one that integrates the series of these events into one pill. Maureen Cavanaugh: I want to ask you both a question about something that Ron said a little while ago, this fex pill has apparently allowed mice to eat a high fat or high calorie diet and they stopped gaining weight and there you got better cholesterol and so forth but is it a good idea to let people eat anything they want if they don’t gain weight? Dr. Mark Jabro: Well I don’t know. I mean I think that the word high fat it kind of has a negative connotation. So I think that recently we have seen that study show that saturated fat and indeed a fat diet doesn’t really relate to causing a heart disease. So I think there are examples where certain populations have eaten a high fat diet and been okay. What I’m more concerned is about the process nature of our diet. So the added chemicals both the fat, the salt and the sugar that are heavily added into our food supply and these can cause an issue long term and then you are also talking about not changing those behaviors and I think there is a part of our eating that drives from the reward system in the brain basically the mesolimbic pathway and if you don’t change the reward system in the brain and you continue to put that food and well then I think at some point it’s probably the medication may not work and we do find this very commonly with surgical operations such as the vertical sleeve gastrectomy or the [indiscernible] [00:15:38] bypass. Basically patients can do well over time but at about 18 months to two years after surgery sometimes that hunger comes back and then patients start to maybe change the way they eat, will take in more calories and at that two year point sometimes we see people go on to regain weight and maybe fail the surgery. There is a significant percentage who do well long term but there is always a relapse that can occur. So I think we have to kind of look at it more than just what you are taking in, we really have to work on the basis which is that behavioral part too and I think it’s encouraging that we could have a pill to maybe increase metabolism but I think if all the pieces aren’t there that long term success is still going to be out of reach. Maureen Cavanaugh: When these trials move from mice to humans are you going to be introducing the concept of behavioral change as well? Dr. Ronald Evans: Not really. I mean that’s going to be up to the other part of a team that would be managing people with diabetes and obesity, which is really what happens now. The reality is that most people don’t behave well. I mean I completely agree with what Mark is saying. But it’s difficult to change people’s behavior in terms of real numbers that some people obviously can’t do that but it’s probably only a few percent of people that are really good changing their behavior. The real challenge is in our modern society we tend to be much more sedentary. We have computers and we have every things that keep us immobile a lot more and our metabolism adapts to that kind of sedentary behavior and it’s very difficult to get out of that thing in our society. And so I think that we do have other issues but in the end I believe pharmacology and medication will be and understanding of the science of the way the body works and the way in which we absorb nutrients is going to be the underlying secret to getting a new drug. Maureen Cavanaugh: And human trials start in a year or two? Dr. Ronald Evans: Hopefully, yeah. Maureen Cavanaugh: Okay. I have been speaking with Dr. Ron Evans. He is Director of Salk’s Gene Expression Laboratory and Dr. Mark Jabro, Director of the Weight Management Program at Sharp Rees-Stealy Medical Center. Fascinating, thank you both very much. Dr. Mark Jabro: Thank you. Dr. Ronald Evans: Thank you.