Proposed weight-loss drugs aim for fewer side effects

Host Amber Smith: Upstate Medical University in Syracuse, New York, invites you to be The Informed Patient, with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith.

Medicines that reduce body weight and normalize blood sugar levels are heavily advertised and have become quite popular.

A medicinal chemist at Syracuse University and his collaborators think they have better refined the compounds, and he's here to tell us about it. Dr. Robert Doyle is the Jack and Laura H. Milton professor of chemistry at SU. Welcome back to "HealthLink on Air," Dr. Doyle.

Robert Doyle, PhD: Thank you for having me.

Host Amber Smith: The medicines I'm referring to are the GLP-1 medications, including Ozempic and Mounjaro and others that are on the market.

Can you explain what these medications do and how they work?

Robert Doyle, PhD: Certainly. They are what are referred to as "glip-1" drugs, essentially GLP-1 drugs. GLP-1 is a peptide that you make naturally and in response to intake of calories. They will respond to those calories, but also the elevated glucose levels in your blood by secreting insulin, but also switching off your appetite.

So they're a natural appetite regulation system.

Host Amber Smith: So they're natural, they're not man-made, chemicals?

Robert Doyle, PhD: The drugs that are out there now are based on these, on your natural GLP-1. So what they do is, they take what is essentially a short-acting, immediate response element in you, naturally, and what they do is, they make it longer-lasting or can be less degraded, will penetrate better into the certain regions of the brain, for example, that you want to exacerbate the effect. And essentially all they do is they take nature's role model, and they just make it work longer, better, faster, stronger.

Host Amber Smith: What are the potential side effects?

Robert Doyle, PhD: Well, the potential side effects are weight loss, which as it turns out, was a side effect of their original use.

Their original use was to treat diabetes. And what they noticed was when treating the glucose dysregulation, patients who were taking these drugs were losing weight. And so it was originally a side effect, and they thought, well, as the side effects go, maybe that's useful. And so these diabetes companies like Novo Nordisk and Eli Lilly, which were companies designing drugs to treat diabetes, became obesity companies because they realized that they could expand on this accidental effect and exploit it.

So now we have these weight-loss drugs, which as you referred to, Ozempic, for example, Zepbound. That's really exciting. But what we also have noted are side effects that include nausea, vomiting, low energy, or what we would call malaise, gastric immobility, so your stomach stops emptying. That's a great effect to make you feel full. After you've just eaten, we all get that, oh, I've had too much Thanksgiving turkey feeling. That's because the food is sitting in your stomach. And of course, instead of moving it out of your stomach to be processed, your stomach stops moving it, and then you feel full, and you stop eating. It's a great mechanical response, but what you don't want to do is drive that response too hard, too far, too long, or any of those responses too far, too hard, too long. And that's why a lot of people ultimately end up feeling pretty bad when they take these medications.

Host Amber Smith: People with diabetes are taking these medications for diabetes, but then people are also taking these for weight loss who don't have diabetes.

Robert Doyle, PhD: Absolutely. And essentially the same drug is being used for diabetes or for obesity. They just give them different branded names because they've had to go through different FDA (Food and Drug Administration) approval processes. So they're the same drug, of different name. But the big difference is that the obesity treatment is at a much higher dose than the treatment dose for patients with diabetes. And so obviously the more you take, the greater the effect will be to try to drive that additional weight loss. But the greater the chance, then, that you may have one of these side effects pertaining to stomach emptying, nausea, vomiting and low energy.

Host Amber Smith: So what are the two new peptide compound discoveries that you've presented at conferences of the American Chemical Society and the Obesity Society?

Robert Doyle, PhD: Strangely enough, we talk about vomiting a lot in my group, and it won't surprise anybody who listens, who's ever taken a medication and felt ill, that a lot of medications, while making you get better, can make you feel ill In the short term or in the interim. We're all fully aware of chemotherapy-induced nausea and vomiting. Patients who are taking drugs to treat tumors often feel pretty ill. And so it's the same with these types of obesity drugs and some of these diabetes drugs, et cetera. So my group is very interested in creating drugs that will do what the current drugs can do, but do it without the side effects.

So we talk about side effects a lot, and we are very focused and have been for the past decade on drugs that will stop these things. And one, or in this case, two different pathways that we've explored a lot are new, drugs to do what these Ozempics can do, but to do it without nausea, vomiting, low energy. It's very hard to do because food intake is often coupled to the emetic response, or the nausea response, and so it's very hard to decouple the two, which is why you see it happen so frequently with Ozempic and Wegovy, et cetera.

That's what we do, and that's what we've been approaching. And thankfully we've, I won't simplify it and say it was easy, but I will say that after a lot of work and a lot of support from the Department of Defense and the National Institutes of Health, we have created two compounds that can do exactly that, and neither of these compounds is what you would call a GLP-1.

It's a completely novel pathway, or pathways, because essentially we recognize that GLP-1's have inherent issues. And so we don't want to just reiterate around those drugs that are already out there. We want to look for new pathways. And so one of them that we described is a drug that goes after a melanocortin pathway.

And people will know melanin from skin pigmentation, but they'll be surprised to hear that there are actually five different types of receptors in this family, and two of them help control your appetite. And so yeah, it's pretty interesting, and so we've been exploring that as a mechanism.

And then we've discovered a pathway that is downstream, is what we would call it, of GLP-1, and so the idea is in this case that instead of waiting to hit GLP-1 and then have all of its signals happen, we will just jump in halfway down the response and completely ignore the GLP-1, and that way we'll still get to the same destination, but we'll start the journey halfway there, and that way we won't have the side effects that triggering these GLP receptors have.

And so two very novel approaches and that are manifesting really nicely to produce significant weight loss and a lot of additional other benefits: lower cholesterol, lower triglycerides, for example, less lean muscle mass loss. Because what we're seeing is glucose uptake into the muscle, so we have a non-insulin-dependent glucoregulation taking place. Our hypothesis is that's what's helping protect the muscle mass, because these drugs we've been talking about also cause lean muscle mass loss. You don't just lose fat, you also lose lean muscle mass. And of course you don't want to do that with an elderly population, for example, or with a young population -- really any population, but some populations more than others.

And so being able to focus on just losing the adipose, or the fat, tissue or mitigating the lean muscle mass loss is obviously much better for long-term use, right? So we're excited about what we are discovering about these drugs, tangential to the main target, right? We're really excited about them.

Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith.

I'm talking with medicinal chemist and professor Robert Doyle of Syracuse University. So how far along are you in creating a medication that would go on to get FDA approval?

Robert Doyle, PhD: Without giving away the farm, we have two compounds, as we've been mentioning, that have been licensed, and a company has been built around these two assets, and the company has put a board together. There's investment, and we are now moving towards what's called a pre-IND, which is essentially a pre-investigative new drug. And we need that because the FDA would review that package, all that data that we put together, and give us permission to put it into humans in a Phase 1 trial.

And so our aim is to move into Phase 1 human trials in early 2026, which would be highly exciting because a Phase 1 trial is normally just to ensure it's safe in a healthy human population. But because we're aiming to see weight loss without side effects, even in a healthy population, we're tracking them for their health, if we notice they're losing weight, or we notice that they're sick or ill or throwing up. So in a way, even though it's a Phase 1 we'll get a lot of Phase 2 information.

The nice thing about these drugs is that you can move them through pretty quickly, and you can gain a lot of insights very quickly, even at a Phase 1 level. So 2026 is going to be very exciting for these two drugs.

Host Amber Smith: Now, would these be injections or pills that you swallow?

Robert Doyle, PhD: So initially, these are injections. They'll be once a week, akin to what you do now with Wegovy and Ozempic, et cetera. So this would be subcutaneous injector pens, and then you sit back for a week and let them do their thing, hopefully without any side effects.

Host Amber Smith: Now, if everything goes well with the Phase 1, 2 and then 3, trials, realistically, we're looking at a few years, though, before this would be available.

Robert Doyle, PhD: Yeah, and essentially, if we look in the three- to five-year space, I mean, that's where we always look. So these drugs that are currently on the market are going to be replaced in the next two to three years, and then those drugs will see competition come in the three to five years from now after that. And so I think ultimately what's going to happen is it's going to be very exciting space for the next five to 10 years, and then the space will settle into those optimum 10 to 12 drugs that have ticked all of the metrics of success that we would like to see: weight loss, no lean muscle mass (loss), no side effects in terms of nausea, malaise, gastrointestinal distress, et cetera, lower cholesterol, triglycerides, and, ultimately, watch this space for the next 10 years.

Host Amber Smith: Do you have a name for the medications that you're working on creating?

Robert Doyle, PhD: So the two that we're, focused on primarily right now are DG-260 and KCEM-1. They are just generic internal names that we have. Obviously, as they move towards human use next year they'll be given some snazzy title, some name usually with a Z and a couple of X's in there, or something along those lines. But that would be marketing, and that is over my pay grade.

Host Amber Smith: Would these new medications that you're working on work on someone who eats a lot of high-fat food and who doesn't do any exercise?

Robert Doyle, PhD: Ultimately, we're going to take away your desire to do what you just said you want to do. You won't want to do what you just said. What we're really dealing with here is switching off hedonism (pleasure-seeking), the hedonistic part of your brain. GLP-1's, the current medications, also switch off hedonism or desire to do what you would call sort of dopamine-driven or hedonistic things. And so what's happening with these drugs right now is that they're being used to investigate addiction. What they're finding is that people who take GLP-1's suddenly don't want to smoke. They suddenly don't want to drink alcohol. They're less likely to go and shoot up. It's extending the satiety period, delaying relapse, or in some cases, just making people who smoke their whole life suddenly be like, "I don't want a cigarette." They've lost the desire to smoke. You're not going to just be able to counteract what it is you're doing. You won't do it.

Host Amber Smith: If you did try it, would it make you feel sick?

Robert Doyle, PhD: No, you wouldn't. You would be perfectly fine. But the thing is, what would happen is, you would either not do it at all or do it so much less that you would generally be better off, healthier, right? And even if you did do it, because it offsets your cholesterol levels, your triglyceride levels, your ability to store fat, it would also counteract it anyway.

If I could predict 20, 30 years into the future, this is the kind of thing they would have everybody taking as if they were taking vitamins off of a shelf. This would be over the counter. You should take this with your gummies. Because it would mitigate all of these nasty habits of yours, but also counteract the ones that you still haven't got rid of.

And so why not just take it? Because, well, the other thing that you're going to see is they increase vasculature (blood vessels), which is another side effect they've noted. And so, they're now currently looking at it for Alzheimer's, because what we really realize is that Alzheimer's is being caused by decreased blood flow or vasculature in the brain and damage to the brain over time.

And so if these drugs increase vasculature and increased blood flow in the brain, they'll almost certainly offset cognitive decline. And so what they'll probably tell people is, as soon as you're 40, start taking it and then take it for the rest of your life. Of course that makes Pharma (drug manufacturers) very happy, but If you think about it, if it's going to stave off heart attacks, and it will, and stave off fatty liver disease, and it will, and stave off Alzheimer's, and it will, and it's going to help you maintain a healthy and active lifestyle, and it's going to stop you from pursuing bad habits, then everybody's going to say to take it.

Then the other argument is, well, are you not just generating a set of boring old humans? Yeah, maybe, and maybe you don't want to take it, but I think eventually that's going to be on offer.

I think it's going to be like taking a vitamin.

If you think about it, before Linus Pauling (scientist who advocated taking vitamin C) in the 1960s, nobody took vitamins or minerals. The idea of taking vitamin C didn't exist until the mid- to late 1960s. And now it's who doesn't take a vitamin is more the question than who does, right? You probably took vitamins this morning, or multivitamins or multi-gummies or whatever, right? That didn't happen 50 years ago; nobody did that. Everybody thought you were crazy. Physicians thought it was crazy. Now it's as common as fluoridated water. Nobody thinks about it. But I think you're going to see something along the lines with this too.

Host Amber Smith: How long would a person have to keep taking these vitaminlike drugs?

Robert Doyle, PhD: Oh, you stop the drug, it stops working. Compensation is pretty quick.

If you're on it, you're on it. It's like someone with schizophrenia, they're on it, they feel great, they decide not to take it because they feel great -- (but then) the effects come back. You have to stay on it: minimal, clinically relevant dose for you, and then you would just stay at that maintenance dose for life, or as long as you wanted to be on it.

Host Amber Smith: Would these become made in pill form at some point?

Robert Doyle, PhD: Yeah. I mean, ultimately, these are peptides, though, so, oral absorption of peptides is inherently challenging, so that's why they are injectables. And because some of these drugs target multiple targets, there's no way to make a small molecule that you could take as an oral medication.

But if you have completely new pathways, and you can have a single target, then turning that into a small molecule is feasible and ultimately would happen. But weirdly enough, there is an oral form of a GLP-1 inhibitor right now, Rybelsus. And it's less than 5% of the market.

Physicians haven't been able to get people to take it. It's just as effective, but it has had a really hard time penetrating into the market. And Ozempic still rules, and Zepbound will now outpace Ozempic, and even though there's an oral Ozempic, and it's called Rybelsus. I think it's 5% of the market.

Peptide drugs were considered persona non grata by the pharma industry forever because they were injectable and they said that people won't take them. And it actually took vanity, in the form of obesity, then people would inject. And it turns out, if motivated enough, people will inject.

Host Amber Smith: So this could destroy the alcohol and junk food industry?

Robert Doyle, PhD: Never say never. First of all, junk food industry and alcohol industry is already declining, right? I mean, people are already drinking nonalcoholic beverages; that part of the market has exploded, and it's getting bigger, and even fast food companies offer healthier alternatives and stuff.

The mindset is already changing, but all these drugs would do is sort of parlay into that and maybe drive it forward a bit more, but ultimately, a lot of people won't take them, will never be convinced to take them. You can't convince some people to take a vaccine, right? You're not going to convince them to take a drug that somebody online is going to say turns them into a zombie who doesn't think for themselves anymore or whatever it is that it would be spun as. But at the end of the day, it's not meant for people to live forever. And it's not meant for overweight people. It's meant to help people who have a high risk of Alzheimer's and dying a horrible Alzheimer's-related death, or people who are morbidly obese and are going to die at 32 years of age. Now, for people who have real addictions to opioids and alcohol, and it's life destroying, it's for those people. It's not for those of us who are an average human doing average human stuff, and who's going to be in and above the average human life.

Now, if you think taking it is going to give you another three years, or four years, or five years, and it's going to make you ripped, so you can go to the beach in Puerto Rico, it's not for you, right? That doesn't mean there's not a population of people who will take it for that reason, but it's not for you.

And the FDA is currently refining obesity and then refining the recommendations for physicians to be allowed to prescribe it.

Robert Doyle, PhD: So what you're going to see now is, it's going to be morbidly obese, then there's going to be obese, and then there's going to be overweight. And they're going to say, obese and overweight shouldn't be prescribed these drugs, and they're going to redefine morbidly obese as "here." And unless you're here, you shouldn't be prescribed these drugs.

And that isn't just because, there's side effects to them, and it's not good to be just giving them everybody, but also people who do need them can't get them because they can't make them fast enough. And so there's that side of it too, right? So there's the bioethics of it, and then the FDA has to catch up, because the field is always ahead and then you have to play catch up.

Host Amber Smith: Good luck to you in your research. I appreciate you making time to tell us about it.

Robert Doyle, PhD: Thank you for having me.

Host Amber Smith: My guest has been Robert Doyle, a medicinal chemist and professor of chemistry at Syracuse University.

"The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe, with sound engineering by Bill Broeckel and graphic design by Dan Cameron.

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