GLP-1 muscle loss: the next battleground in obesity treatment (Part 2 of 3)

0:05Welcome to Beyond Biotech and part 2 of our three part series on GOP1s and the future of metabolic health, a series we're calling the metabolic moment. In just a few years, GOP1s have become a phenomenon. They've transformed how we treat diabetes and obesity, created one of the biggest markets in pharma, and sparked a cultural conversation that reaches far beyond the clinic. Now that market is shifting. Cheaper alternatives are coming. New mechanisms are entering trials, and some companies are aiming for something closer to a cure. So what happens next for patients, for the companies leading the field, and for the startups hoping to overtake them?

0:48Across three conversations, we'll follow the money, the science, and the people behind this metabolic moment.

1:13GLP-1 drugs have transformed obesity care, but they come with a catch. A meaningful share of the weight people lose is muscle, and that matters especially for older patients. So what if a drug could help the body burn fat while protecting or even building muscle? That's the idea behind a trogi, a Swedish biotech developing ATR258. It's a first-in-class oral therapy designed to mimic some of the effects of exercise. The aim is to keep the metabolic benefits while avoiding the cardiovascular side effects linked to older beta-2 agonists. The company has completed a 69-person Phase 1 trial and now has new proof-of-mechanism data showing gains in muscle power.

1:58Phase 2 is planned for 2027. Joining me today is Paul Little, CEO of Etrogi. We talk about what GOP-1's left unsolved, the science behind ATR258, and how a small company competes in a market led by giants. Paul, welcome to Beyond Biotech. Pleasure to be here. Thanks for having me. Paul, you're the CEO of Etrogi. You have been since November 2025. But before that, you were CEO of Vesper Bio. You had some programs in clinical trials. You've had a PhD in organic chemistry. I mean, you've been in the industry now for a quarter century. How does this shape what you're doing? How does it shape the work that you're doing in drug discovery?

2:44Well, it's a great question. I guess when you reflect back, I've seen a fair few things happen over the 25 years. And I think the first thing that I've seen that is interesting for today's conversation is I went through one of the first attempts, to get an obesity drug on the market in the zeros. And at that point, we were arguing quite a lot with investors and pharma companies about whether there's actually a market in obesity. I think we've now answered that question finally. I think some of the other things we've worked out is how to outsource and work with collaborators across broad geographies to leverage smaller teams in a cash-efficient way.

3:30We've understood what our customers are looking for, and that's an ever-changing landscape of desires and needs, of course. But I think the most important thing is really thinking about clear communication, understanding how our message is getting across. It's not always just about the science and the data, but that's obviously a big part of it. and at the end of the day the biggest thing is it's a team effort there's a lot of people involved everyone needs to be involved and how you shape that team is really part of the the difference between winning and not winning you know you said you worked on an obesity drug back in in the early 2000s but you joined a troge in late 2025 what convinced you to take on that role what did you see in the science that was promising enough to to jump on board again a great question because i i took a quite a few uh looks at the data before coming on board and each time i looked at the data it got more and more exciting uh the strength in depth of the data was amazing the team were phenomenal and it looked like the opportunity uh that couldn't be missed in the sense that you know here's a product exactly at the right time to solve what we think is the next problem facing the obesity field and the metabolic field and the muscle field and so it it was kind of a decision that made itself in the sense that i'd seen a lot before and this really ticked all the boxes you know it's almost hard to believe that even just 25 years ago people were still wondering if there was a market here in obesity because right now the GOP1s have transformed the way that we think about obesity and how we care for that particular issue what problems are they not solving though?

5:26Well what are we not solving? We're not solving the unintended consequences of rapid weight loss right so GOP1s are really powerful drugs I think the market leaders have have done tremendous work to create therapies that overcome the challenges of short half-life and nausea and all of that. And now we've got very, very powerful drugs that help people lose weight very, very quickly with some nausea, with some side effects, because there always is with a powerful mechanism. And what we are seeing now is that, you know, quite a large percentage of the weight loss is in fact muscle mass and muscle is clearly important for life feeling good the ability to get about and that is the the next big wave it's really brought into focus the muscle aspect right that's one thing and that combines with an aging demographic around the world right and we are all more sedentary than we should be and all these things combine into uh you know there's a next wave of therapies to look at.

6:35The other thing that GLP-1s and incretins don't necessarily solve just now is what happens after the therapy, right? You take GLP-1 and you lose weight quickly. What happens when you come off it? You rebound weight quite quickly. I know there are obviously attempts to solve that, but we haven't solved it yet. And that in itself is not necessarily a great thing. But the powerful drugs, you're really helping people not just lose weight, but that weight loss comes with real benefits for all-cause mortality. So it's fabulous, but they've created a little bit of an opportunity for some additional work to be done.

7:18You mentioned a couple of things there that I want to see if we can connect them together. One is this problem of muscle loss, and the other is this aging population. Why is this such a problem, especially for these older patients? Right. So, you know, we all need muscle to get about. And above the age of 50, unfortunately, I'm there. We're losing roughly 1 % of our muscle mass every year. Right. And as that accumulates and as the population on average gets older, you know, get up towards 60, 70, you're getting frailer. you're getting lower limb loss of muscle, which is called sarcopenia, that will mean that you end up slowing your walking pace, your ability to get out of the chair is impaired.

8:06And these are real issues that make daily living more challenging. Imagine trying to cross the road when the pedestrian light is on for walk. You've only got a few seconds. If you don't get across, you're in trouble. if you're stuck in a chair all day your life quality is lower you know if you've been in in hospital in bed for a long time because maybe you've had a hip replacement there's been an infection you've had to stay in bed for a while all these things add up to you know problems that really impede quality of life and function for people and is actually directly linked to mortality it seems right that if you don't have the muscle to to live your best life your chances of of dying increase so we've got these therapies the glp1s they're having you know side effects or unintended consequences or just consequences for health do you see then the future of treating these metabolic diseases as being glp1s plus some sort of add-on or is there room for just an entirely different drug class there to compete or complement them well yeah i think you know compete complement uh i think gfp ones do now have a very strong position they will always now be a part of the armory of treating you know uh obesity and and maybe that becomes a more and more specific population maybe uh maybe you end up having different products different incretins triple agonists etc moving in right it could be that something comes along and and supersedes them that's something that you know time will have to tell but i think now we have these powerful drugs they do have a position they're really helping people i but that's the nature of life right we will find things are the better uh and and that will eat away at the market position of the grp1s exactly what takes the market.

10:14We'll have to see. But there's still a massive unmet need out there, not just in obesity, type 2 diabetes, and all sorts of other metabolic diseases, and of course, the muscle wasting effects. You know, all of this brings us to the work that you're doing now at Etrogi. You've got your own candidate there, ATR258. It modulates the gpcr signaling and you've got it in clinical trials maybe walk me through that how is gpcr signaling linked to the metabolism and the onset of these diseases yeah so at the very basic level gpcrs they sit on the cell membrane and they take instructions from from signals molecules floating around in in the in the blood in the plasma and convert that into instructions and signaling within the cell that signaling then leads to various outcomes within the cell that can include changes in in the proteomics of the cell and that then leads to downstream effects now the beta 2 itself is not involved in in the obesity per se it's involved in if you like our response to exercise.

11:28It's involved in that type of area. So the GPCR, there's about 400 of them. They're the targets for many, many drugs and, you know, very, very successful class of receptors for drug candidates and drug products. What we're seeing now is that it's not just about hitting that target with anything that hits the target. You can actually tune what you're hitting the target with to send the right signal to send the right information into the cell and that's really where a trogi has made a leap forward by by finding a way to tell the cell what it we would prefer it to do rather than what other agonists have done in the past you know you mentioned exercise just then and you've described atr258 as a therapy that mimics the effects of exercise elaborate on that because it sort of sounds like we've got uh glp1s which is these magic uh lose weight drugs have we got one that is the magic no need to exercise drug well so there's no magic here in the sense that glp1s are very very good at turning off your appetite that's really what they're there to do right so you've got this this lizard the gila lizard that that has exendin in its saliva and it can hang around for a couple of years without eating.

12:52And that's kind of how some people got into this, if I remember rightly. And in terms of the beta 2, we know it's involved when you have an adrenal, an adrenaline response, it sort of kicks in and that's part of what happens, a wide range of downstream processing that upregulates various things, specifically in response to exercise we know that the beta 2 is involved in in then how you repair and rebuild and and respond to exercise and essentially what we're seeing is something that looks very much like uh like that we give the pill the body responds by growing muscle by growing function by burning fat by and in that way by building muscle soaking up additional sugar from the blood it sort of moves things around like glucose transporters it's and it does all the same sort of things as you would see from from exercise so if you do a heavy exercise routine and then take a muscle biopsy you will look at you know the the changes in in the proteins and so-called proteomics and then you look at the response to our drug and it looks very similar so it's not a magic pill we're basically understanding the the mechanisms ongoing in the body and trying to use them to our benefit these beta 2 agonists so they've been used in the past to treat things like like asthma lung diseases how does that connect with the sort of indications that you're targeting well exactly i mean this this was a question that that takes a number of answers if you like you can think that even chinese medicine was using uh products that had in them products that would uh that would target the beta 2 that's sort of 5 000 years old so a lot of products on the market at some level originate from from natural products but through the years we developed more and more beta 2s as we learned more about the receptors and and how to design compounds that actually target them efficiently and directly.

15:14And that led to something called clenbuterol, which came out in the 70s. And that was targeted specifically towards aspirin. It was looked at in terms of the muscle, even at that stage. But the challenge for that particular product was that you could see the off-target effects or the unwanted effects were not suitable for the muscle-wasting diseases as we knew them at the time, right? So the risk-benefit ratio certainly wasn't there for clenbuterol in the muscle. There wasn't the understanding of muscle-wasting diseases. Plus, we could see that actually asthma itself is a massive market, and these products have done a huge amount of good, saving lives all around the world and showing that fundamentally targeting this receptor is safe.

16:09It's safe, but it has been associated with some side effects in the past, cardiovascular side effects. How are you designing it now to try and circumvent some of these? It's an interesting one. So I think if you look at the data, the cardiovascular side effects actually feel a little bit overblown to some extent, And even with the traditional agonists, of course, I'm biased when I look at that. But if you look at the meta-analyses, it does look that way. What we've gone in and done is designed something that specifically sends a signal through the beta-2 receptor to target this GRK2 intracellular signaling pathway and also avoid a separate pathway, which is called beta-arrestin.

16:57And it's that beta-arresin pathway that desensitizes the Bina2 receptor. And because you desensitize a receptor, what people would normally do would be to up the dose of the product to get the desired effect. And, of course, if you overdose on any drug, you're likely to see problems. So we've designed something that doesn't desensitize the receptor. It's more specific for the receptor that we're looking for. And even more, it's pushing the signal through a specific pathway that we know is avoiding even the hint of the cardiovascular side effect. Let's talk about the drug a little bit more because you've got it in the clinic.

17:42The phase one trial was 69 people, healthy volunteers and patients with type 2 diabetes. Tell me what you learned from that study. What was the safety profile like? yeah so the what we learned from that was exactly the safety profile the pharmacokinetics the uh the first signals of efficacy or target engagement in the population so we ran the type 2 diabetic type 2 diabetic population small cohort but we ran them for 28 weeks 28 days my apologies 28 days and we followed things like their insulin sensitivity etc etc and we could see that we did have target engagement what we did also see that if we went in with that particular version of the drug product we would see on the first day you would get a small spike in in heart rate nothing that was considered to be serious but that was sufficient for us to take a look and say well okay let's dose this in a slightly different way and avoid that and that's what we've done with the latest trial we've avoided that small heart rate increase on the first day and that has allowed us to access the the efficacy that we could see the signals of so that that's that's the answer you know the the results that came out relatively recently now there was a 13 percent improvement in lower extremity muscle power from baseline 1.1 kilo reduction in fat mass and a 0.8 kilo increase in that lean muscle mass talk me through those what's the significance of results like that well firstly let's point out that they are statistically significant which is amazing given the the size and duration of the trial and i think morten hustrup and his team have done an amazing job of course they did because he's done uh 50 odd trials with beta 2 agonists in the past he knows what he's doing he's worked uh in in muscle physiology and performance for for many many years so really really good what what is the significance well it's a unique profile it's a unique profile for several reasons one it's very rare that you get muscle gain whilst you're losing fat right normally if you're on the diet you lose both fat and muscle at the same time under caloric restriction the the body itself wants to take energy from the muscle so it's the natural way to go.

20:09So building lean mass, and we will call that muscle for the sake of argument, is amazing whilst losing fat at the same time, especially in the cohort of individuals that were not told to change their daily routine. They were not told to be on the diet. They were not expecting to have any specific effects. In terms of the real uniqueness here, the real win is the function that's what that is the thing that we haven't seen combined with fat loss and lean mass gain in any product that i know of globally that is unique and amazing and to put the 13 into context because i think that's really important in morton's own hands it seems to be roughly twice the amount of functional gain you would expect from doing resistance training for the same period of time right that's pretty impressive if you did resistance training plus to a classic beta two that's one of the ones that only works for a few hours or days before desensitizing who did the two combined we still beat that slightly right so this is a powerful outcome in just eight weeks if i go out on the limb and say how do i contextualize that for how people feel, it could be the same as reversing four to five years of psychopenic decline in that population in terms of the amount of power we generate.

21:40It would be enough if it was in that population to help people cross the road more quickly, get out of the chair more easily, live a better life. And we find that truly encouraging. And we also see very good signs that we might see improvements even earlier than eight weeks. So great results in the phase one trial. What does the phase two plan start to look like then and what indications are you going to target? Well, I think that there are three options ahead of us and one of those is to exactly offset some of the unintended consequences of GLP-1 by doing a sort of co-therapy with the GLP-1. That's clearly something that is interesting, and there's a very clear route forward how we could do that.

22:33The second one is to go into a more sarcopenic population, an older population, 50 plus, who are losing lower limb function, but maybe also are still carrying quite a lot of weight around. That's a great opportunity to see how this performs in that population. the third opportunity is to go you know very specific into a rare disease population where there is muscle wasting clearly evident so there are three options ahead of us and we're looking forward to telling the world which one we pick let's talk a little bit more about what makes you different and maybe take a little bit of a look forward as well this is an oral therapy an oral drug that's designed to preserve the muscle.

23:21Is that a big advantage when it comes to the commercial side of what you're showing to investors and what you'll take to market? Well, I think, yeah, I think oral does be that injectable, but we're not alone with orals now because there are oral GLP-1s and oral incretins. I don't think it's a big win for patients to know that it's more sustainable to have a small molecule rather than, you know, the low bioavailability pill that that doesn't really matter what matters to people is the function i think what does matter to people will matter to people is that there are no gi side effects with this approach uh that you know this is a fairly gentle uh product of course as with any product when it gets uh when you take you should follow all the prescription and label and all of that.

24:13It is unique in the profile, right? And I think it's one product that delivers a lot of what we're hoping to achieve. And by building muscle, you're actually building in the long-term weight maintenance that we really need because it's the muscle that soaks up a lot of the extra energy if it's in the form of glucose in the blood before it gets laid down as adipose. And I'm a bit on thin ice there because I'm a chemist, not a biologist. But essentially, if you've got more muscle, you will buffer yourself against the overeating that is natural in terms of rebound when you come off an incretin. I think those are the areas where we clearly see a benefit The real uniqueness, of course, is the function.

25:06Functional benefit is mass we-uniting. That's true, but there are still some drugs out there around preserving muscle mass, promoting muscle growth, myostatin, activin inhibitors. Where do you see your approach and your drug sitting in relation to those sorts of things, which are already on the market? Yeah, I think it's all about function. It's not about just the mass. And I haven't seen convincing enough information to say that there are other drugs that have the muscle function gain that we're seeing. We can see products that appear to reduce loss of muscle function. But that's a different thing than muscle function gain.

25:49Right. We're not talking just about preserving muscle mass. We're talking about building functional muscle. and by building folks the muscle, giving people the ability to live their best life. You know, if we go back to this market where you're going to be working in, competing in, you've got Novo, you've got Lilly, some of the biggest players in the world there. You're a small Swedish company. You know, what do you predict the competition's going to be like or are you going to end up partnering with one of these big firms? Is that part of the process, part of the goal? Well, I think it's natural for a biotech to think that at a certain point, partnering is the real way to go forward, not least because these are experts in the field, right, in terms of clinical development.

26:38They know it. They know the regulatory pathways. They know how to do it. They have everything set up. So a partnership is a great way to go forward. And that would make most sense, right? But of course, you can't guarantee a partnership until you get to a certain point. So until that point, we're on our own. But then it's not really competition because it's drug development. And then what we need to do is our very best controlled clinical trials to generate the data that eventually will persuade people that this is a great product to bring into their pipeline. so if I'm at Novo, if I'm at Lilly or if I'm just interested in the work you're doing where could I go to learn a little bit more about what Etrogi is doing to keep up with the science?

27:27Well we're around about all over the place we'll be at Optimum's annual summit shortly, we'll be at BioEurope, we'll be at Jeffries LSX there in London we'll be at JP Morgan and multiple other scientific conferences around and about as well. So we're definitely out and about, happy to talk to everyone. And of course, we can be reached through our webpage as well. Paul, it's been great talking to you. I want to thank you for joining us today on Beyond Biotech. Thank you so much. That was great. That's it for this episode. Don't forget to check out all the latest news and analysis at labiotech.eu.

28:12I hope wherever you are in the world, You have a great week ahead. Thanks for listening, and I hope you'll join us again next time for another Beyond Biotech.