Go into it. So thanks for joining us. I'm Terence Flynn, Morgan Stanley's U.S. biopharma analyst. For important disclosures, please see Morgan Stanley's research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. Very pleased to be hosting Structure Therapeutics this afternoon, or this morning, I guess. We're still in the morning. We have the company's CEO, Ray Stevens. Ray, thanks so much for joining us. Really appreciate the time today. Yep. Thank you, Terence. I think we'll focus a lot on some of the recent pipeline developments. Obviously, you guys had some data out for both aleniglipron and your oral amylin. Maybe first, just to start on aleni. Obviously, the obesity market is growing rapidly here. We're seeing the first two orals enter the market and seeing market expansion. As you think about the profile of aleniglipron that you guys have generated so far, what are kind of the key features we should think about on differentiation? Yeah, I think one of the big key differentiators is our dynamic range. We can go from 2.5 mg- 180 mg. What this really translates into is potentially best-in-class efficacy. The data that we showed last week was up to 16% weight loss. We are starting to see a separation of the pack, where many of the competing molecules are in that 11%-12% range, and we are out at 16%. That 16% is after only seven to eight weeks median on the top dose. I am excited about the phase III when we have been out to 52 weeks. Hopefully, we will see even more efficacy. I think dose range and potentially best-in-class efficacy is really what separates aleniglipron from everybody else right now. Great. I kind of alluded this in my opening remarks, but as we look at the launches of the existing orals, what have been your kind of impressions of what we have seen so far, just from a high-level takeaway side? It was about a year ago, I was on stage with you at this same conference. A year ago, the conversation was, is there room for oral GLP-1s? People were still debating this a year ago. Fast-forward only a few months, it was January, JP Morgan conference, or Wegovy came out. Then in April, we had Mounjaro come out. Now it has only been seven, eight months of data that we have. The orals have already taken 17% of the market, and it is still ramping up. I think the number is 80% are new entrants into the market. That means that it is all about expansion. What we are seeing is, with the orals coming on, there was a big pent-up demand. We are seeing then really good launches. Big question we get is with Mounjaro, has the launch been slower? My attitude is give it time. I think let us keep in mind, this has only been a few months. They have been fantastic launches. The estimate is market analysis, by 2030, 50% of the market is going to be oral GLP-1s. Great. Maybe talk to us about scalability. I know that is something else that you guys have highlighted. As we think about not just the U.S. opportunity, but also as a global opportunity and why scalability is so important. Yeah. This is somewhat of a sort of reminder to the previous question. In this space, in GLP-1's class of medicines, one of the other things that is really starting to be appreciated is ex-U.S. market is just as big as the U.S. market. We are really seeing that this is unique from, I think, a lot of other medicines. Now, to aleniglipron, we designed this molecule at the very beginning. We thought about manufacturing, cost of goods. We thought very carefully about that. Our tagline for the company is making medicines accessible to all. So when we designed the molecule, obviously efficacy, safety, tolerability was top of mind. What was also on our mind was manufacturing. Could we make the manufacturing as streamlined and as simple as possible so we could truly get the cost of goods down as low as possible, so we could address a very large global unmet need? I am really proud of our CMC team. They have done a phenomenal job at really making these medicines at the right point. Great. Maybe we will pivot to some of the recent data that came out. So you had the 72-week access open-label extension data. Maybe just give us kind of the highlights from both an efficacy perspective, durability, but also safety tolerability, as again, particularly at the 2.5 mg data. Yeah. I will start with the purpose. We have done more phase II studies than I think anybody else has done in characterizing, particularly for an oral GLP-1. Dr. Blai Coll, our Chief Medical Officer, again, has just done a phenomenal job there. We are really, really happy with the 2.5 mg dose. Starting at that dose, we saw a 2.6% discontinuation rate due to AEs. This is the lowest discontinuation rate that we have seen with any of the GLP-1s. First of all, in terms of that aspect, fantastic job. The 2.5 mg start, we also wanted to see what the physicians are telling us is that what they want is gradual weight loss. They do not want to see that sort of rapid weight loss. Could we have a sort of linear profile, a linear shape to the weight loss? That is important, and we are able to see that. We see weight loss in the first four to six weeks. That is really important. Otherwise, they think it is not working. They will give up. We think that is an important component, but that linear shape of the line is really important. That is the 2.5 mg start, and the start low, go slow really, really works well. Then the question is in that data, 72 weeks of data, safety. What I am really pleased with is, if we look at these sort of liver tox, ALT, AST, we did not see any issues at all. We have been in over 800 participants, 72 weeks. This is a very safe drug, so that is really, really important, the safety profile itself. Then in terms of efficacy, again, after only seven to eight weeks at the top dose, 180 mg, we are seeing 16% weight loss. That is significantly above all the competition out there, and I think it is only going to get better from there. We are really pleased with the aleniglipron data that we shared last week. In talking to the KOLs, what they have highlighted is, again, we are separating from the pack and we are able to maintain that solid weight loss. Great. I think there is a couple more readouts coming up here in the fourth quarter. So you have a body composition study, you also have a switch study. Maybe just remind us kind of what we are hoping to learn from those two studies in the fourth quarter. Yeah. Next quarter is actually going to be three studies. The body composition will read out. This is where we're looking at fat versus muscle. This is an important question. This is now required by the FDA in this class of medicines. Part of it is really making sure that we do these studies optimally. We're also starting at 2.5 mg, and we'll go to 180 mg in that study as well, 44 weeks. The second study that'll read out is type 2 diabetes. These are individuals with type 2 diabetes who are overweight. Here in our previous type 2 diabetes, we only went to 90 mg. Now we'll be going up to 180 mg. We think that's an important readout also. That will help us to inform the ACCOMPLISH-2 study, phase III study that's now underway. The third study, the switch study, we know that those on injectable GLP-1s, the discontinuation rate is 85% after two years. Most people stop taking injectable GLP-1s after two years. One of the big words in the recent FDA update was maintenance, long-term maintenance for this class. What the FDA wants to avoid is what is often referred to as the yo-yo effect. People lose weight, gain weight, lose weight, gain weight. We wanted to ask the question, could you switch from an injectable GLP-1 over to an oral? If you switch, do you have to re-titrate, or can you start at dose X on an injectable, and can you seamlessly go straight to a similar dose of an oral? That's the question that we're asking in that switch study. All three of those will read out next quarter. Great. Maybe just a couple follow-ups on the switch study. I know Lilly had some data for orforglipron from ATTAIN-MAINTAIN. Any key differences in terms of design for your trial versus their trial as we try it? Everyone's going to do these cross-trial comparisons, but anything we need to be mindful of there? Yeah, I think Lilly did. For Eli Lilly, I think that was a very well-executed study. Orforglipron can achieve 11%-12% weight loss. They compared it to tirzepatide, a GLP-1/GIP, and that's putting the bar pretty high. What we're doing is we're looking at, with GLP-1s, we think that first of all, aleniglipron is showing currently 16% weight loss. So we have potentially best in class in terms of efficacy, GLP-1. Can we maintain that weight loss? Or can we possibly get additional weight loss as well if you're on a GLP-1, or can you maintain to a GLP-1/GIP? I think it's really the biggest difference is we have potentially better in class molecule. Can you maintain that? And so just because, so you are not doing the tirzepatide transition, you are only doing the GLP-1. Yeah. We have not updated. What we have stated is that we are doing GLP injectables. Yeah. It may be a combination. Okay. And what, just remind us the size, like how many people are going to be in this? I don't have the exact number off the top of my head. Okay. But it's fairly, that's like a decent sized trial. Yeah. Okay. Okay, great. On the type 2 diabetes side, again, you mentioned you previously went up to 90, now you're going up to 180. I'm assuming you're going to gather not only weight loss data, but hemoglobin A1C data. Maybe just remind us what you guys saw before at the 90 mg dose. Yeah. At the 90 mg dose, what we saw, I think it was around 3.5% weight loss. For those with individuals living with type 2 diabetes, they typically see less weight loss than those without, that are not living with type 2 diabetes. It was also at a lower dose. We want to sort of basically test at a higher dose, can we see further improvements in hemoglobin A1C? That is really the main driver is hemoglobin A1C for individuals living with type 2 diabetes. We have recently seen some very encouraging data on orforglipron in type 2 diabetes, and we think this is an important question to ask. Okay. Okay, great. Maybe now, you alluded to this, but you guys have already moved into the phase III program, so maybe just high level set us kind of the scope of that phase III program that started and then how to think about additional trials and other indications. We have two different studies going on, ACCOMPLISH-1 and ACCOMPLISH-2. This data will read out at the end of 2028. They are individuals that are on maintenance dose for 52 weeks. This is the FDA guidelines. Approximately 5,000 participants total. There will be three different cohorts going up to 45, 90, and 180 mg. The starting dose will be 2.5 mg. Again, what we have learned from all the studies is individuals are very happy at that 2.5-mg start, and start low and go slow. Titration steps once every four weeks. Again, we know that is the right sort of titration step, both for tolerability but also that linear weight loss that we are trying to achieve. Those are the rough parameters. And then one other thing I would say is I think, again, Blai has done a phenomenal job at doing additional studies to help us do the best optimal sort of phase III. One of the experiments that he did in phase II was what we called an open-label extension. One of the challenges in the field are placebo groups in this space. Blai wanted to ask the question, if you do an open-label extension where you can extend, basically in the phase III, for an additional year, does this help with the clinical trial execution? It certainly helped in the phase II study. We believe it will help us in the phase III study. The use of heat maps, again, Blai has been very creative. He was the first to use an open-label extension in obesity, first to use these heat maps where we look at the patient journey, what happens if you skip a dose. That has also really helped us understand how to do the titrations, how to do the steps, and how to have the best possible patient experience as they go through titration phase all the way through maintenance. All those things combined give us the confidence that the phase III will be very well executed. Great. Anything else on baseline characteristics about this population you're enrolling versus maybe the phase II trial? No, it'll be very similar, phase II to phase III. Okay. Great. How do you think about the rate of discontinuations due to AEs that would be competitive? Maybe just frame for us that, and then, again, you mentioned the 2.6% I think you guys saw in the latest cut of the data. Is that the right level to think about here from the phase III program? Yeah, that was a smaller study in a shorter period of time, so I have to sort of factor that in. We need to be competitive. At the end of the day, we got to be competitive in all the different categories in terms of efficacy, tolerability. We do think discontinuation rate. At the end of the day, what really matters, individuals are taking the medicine and it's working, and that they don't discontinue. So that 2.6% rate, we're really proud, again, I think best in class in the field. That was a smaller study. I'm not going to give a specific number, but we need to be competitive with everybody else. Okay, great. The second part of my question was just on the other comorbidities you might consider. We've seen Lilly, Novo lean into some of these other indications like sleep apnea, for example. So how are you guys thinking about that next cohort of potential trials? For this particular, the way that we analyze the field, the foundation is chronic weight management. This is the biggest market opportunity. It's also the market that's becoming direct pay in terms of growth, so we are laser-focused on chronic weight management as the primary foundation. We're also doing individuals who are overweight with type 2 diabetes because we think that that's also a really important subset as well. That's where we're focused for the phase III. That's ACCOMPLISH-1 is individuals who are overweight. ACCOMPLISH-2 is individuals overweight with type 2 diabetes. Yeah. Okay, great. Latest thoughts on potential partnership for aleni, like where are we at? Any timelines? We continue having dialogues. We enjoy interacting with everybody in the industry. We are laser-focused on execution as the strategics still understand this space. This is uncharted territory. It is consumer product together with the pharmaceutical market. It is a field that is growing really, really fast. What we think with our aleni data being best in class, it is highly differentiated. The dose range, 2.5- 180, is differentiated. All the different properties. We think that this is going to be a really great molecule. We are focused on execution. Strategics, we will continue having dialogues, but we think it is significantly de-risked with this latest data. Okay. Great. Maybe we will move on to your second program, 2671. This is the oral amylin. Again, an update about a week ago from the SAD portion of the phase I. Maybe just talk to us about the highlights for those that did not see that data, and then we will dig into some more. Yeah. This is a molecule many of my friends at other companies used to say, "Ray, you can never make a small molecule to amylin. It is just too challenging." These are peptide receptors, and this particular amylin is a complicated biological system. First, I am really proud of the chemists and the biologists. They did a great job at coming up with this molecule. The highlights from the data release that we had last week, first of all, it is an oral small molecule. Second, it has a half-life. We shared PK data, a half-life of 6 days. This is right in line with the peptides. Again, this is something that we knew it was going to have a long half-life. We shared data at the American Diabetes Association meeting this summer in New Orleans, 60 hours in human primates. We are quite pleased. It was actually even longer than we thought in humans. That 6-day half-life gives us the opportunity to do a once-a-day dose daily or once-a-week dose. That is something that we are going to explore in the MAD portion itself. We also were very pleased with the. We had three different levels of target engagement to show that we really do have a drug that works. The first was, if you go to a very high dose, do you feel adverse events? If we did not see anything, people would have said, "Your drug does not work." We viewed that as something that was important. At the 1 mg and 2 mg dose, no AEs, zero. 5 mg, you start seeing AEs, 10 mg, you see AEs. It was right in line with what was expected. Second, we did see, even though this was not a weight loss study, we give people a single pill, but after 17 or 24 days, we saw weight loss. That was also another sign of target engagement. Then the third, this was very exploratory. In the amylin space, there is a debate between DACRAs, dual amylin and calcitonin receptor agonist, and SARAs, selective amylin receptor agonist. We wanted to ask the question, the calcitonin component, is there a possibility that this class of medicines could be important for bone health? This is an important segment of the population. We evaluated, we looked at CTX-1 as a bone biomarker, and we were very pleased to see that we saw a target engagement with CTX-1 as well as with bone Alk Phos. So three levels of target engagement in an SAD study, all the information that we needed to educate us on how to do the MAD portion as well as possible. We will be starting in the MAD, obviously, at 1 mg or 2 mg, no AEs. We will titrate like everybody else does in GLP-1s and in amylins, and excited to see that data in the first half of next year. Okay, great. Maybe just remind us, what is the benchmark there from some of the early injectable amylin studies? When we look at the data, what should we compare it to, I guess? If we look at the DACRAs, there is petrelintide, there is cagrilintide. Those were kind of our benchmarks when we originally designed the molecule. There are some additional molecules that have come out more recently. We think those are the right benchmarks for the DACRAs. As a reminder, we have both DACRA and SARA, small molecules. But for the right benchmark for this, we think the DACRAs are the right benchmark. Okay. Is it going to be a four-week or 12-week MAD study? Yeah, this will be a 12-week multiple ascending dose study with titration steps starting in the 1 mg-2 mg range. Okay. Is it a four-week titration, I am assuming? We can titrate roughly for half the time. That is actually a really important clarification point, Terence, is because it is only 12 weeks, we can only titrate for half of that, six weeks. We cannot do the titration steps once every four weeks. So this is an accelerated, roughly once every one to two weeks titration steps. So that is an important distinction. If I think about our aleniglipron program, when we went from our SAD study to our MAD study, six weeks was titrating, six weeks on maintenance. When we switched to our 36-week study, we were then able to switch to once every four weeks, which we know is the right point we want to get to, and we were also able to go to higher doses as well. With aleniglipron, SAD went to 90, we went to 120 in our 12 week, and then we went to 180, 240 at our 36 week. We have a really good path for how we are going to execute the amylin program. Okay. Do you think that you have enough time, or you will get up to doses where you can show equivalent efficacy to the injectable amylins and those benchmarks? Is that a fair comparison, just given some of those dynamics you walked through? Yeah. I think that we have to see. Again, I am going to use the analogy with aleniglipron, where we only went to 120 mg in our MAD study, 12 weeks, because we could only titrate so much. In a 36 week, we could titrate in steps of four. We had longer time. We could go to 180 and 240, where we have really been able to separate from the pack from everybody else having this full dose range opportunity. Okay. The other area obviously is combinations. I think that is the end game for most of these is you have a GLP backbone, you add on another pathway, whether it is an amylin, a glucagon, as everyone knows. We have seen a lot of that in the injectable space. Obviously, this is in oral now, so it gives you that flexibility. Talk to us about what the combination strategy is and timelines for when we might see some. I know you guys have preclinical data, but timelines for clinical data. Yeah. I view aleniglipron and our amylin as monotherapies, and these, I think, are great monotherapies by themselves. We will be starting next quarter, combination trials. Well, actually, we've already started in the MAD portion. We have an add-on arm where individuals that are stably on an injectable GLP-1, we give them 2671, and we're asking the question, do they have additional weight loss by giving them 2671? I think that add-on, this is already part of the MAD study, is currently in progress. Next quarter, we'll combine two different oral molecules, and we'll look at GLP-1 plus amylin, and that's for increase in efficacy. Then we also have a GIP small molecule and our glucagon small molecules. We start to get into those combinations, as well as other non-incretin. We've always viewed this as life cycle management. Again, monotherapies, two different backbones. Those are molecules for the masses, for the large numbers of people. Then the combos are more specialized molecules for different disease subtypes. Okay. The MAD, you said some data first half 2027. Is that going to include the injectable add-on data? That will include the injectable add-on data, correct. Okay. And those people, I'm assuming, will have had to be stable on a GLP-1 for some certain amount of time? Stable on a GLP-1, stable tolerability, everything. Then if you give them 2671, what is the effect? Okay. Then what's the expectation for when we could see some data from an oral-oral, like a GLP-amylin combo data for oral-oral? The plan is right now to start that in Q4 next quarter, then we'll have updates in 2027 on that program. Okay. So probably second half is more likely. Yeah. Okay. Okay, great. Just remind us there, so you are for the GLP, you are going to be using aleni, is that right? We haven't updated on that. Okay. We have multiple molecules. Okay. GLP-1, just like we have multiple molecules for amylin. Okay. So TBD. Yep. Okay. You mentioned this a few minutes ago, but DACRA versus SARA. Just give us an update in terms of how you're thinking about the pros and cons of both of those, and then the timeline for your SARA. Yeah. We're very intrigued by the eloralintide data, and we think it's very good data. We're excited at EASD, we're going to get an update of eloralintide together with tirzepatide, so that's going to be interesting to see. The way that we sort of look at this is, and it's why we're exploring bone health. The difference between the DACRA and a SARA is calcitonin. That's the simplest distinction. With the DACRA, is there an opportunity there for bone health? So we view them as two different products, is how we look at it. We don't look at it as an either/or, so we're developing both. Okay. How do you think about maximizing value from the oral amylin program at this point? What are next steps, and how do you think about, again, retaining it further through development versus potentially partnering it? Yeah. So at Structure, we are in the very fortunate position. We have a portfolio. We have our phase III aleniglipron. We have our amylin 2671 that is now in phase II, phase IIa. The other molecules as well, and the combinations starting to emerge. We know there has been a lot of interest in the amylin. It continues to be a very exciting space. We are going to see other data from other companies in the injectable peptides that is going to further validate and clarify the field. So we think that we are in a really good position. Your question about strategics, I think many have been looking forward to this data, and we were excited to release that data last week. We will continue now with the MAD underway. That will generate additional data. We are going to stay laser-focused on execution for these while we continue dialogues with strategics. The IP goes out, what, 2040s, I would imagine? Correct. Okay. We have been very The benefit, I think, of our platform, our name, Structure Therapeutics, structure-based drug discovery. By being able to visualize, see the binding pocket, we are able to really cast a wide net in terms of intellectual property patenting of molecules. This clearly was an opportunity for us in the GLP-1 space, with doing a deal, somebody having to come to us to license molecules. Our amylin strategy is very similar, so I view this as we protect the castle, our main molecules, but we also create a moat to make sure, we have made these molecules because we have been exploring the space, because we can visualize the binding site computationally. We want to make sure that we win in the space. This gets to a common question I get, Terence, "Why do you have a second amylin going in?" It is a different chemical scaffold. It's all about winning in this space. Great. Just remind us, you mentioned a GIP and a glucagon. How long did it take you to get the amylin program to lead into the clinic, all that kind of stuff? As we think out for timelines for these other targets, is this two years, three years? Yeah. I'm sort of calculating in my head. We had the big breakthrough, I would say, in this whole space, we had the big breakthrough in the Class B G protein-coupled receptors. 2015, we got the structure of GLP-1 and glucagon. Those were the first two. It was 2018 that we got the three-dimensional structure using cryo-electron microscopy for the amylin receptor, and that was with different peptides that we were able to see. We made a decision a couple years ago that we saw the importance of amylin, and our GLP-1 program was well underway. We basically shifted all the troops to focus just on amylin for a period of time. I don't have the exact sort of answer in terms of timeline, but we put a heroic effort, which we continue on amylin, again, to make sure that we win in that space. It did come at a cost of us slowing down our GIP agonist program. Okay. But that is now I think that has gotten some good steam, and we hope to, next year, have some good updates on both GIP and glucagon. It sounds like the troops are back on GIP. We've been able to expand the troops. Okay. We've been able to recruit more troops. It's an army. We're at war. I would say we're expanding. We're not shifting. Okay. Got it. Great. Well, thanks so much, Ray. Always a pleasure, and best of luck. Absolutely. Thank you, Terence. Thank you.