Sorry we're getting started a few minutes late here. It's very much my pleasure to welcome members of the leadership team at Structure Therapeutics. The CEO, Ray, is to my right and CFO, Jun, is to his right. I thought that we could start off maybe just with some, a little bit of opening comments from you, Ray, in terms of the company and what you're focused on this year. Then we'll go into the discussion. Yeah. Thank you. T hank you, Dave. As many of you know, we started Structure Therapeutics really around accessibility, making medicines more accessible to all. Our platform is what, you know, really drives us: go after your favorite biologic, antibody, peptide drug, and convert it into an oral small molecule. The lead program, GLP-1, which we started, I have been working on GLP-1 for about 20 years, had a big breakthrough around 2015. One of the things we are really excited about in 2025 is that we are going to finally see this accessibility really come to fruition. What I mean by this is this is a field that has been dominated by the injectable peptides. We stand on the shoulder of giants, as many people say: Eli Lilly, Novo Nordisk have just done a wonderful job in terms of setting the stage, showing what this class of medicines can do. The fact is, these medicines are not accessible to all. Not only are they not accessible to all, but more than half of people that go on this class of medicines, the injectable peptides, discontinue after the first year. There is a variety of different reasons that, you know, we can get into as to why that is. It is clearly, you know, this is really a small molecule area. In the recent FDA guidance that just came out in January, first update since 2007, it was highlighted maintenance 7x in that document from the FDA. The maintenance people are not staying on this class of drugs. We know that this is a problem, that people need to stay on these drugs for life. At Structure, we released last summer very positive data. Our phase IIa, 12-week data showed very strong weight loss, very good, very low discontinuations. We have two different phase IIb studies ongoing called ACCESS and ACCESS II. These are 36-week studies, 300 participants total. The ACCESS study itself is targeted at 120 mg dose. This is a dose that we believe will be equivalent to orforglipron. By the way, we think that 2025 will be the year of oral small molecules in this space. I say that because orforglipron, we're going to see some data from Eli Lilly in Q2 in those living with type 2 diabetes. In Q4, we'll see data in healthy overweight. We'll see our data in, sorry, Q3, we'll see their healthy overweight. Q4, we'll see our phase IIb data. We think our 120 mg dose will be equivalent to Eli Lilly's 36 mg dose. The follow-on study that we have called ACCESS II, we're really excited about that. That's allowing us to go up to 180 mg to 240 mg dose. We've always wanted to go to this dose. We have one of the most potent GLP-1s out there for small molecules. We did not feel in the 12-week study we could go to that higher dose of 180mg, 240 mg. It just would not be right for the participants. We are quite excited in a 36-week study to be able to go up to 180 mg and 240 mg dose to really see what aleniglipron, the name of our drug, can do. We are hoping to see even more improved efficacy in that ACCESS II study. Lastly, Dave, quite excited about the Amylin Oral Small Molecule that we announced back at the end of the year. This is the first, as far as we know, the first oral small molecule. And that is now completing GLP tox studies. We expect to be in the clinic with our oral Amylin called 2671, in the clinic by the end of this year. These are two molecules, aleniglipron and 2671, GLP-1 and Amylin Oral Small Molecules. We see as backbone therapies, monotherapies, and then we have our combination, fixed-dose combination with our GIP, GCG, Apelin programs. That is kind of a snapshot. This is a big year for us. It is a big year for small molecules and GLP-1s. I think for small molecules, it is really going to be tailwinds this year. I think it may potentially be headwinds, I think, for the peptide field. Excellent, excellent. Thank you. Maybe you could just talk about the scaffold of aleniglipron. Am I pronouncing that correctly? Yeah, you're correct. And just any differentiating features versus orforglipron? Yeah, absolutely. There are four different scaffolds that are out there just to sort of set the stage a little bit. Many of us are familiar with the danuglipron scaffold that came from Pfizer. The Chugai, what we call this sort of Chugai scaffold, originally from the company Chugai, that's what orforglipron is. Our molecule, aleniglipron, is of the orforglipron or Chugai scaffold. We have a number of different patents that we filed also in the danuglipron scaffold area. We've been very aggressive in terms of IP strategy, really trying to understand and capture as much intellectual property as we can in both of these scaffolds. We prefer the larger, the orforglipron-like or Chugai scaffold. We think that it has more muscle in a sense. The danuglipron scaffold is smaller. It's in that 450 molecular weight to 500 molecular weight. The Chugai orforglipron, aleniglipron scaffold is more in the 800 molecular weight to 900 molecular weight. weight to 900 molecular weight. The two other scaffolds that do not get talked about a lot, they are more in the 1200 molecular weight to 1400 molecular weight. molecular weight. They are really not drug-like molecules. You have not heard a lot about them because those have not entered the clinic. There are four total scaffolds. The main difference that we have with aleniglipron, we really focused on, one, manufacturing. We were able to remove any chiral centers that require chiral separation. We were also able to modify the structure really around safety. We wanted to, for a drug that is going to be taken by so many people, we wanted to make sure the safety profile was as strong as possible. We are very proud of our rat NOAEL at 1,000 mg/kg. Very safe molecule, both preclinically, off-target, safety what I'm talking about, as well as what we've seen so far in clinical studies that allows us to go up to this much higher dosage. Excellent, excellent. In terms of the crowding that's happening in the GLP-1 space, could you just comment on that and provide your thoughts, as it relates to Structure? Yeah. Out of these scaffolds that I was describing, about 90% of all the efforts that are ongoing in China, rest of the world, about 90% are based on the danuglipron scaffold. The reason for that is, as a chemist, it's a beautiful molecule. It's a beautiful scaffold. It's very easy to synthesize, very easy to derivatize. We think one of the challenges, though, is it's hard. GLP-1 receptor has a very big binding site. To control that binding site, it takes a degree of, I think, sort of strength there. We've gone more towards the, again, the Chugai orforglipron scaffold. A smaller percentage is in that orforglipron scaffold. One of our observations to date is that we are seeing a lot of overlap of existing IP. Many different companies right now are stepping on each other's IP in this space. We are paying close attention to this, particularly given we have more patents on GLP-1 and Amylin than any other company. Excellent. That comment struck me. How do you know that relative to, let's say, large companies like Pfizer and Lilly? When you file a patent, 18 months later, your patents will publish. You do have the ability to sort of accelerate these things, particularly towards issuance. We're constantly monitoring the patent literature. When I say monitoring, we're looking at all regions. We look at Chinese patents. We look at U.S. We look at European patents all across the board. We're always monitoring this so t hat's what gives me the confidence. Based on everything, everything that's out there that's been published from the patent office, we have more patents than anybody else, both in the GLP-1 small molecule space and, again, obviously in the Amylin space as well, small molecules. Excellent, excellent. Very impressive. With respect to aleniglipron, one of the pushbacks we get is the half-life is short, which could impact the efficacy and tolerability when you generate results late this year. Could you just comment on that, please? Yeah. We get this question a lot. You know, it's either, you know, the flavor of the month was half-life. Then, you know, more recently, it's been peak-to-trough ratio. The way that we designed aleniglipron was we knew that this was a molecule that was going to be taken by 100 million people plus. We knew it was going to be taken for life. I had mentioned earlier, Dave, that prioritization of safety. We made sure safety was at the highest possible level. When we designed the molecule, we thought about we knew it needed to be QD, once-a-day dosing. We wanted to make sure that we had drug exposure at 24 hours. That was one of our anchor points. At least 2x coverage at 24 hours. We also knew AUC, Cmax, was important for efficacy. Those are the most important PK properties that we really optimized around. Where the half-life sits, we were not as worried about this. What does worry me is we are hearing about more and more companies having longer and longer half-lives. Now, in the peptide space, I get it. Peptides are very safe. You want to have a long half-life if you are a peptide. If you are a small molecule, do you really want to have this small molecule accumulating and hanging around the body? I cannot see any good, ultimately sort of coming from that. We really wanted to make sure that we did not have much exposure after that 24-hour time period. Again, making sure that we had exposure at 24 hours when you take the next pill. That would give us the maximum safety profile. We are really pleased. We think we have the maximum safety profile in terms of all the PK parameters. Got it. Thank you. And then, turning to the phase II trial designs and readouts, could you provide, you know, some details on those? Yeah, absolutely. We reported last week or the week before in our 10-K. We've completed enrollment for both ACCESS and ACCESS II. It is on track. Both of those will read out at the same time at the end of or in Q4 of 2025. As I mentioned, 300 participants, 36- weeks. The trial is going very well. To date, we're very pleased with everything. I've already described the two differences between ACCESS and ACCESS II, two different dosages. Got it. Okay. Thank you. And then how are you setting the bars for efficacy and tolerability? Just what are you hoping to see? Yeah. I think that, you know, there's really been two big questions in the field about oral small molecules and GLP-1s. The first question was, can a small molecule be just as efficacious as a peptide? Semaglutide being the gold standard for a selective GLP-1. I think that question, by the way, has been answered two years ago at ADA, 2023 in San Diego, where we actually hosted one of our first dinners. I remember that at a steakhouse. We didn't get to eat. Sorry for that tangent. The bar, I think, in terms of efficacy, small molecules do need to be just as efficacious as the peptides. The second question, the question now that's on everybody's mind is, can small molecules be just as tolerable as the peptides? This is, it's a, it's an important question. We believe that the small molecules will be just as tolerable. This is why the Eli Lilly orforglipron data is so important and, again, why we think it will be tailwinds for the small molecule field. This will be the first time we're going to see data where a small molecule has been titrated with a once-every-four-week titration scheme. That once-every-four-weeks is important to allow the body to have use to be able to adapt to this class of drugs. Why do we think it's going to be any different than the peptides? The peptides go to once-every-four-weeks. The small molecule's going to be the same. Most all of the data that we've seen to date have been one-week titration, two-week titration, at most three-week titration. By finally seeing once-every-four-week titration, we're finally going to see real fair comparison on tolerability. The first data in Q2 will be for type 2 diabetes, which typically has lower weight loss. In Q3 with orforglipron, we'll see the healthy overweight population where we expect to see more comparable weight loss in that population compared to selective GLP-1s, semaglutide. Excellent. And then could you just update us on whether you're considering additional formulations of aleniglipron? Where does that stand? Yeah, absolutely. The direct answer, Dave, is yes. We continue to work on formulation. We've been working on formulations for many years, as have others as well. First, we completed our capsule to tablet conversion, and we're very pleased with those results that we shared last summer. Switching over to tablets, we wanted to go to tablets because it's really for the advantage of manufacturing. We can manufacture tablets at a very large scale, very reproducibly. The formulation extended release, just as an example type of formulation, is really, we've designed that for there are some individuals that are more sensitive. We know this. There are some that have no tolerability problems at all. There are some, an example, individuals living with type 2 diabetes, you know, they're on, for example, high dose of metformin. They're on a statin. They're on other medicines. Having something that has a modified formulation release, that can be advantageous to them if they do have tolerability problems. Got it. We will be updating more on our formulation studies in 2025. Great. And then, you know, assuming the data is compelling for aleniglipron, how, how are you thinking about, you know, potential partnership in the future? Maybe I'll jump in there. Yeah. You know, just give Ray a break to speak. In terms of partnership, as you've heard from us before, we've started this process last year. We had the data middle of last year from the 12-week study. We've had great discussions. We continue to have good discussions. This is a process that's going to take a little bit of time. I mean, we've seen some early-stage deals that have occurred. Strategics are also looking for ways to de-risk, look at assets, right? The fact that, you know, we're in a space with an oral small molecule, second-most advanced oral small molecule, GLP-1, going into a 36-week study, and we'll have that readout at the end of the year. We're laser-focused also on the Amylin agonist that's going to be going to the clinic. We're building an oral small molecule pipeline, with two backbones along with GIP, glucagon, and Apelin as potential combinations. It puts us in a really good position as we get to the end of the year, for a potential partnership. This is a process that's still ongoing. We're seeing, again, more interest than we've actually ever seen last year. We'll continue to have those discussions. If I could add just one thing, Dave, you know, what we have over the kitchen sink, you know, in our kitchen is making medicines accessible to all. We know in order to really achieve that mission, which we're very passionate about, really making a drug that's available to everybody that needs it, both from a cost perspective, manufacturing, cold storage, et cetera. In order to do that, we need a partner for commercialization to really achieve our company mission. We are committed to partnering for commercialization. Got it. Excellent. It would be great to just get a little color on Amylin and then go into some of the other pipeline candidates. With respect to the Amylin phase I trial that you'll start later this year, will that be in healthy obese such that you'll get weight loss? How quickly might we be able to see, you know, the efficacy of that drug next year? The first study that we'll do will be healthy individuals, so both SAD and MAD. We are doing a few things to try to speed up the progress on this. Things like, you know, doing our tox studies so that we don't have to wait, you know, doing a one-month or a four-week study where we know half of the weight loss is water. We'd like to be able to sort of more efficiently go straight into 12-week and then into the 26-week, 36-week studies. We're looking for ways to accelerate this, as much as possible. The first study, to directly answer your question, this will be in healthy individuals, SAD and MAD. One other point, if you don't mind, Dave, is don't be surprised if you see multiple DCs coming from us in the Amylin space. Again, having the first oral Amylin small molecule, there are some things that, you know, we wanna explore. For example, this molecule, what we call 2,6,7,1, this molecule is referred to as a DACRA, a Dual Amylin and Calcitonin Receptor Agonist. We're also continuing to work on what we call a SARA, a Selective Amylin Receptor Agonist, as well as different properties, for this molecule, being first. Just like in our GLP-1 case, we had multiple molecules that we're planning to put into the clinic until aleniglipron just came screaming out in terms of its profile. With Amylin, we expect to put multiple Amylin molecules into the clinic. Once we do complete that SAD and MAD study, one of the things that we're very excited about is fixed-dose combination. You know, we think the ultimate application and utility for both these two monotherapies is how to use these in fixed-dose combinations. And we're able to do that once we complete that SAD and MAD study. Got it. Okay. And then turning to the Apelin or Apelin candidate, that's been phase II ready for a while. What should we watch for next? Yeah. Yeah. Actually, yeah, I could jump in there. Let me take a minute on Apelin. Apelin is a non-incretin modulator in muscle that we've been exploring in the literature and in our preclinical studies. We've actually seen, you know, lean muscle mass preservation. We like this mechanism. We've got a molecule that's completed phase I single and multiple dose studies. We're just right now in the process of doing the six-month and nine-month chronic tox studies. We feel this is really, really important as we think about combining this molecule, you know, with a GLP-1 or an Amylin. We don't think this molecule will be a standalone weight loss molecule, but it's really going to be one that would be used in combination for selective weight loss. That said, again, the chronic tox studies will have that readout later on this year and position us to move into a potential phase II combination study shortly thereafter. We will provide more guidance later on this year. We're really aggressive in places like IP and how we're sort of pushing our programs. The one place where we're not aggressive, in fact, we're extremely conservative, is safety. You know, this is a, we're talking about medicines that are going to be taken by a large population potentially for life. We had implemented additional safety studies prior to even hearing some of the news last year in terms of another Apelin molecule. We're extra careful, extra conservative when it comes to safety in making sure whatever we put into individuals, it really has the highest profile possible. Yeah. And to remind you too, this molecule particularly was actually being developed for pulmonary arterial hypertension, which had a different safety bar. So again, it's one of the reasons why this chronic talk studies is really important for us. Got it. Excellent. And then, maybe we could pivot to GIP, just the latest there. Yeah, absolutely. With GIP, we actually have two different molecules, both an agonist and an antagonist. There's this whole debate in the field. Personally, my personal opinion is I believe more in the agonism of GIP, for those sort of keeping track of, you know, different companies have different opinions. As scientists, we are in the position where we actually were able to make both an agonist and antagonist, so we're parallel processing those. We like GIP in terms of the antiemetic properties that we think that it sort of brings to the mechanism. GIP by itself, again, doesn't do a whole lot. Part of the reason we slowed down a little bit on GIP was we prioritized Amylin over the past year, year and a half. You know, we really felt we started getting some preclinical data that really got us excited with Amylin in terms of both the tolerability profile, the potential for muscle preservation, muscle preservation of lean, lean muscle. Given all that, we started putting a lot of resources on Amylin, but we continue to be excited about GIP and GCG, glucagon receptor as well. Kind of just to connect two dots, Dave, you know, we're in the fortunate position where with selective weight loss, we have the Apelin to tie back to one of Jun's comments. We have the Apelin for selective weight loss. We also have the Amylin for selective weight loss. You know, we're looking at both of those very carefully. Ideally, if we can go with one molecule like an Amylin versus a combo, an Apelin GLP-1, we'd like to go for sort of the single molecule, being prioritized. That's very helpful. GIP, we remain excited about it, still working hard on it. You'll see more from us later this year. Excellent. And then with respect to glucagon? Glucagon is sort of in the, I'd say in terms of prioritization behind GIP. We like it in terms of liver disease, more for liver disease. We also, as we look at the landscape, you know, again, we have these two backbones of aleniglipron and our Amylin 2671. There's a lot of different combinations. One of the things that we're really excited about is we can combine these two backbone molecules with other incretins, or Apelin, as Jun said. There's other opportunities that we can as well, such as SGLT2s or THR betas or PCSK9. There are a lot of combinations that we can work with. This is something that we'll be updating later this year. There are a lot of different fixed-dose combinations that we can work with, with different indications. Liver disease is something that's really important market. We continue to sort of follow that. Glucagon plays in that sort of area. There is a, we have a few different options for liver disease, in addition to just glucagon receptor GCG. Excellent, just one final question before we wrap up. Jun, if you could just frame the company's current cash position and the runway as you've described it and, you know, what the key spending plans are over the next couple of years. Yeah, absolutely. The current cash balance, $883.5 million, we reported as of year- end 2024. That runway allows us to get through the end of 2027. It includes all of the studies that we've described in terms of ACCESS and ACCESS II to reading out through the end of this year, along with our pipeline programs for the Amylin going into the clinic and the early clinical studies related to Amylin, GIP, glucagon, and APJ. What it doesn't include are the phase III registrational costs. That's something that we're currently strategizing in terms of phase III costs and phase III planning. Right now, the current runway is to the end of 2027 with all the different activities we have planned. Excellent. Wonderful. We are out of time, but thank you so much both for joining us, r eally appreciate you being here. Excellent. Thank you, Dave. Thank you, Dave.