Right. Welcome, everyone, today to Jefferies' London Healthcare Conference 2024. My name is Roger Song, one of the senior analysts covering biotech in the US. It's my pleasure to introduce our next company, Structure Therapeutics, and welcome CEO Ray, and Ray is going to do a brief company overview, and then we will—he and CFO Jun are going to join us for the fireside chat. Thank you. Thank you, Roger, and thank you to Jefferies. Good morning, everybody. Before I begin, I need to make the forward look. I will be making statements that are forward-looking. For any additional details on the forward-looking, you can see our SEC documents for that information. So 2024 has been a very good year for Structure Therapeutics. Starting at the very beginning of the year, we continued to grow our management team and evolve that. We, in June, announced (and I'll be showing you a slide coming up) on releasing our phase II-A data and chronic weight management. Showed very positive data there. And recently announced the phase II-B plans for continuing GSBR-1290. What I'm most excited about and why I think 2025 (I'm already starting to make predictions) is that I think 2025 is going to be the year for small molecules and GLP-1s. The reason why I think that is we're going to start to see later-stage information, data coming out for GLP-1 small molecules. Right now, the field is largely dominated by the peptides. But small molecules, what I have up here in the middle of the screen, small molecules really help with broader accessibility. You're able to manufacture these at a much larger scale to really fit and meet the needs of the patients. It also gives the patients optionality for those that don't want to take an injectable, the primary care physician. Having that optionality is really important. The oral formulation provides more patient options. Potential for long-term chronic weight maintenance. This is something that's starting to be discussed. Many individuals that start on the injectables stop after a year or two. Why is that? There's different hypotheses for it. But we're really talking about this. This is something where people do need to maintain this. Small molecules have that optionality. Small molecule pills. Large-scale manufacturing capability. We've already reported in 2024, we have the capacity today to manufacture more than 6,000 metric tons. This is enough at a 120 mg dose to generate material for 120 million patients today. Put this in perspective, in 2023, between semaglutide and tirzepatide, they only met the needs of five million patients. So broader accessibility, lower cost of goods. And then finally, one of the areas when we built Structure Therapeutics, they were quite excited about the opportunity for fixed dose combinations. We really think that there is a tremendous opportunity in combining doses, GLP-1s, whether it's with another incretin, GIP, tolerability, GLP-1 plus amylin, as I'll be showing you as an example, GLP-1 plus glucagon receptor, particularly targeted towards liver disease, MASH or NASH, GLP-1 plus apelin receptor, where we have an agonist that's finished phase I for selective weight loss, where you maintain that muscle. So a lot of opportunity, potential for fixed dose combinations. All of this is being done with our structure-based drug discovery platform that we've developed, where we see the three-dimensional structure with the validated targets and the peptides on the left-hand side of the screen, and then on the right-hand side, you see the small molecule mimicking that same activity. Probably don't have to sort of address this. For those of you that might have been at the McKinsey presentation yesterday, the room was absolutely packed on GLP-1s. It highlighted the sheer magnitude, the size of this market. One of the things that really struck me, though, the most during the McKinsey presentation yesterday afternoon was it wasn't just the obesity market. It's how many different disease indications are being addressed with GLP-1s. And it's not just the weight loss aspect. We're now starting to understand the anti-inflammatory effects of GLP-1s as well. So we're starting to see that. Last year or a year ago, pretty much from now, the American Heart Association meeting, the SELECT trial that read out the cardiovascular benefits, that was a game changer for the whole field. It showed positive data, solid scientific data, that these medicines help have a health benefit. So the data that we released earlier this year, back in June, 6.2%- 6.9% weight loss, weight loss placebo adjusted at 12 weeks. One of the numbers that I was very excited about, and we've been studying the patient segmentation, 33% of participants had more than 10% weight loss in this 12-week study. That's significant in a 12-week study. In our second cohort, it was 9.2% overall. Again, with small molecules, the big question is always safety. We had no liver liability. Very important. We're very proud of our NOAEL, over 1,000 mg per kg. When we designed this molecule, besides efficacy comparable to the peptides, we wanted to make sure that it had the largest possible safety window. The reason why that was so important to us, we knew the market was going to be more than 100 million people. It had to be a drug that was really, really safe, so that we're quite excited about. 5%-11% AE-related study discontinuations. In other 12-week studies, this number has been between 33% and 54%, so this is one of the lowest numbers in terms of study discontinuations. Again, we think this is the metric that one should be using. Why do participants stop the trial? We work really hard to make sure that the participants stay on trial taking these medicines so we get the full data set, the full experience. PK supports QD dosing. Again, part of our TPP, target product profile, was to make sure this was a QD drug. Really important, again, because of the sort of market opportunity, the patient preference needed to be a once-a-day drug. We dose this once a day, and we saw a very strong efficacy. And then scalable, as I mentioned at the very beginning. We have the capacity right now today. We thought about our manufacturing on day one in designing this molecule to make sure that we could manufacture this at the scale that is needed. So GMP batches for phase II-B studies. Obviously, we initiated our phase II-B study. All of that is made. So where exactly does GSBR-1290 fit into the GLP-1 receptor agonist landscape? And how do we win? So first, we think that we have potential to be best-in-class profile. This year, 2024, has been really great. We've seen a number of different data releases. And I stand before you now today. We feel really, really good about having the potential best-in-class profile, having seen others' data now to date. Favorable tolerability profile, chronic weight management as an option, that's really broadened, and we see a real big opportunity there. We think, in fact, this is the biggest market opportunity for the oral small molecules. And then broad accessibility. So we've completed in 2024 the phase II-A proof of concept study. You can check off that box. We've initiated, and I'll show you some information on this. We've now initiated our 300-participant phase II-B study called ACCESS and ACCESS-2. This is a dose range finding study. This will be 36 weeks. And we're working very hard to make sure we can do a very seamless transition from phase II-B into phase III to address this and move this forward as efficiently as possible. And then finally, the oral fixed dose combination. This is our ultimate. This has always been our ultimate goal. How can we combine GLP-1s with other medicines? So much opportunity there, so many different disease indications, so many different products, opportunities. Let me say a few words now about ACCESS and ACCESS-2. This is a late-stage phase II, two separate studies designed to accelerate timeline to phase III while providing the potential best-in-class efficacy with higher doses. ACCESS itself, start low and go slow. This has been the mantra in the peptides for years, and we've been listening to this. In a phase II-A study, everybody only has three months of safety data. They do weekly titrations. We've been waiting for this moment for a long time. We will be doing once every four-week titrations. This is where the peptides ended up. This is where we're seeing orforglipron end up in the phase III study. We'll be doing titration steps of once every four weeks. Second, we're going to start at five mg. We learned a lot from our phase II-A study, in particular where to start and where to get that best tolerability profile and sit there for the four weeks. Designed to confirm competitive efficacy at this dose, we'll be at the maintenance dose for 16 weeks. This gives us ample time to really show the true power of what GSBR-1290 can do. And then finally, we'll be doing 45, 90, and 120 mg to confirm the efficacy. Now, separate from the ACCESS trial, we're going to do an ACCESS-2 trial. And the reason why we're doing the ACCESS-2 trial is for two reasons. One, we have a very big safety window. As I mentioned, that 1,000 mg per kg, NOAEL, we have a 150-fold margin at a 120 mg dose. So we're going to go up to 180 mg and 240 mg. We feel very confident that we can achieve these doses in order to understand how much more can this drug do. This is where we think we're going to get that step up in terms of best-in-class efficacy. We already feel like we have the best-in-class in terms of safety. Separate study evaluate the higher dose will help us establish the maximum dose for the phase III study. And then lastly, I want to touch on how we've been building Structure Therapeutics over the years. We've been building a metabolic franchise, thinking about lifecycle management from the very beginning. So GSBR-1290, our GLP-1 selective oral small molecule. I've just been talking about the 2A data that we released. We've also. I've just updated you on the ACCESS and ACCESS-2 programs. So oral small molecule, daily dosing, monotherapy for chronic weight maintenance, potential best-in-class efficacy and safety, potential fixed dose combinations with other drugs as well. Second, our amylin molecule. We'll be declaring a DC by the end of this quarter, and we're very excited. A number of people told us over the years, "It's going to be impossible to make an oral small molecule for amylin." And I sort of smile sitting here in front of you today because we've been able to do it. And we'll declare a DC by the end of this year. What excites us about the oral amylin small molecule, again, same TPP, daily once daily dosing. It has the potential for better tolerability. It has the potential for lean muscle mass preservation and potential fixed dose combination with oral non-peptide drugs as well. So again, DC end of this quarter. We see these two as our backbone molecules. And both of them can be used in combination with other molecules. As a monotherapy, we think both of these work for that medium weight loss that many, in fact, many people want to achieve in the teens weight loss. If you want to achieve the more significant weight loss, you can use those in combination. We shared data at ObesityWeek two weeks ago now in San Antonio, where that data we showed the two in combination has a very synergistic effect. When you add GLP-1 with our amylin small molecule, you get a significant increase in weight loss. So that combination is quite powerful. So the GLP-1 amylin combination potential for greater body weight loss and enhanced tolerability. We have the ability to work on the ratios to maximize the patient experience, to minimize tolerability challenges while trying to maintain that weight loss efficacy. Again, our view from the very beginning was to do these all in combination. We view this as a franchise, again, lifecycle management example. GLP-1 plus amylin. I just talked about our GLP-1 with GIP. We have an oral small molecule, both an agonist and an antagonist for those of you following the interesting debate in the field about GIP agonism versus antagonism. Our GLP-1 plus GCG small molecule, again, focusing there towards liver-associated diseases, MASH, NASH. Then selective weight loss, our GLP-1 plus apelin. We really see having an opportunity, particularly in the older population, where muscle loss becomes a much more significant factor. All of these apply to the right-hand side. So many different disease indications that we're learning over and over again, new areas, again, highlighted in McKinsey's presentation just yesterday, yesterday afternoon. And so my last slide before I wrap up and we switch to Q&A is that a robust portfolio. We're well-financed. We have more than $900 million right now in cash. The anticipated milestones for our entire small molecule portfolio, very excited about the number of milestones that we have, both for GSBR-1290, our amylin program, our GIP, our GCG, the apelin, and what I haven't talked about today, but we did start our LPA1 phase I study also this summer, again, a major accomplishment for us, and that'll have a data readout in 2025. So in closing, again, I think 2025 is going to be a transformational year for the oral small molecules for GLP-1s. Phase III data coming out with orforglipron. Our later stage phase II-B data will be coming out by the end of the year. We continue to see more activity, our amylin molecule entering into the clinic. Quite excited about 2025. Thank you very much. Great. Thanks, Ray. This is a very good company overview. And then congrats for the 2024 so far, and then look forward to your exciting 2025 as well. So maybe we can zoom in a little bit for the GSBR-1290, given you just recently started phase II-B. I think it's a pretty thoughtful design. If you can just remind us the high-level design, my specific question is, given this is a 36-week, and then we'll be very informative in terms of the phase III, how should we think about the expectation around the weight loss, GI tolerability? Maybe you also highlight this discontinuation due to AE. So what's your expectation? What's the benchmark there? Yeah, Roger. So I think starting off, in terms of efficacy, our expectation at a 120 mg dose, we think that we will be equivalent to the best in the field right now. Our excitement is at the 180 mg and 240 mg dose. That's where we really see the opportunity to get even more efficacy. So to reiterate, at 120, we think we'll be on par with others at the top end. 180, 240, we expect to do even better. So that's one. In terms of tolerability, the metric that we really have always focused on was discontinuations. We think that's the number we think that's really, really important. And so we expect the number to be less than 20% in terms of discontinuations. Now, again, looking at the 12-week data, we saw that in 12-week data for others, it was between 33% and up to 50%. We 5% - 11%. So we feel very comfortable that we'll be able to do, we'll continue to do low numbers in terms of the discontinuations. So those are the two primary areas of efficacy and tolerability. And then in terms of, sorry, the AEs, we think that we will be on par with everybody else in the field, whether it's semaglutide studies or the other small molecules. We think we'll be in the same range in terms of the AEs. Okay. Great. So that's very helpful. And then in terms of the weight loss, given you have a higher dose than the 120, which you tested in phase II-A, already very promising efficacy. You just say you want to benchmark to the high end of the industry for the class. So how should we think about what will make you to feel comfortable moving to the higher dose for the—in terms of the weight loss benchmark, how much incremental weight loss you're looking for in order to push forward the high dose? Yeah. So what we're hoping for is with the higher dose, 1.5%-2% increase is where we're sort of putting the sort of mark that we think that we can achieve that beyond the 120 mg dose. Got it. Yep. And then obviously the next step will be the phase III. So how should we, maybe just at this point, it's a little bit kind of hypothetical and then conceptually to talk about the high level of the phase III design, particularly for the dose, given you are pushing forward the multiple dose. How should we think about how many doses you're going to push forward in the phase III? What's the rationale behind selecting multiple dose? Yeah, absolutely. It's a really important question. So first, we fully expect to go into phase III in more than one dose. So that's the expectation. By doing the trial the way that we've done with the ACCESS and ACCESS-2, we go from 45 mg, 90 mg, 120 mg, and then 180 mg, 240 mg. We have a really good range to sort of choose from. And the ACCESS and ACCESS-2 studies will help educate us as to which ones we ultimately sort of pick. But we will be going into phase III with more than one dose. So it seems the 120 mg potentially can be the anchor dose, right? So for maybe the rationale why you want to go with a little bit lower dose and then particularly related to the tolerability and the maintenance. Yeah. And again, it's a really good question. The answer is we see - we're seeing efficacy at 45 mg. So it's important for us. Again, the purpose of phase II-B is dose range finding. And we're seeing some efficacy at 45 mg. So we want to explore that in order to see what we might be able to do there. So it's an importa nt question of phase II-B study to study that. Yeah. Okay. Good. And then maybe just quickly remind us where you are in terms of the diabetes population, diabetic, obesity, or the pure diabetes patient. Yeah. Let me turn this over to my co-founder, Jun Yoon. Yeah. So Roger on type 2 diabetes. That's an important indication. We all know that type 2 diabetes is a leading comorbidity for obesity, and in 2024, our focus has been on getting the phase II-B ACCESS and the ACCESS-2 studies up and running. They're now enrolling, and we're doing additional formulation studies on the GSBR-1290 molecule. We'll be moving into those for type 2 diabetes and providing an update very soon. Excellent. Great. So maybe stay on the GSBR-1290 before we move on to the amylin, which is also a very exciting program for you, and maybe just overall, how you see, you just mentioned 2025 can be a big year for oral small molecule, GLP-1. And then how you think GSBR-1290 is going to fit into the future obesity landscape, particularly as an induction maintenance monotherapy combination therapy, how you think GSBR-1290 is going to fit into? Yeah, Jun. Yeah, I can take that too. So GSBR-1290 as an oral small molecule GLP-1 has a lot of advantages as an induction and maintenance therapy. The agency hasn't defined separately induction or maintenance therapy. So from our view, our purpose is right now focused on developing GSBR-1290 as a chronic weight management indication. And we'll be able to move that forward. In terms of monotherapy versus combination, our primary goal right now is to continue developing it as a monotherapy, but we're going to be moving very quickly into combination studies since that's where the field is rapidly moving into. So the opportunity to be able to combine with other related mechanisms to be able to enhance the weight loss as well as tolerability will be important through the combination studies. Great. Okay. So another breakthrough you have just recently made is related to the small molecule amylin. Maybe before we talk about this program, how difficult is developing amylin? Seems that that's a decade kind of effort from Structure. Yeah. So Roger, that was at last night's dinner. It's one of my favorite questions. People say, "Ray, you're so excited about amylin." I'm also excited about GSBR-1290. So I want to make that sort of very clear. Directly answering your question, I think the reason why many people thought that it was so difficult was sort of three different reasons. One, the binding site for amylin is very uniquely different than GLP-1, GCG, or GIP. It's much flatter. It's like a true protein-protein interaction. Think KRAS that many thought was undruggable. So I think there is that technical challenge of the sort of flatness of the binding site. Second, the definition of amylin is calcitonin receptor plus an associated protein called RAMP. This adds an equilibrium of RAMP binding to the calcitonin receptor with ligand binding. It's more complex simply when you do the drug discovery aspects. And then thirdly, there is this equilibrium between calcitonin and amylin receptors. And some people right now, there's a big question in the field is what's calcitonin doing? Is there a reliability associated with calcitonin? And this is something that a lot of people are really investigating into. So with our program, our first-generation molecule, we've really used cagrilintide as our benchmark. We think that's the right sort of benchmark right now in achieving that sort of efficacy. But as we continue to progress, we will have multiple DCs in amylin. We expect our next DC could possibly be selective amylin, where we can test that hypothesis of what is the role of calcitonin, is there a liability associated with that, biased signaling with these different receptors as well. So there's a lot more questions. Being first in class, pushing the boundary of innovation in this regard means that we have to explore more than just one thing. So that's why it was more difficult than GLP-1 or GIP or GCG. Yeah. Thank you. And congrats for being able to do that. So maybe related to the amylin, you're going to have the first DC by the end of the year. What are the key properties you are looking for? And then also, what's the development plan for the amylin? Yeah, absolutely. So the design elements and again, the TPP, very similar. The experiences that we have in GLP-1 has really helped us with our amylin program and be able to sort of progress it as quickly as possible. So TPP, again, has to be QD dosing. The efficacy has to be on par with the peptides. We think that's really important. The safety, again, we're trying to achieve that high safety bar. We see a very large market opportunity, but that means the molecule has to be really, really safe. So those are the things that we look at. For the QD dosing, the PK parameters that we care the most about, we continue to believe AUC is where you get efficacy. C_trough, having that once-daily dosing is really important. So we have exposure at 24 hours. Those are the things that we look at in terms of designing the best possible molecule. Okay. Last minute. And you do have a big kind of pipeline. So how should we think about the other pipeline moving forward? And then what's your cash runway? Yeah. So cash runway, you have plenty of stuff. Yeah. No, I mean, so cash runway, $915 million. We've got sufficient runway to the end of 2027. You saw the milestones that were listed there. We got a lot of activity in the roadmap. And for 2025, I mean, look forward to the phase II-B ACCESS and ACCESS-2 data at the end of 2025. We'll be looking at the amylin DC at the end of this year and then look for a second DC sometime next year. We'll have the LPA-1 asset with phase I data reading out next year. And then the apelin program will provide an update with regards to that. We're doing some long-term chronic tox studies with regards to apelin and moving that into potential combination studies. Excellent. Thank you. Thank you, Roger. Thank all of you. Thank you. Thank you.