Structure Therapeutics Inc. ($GPCR)

Amazing. A lot of news from ADA. A lot of news, let's say kind of like the high-level obesity market landscape. I would love if you could talk a little bit about your philosophy on where the obesity market is going over the next let's call it, 5 to 10 years, recognizing we're in the midst of a lot of change right now. And I would just love if you could kind of talk about the direction of travel for the market.

Yes, Core. So if you actually just go back 6 months, let's go back to December. Is there room for oral pills. Now, people are sort of still debating the like. injectables are fine. Injectables are actually the convenience of once a week and everything, fast-forward only 1 month or wigobilaunch. It is the fastest launch 5 months later now 1% of the market is already oral pills. And this is all growth. This is 80% of it is growth. And so I think the oral pill market is -- and now we have Fundao and they're really starting to advertise. So I think the oral pill market is just going to continue to grow the field, and that's a really good thing. It's all about giving patients options at the end of the day. And there was all this pent-up demand for oral pills. So I think that's sort of 1 place where it's going to continue to grow. I think the other area that we're going to continue to see is patient segmentation and combinations are going to be really important in terms of patient segmentation. So we're excited. We'll start our Phase II way for AML next quarter. And then we'll start our combination of our GLP-1 with our amylin in the fourth quarter. We're seeing more and more of these combos for specialized markets. a combo with GLP-1 glucagon for liver disease, a combo for you can imagine a PCSK9 or an SGLT2. So we're going to see 5 to 10 years. combos are going to become more and more important. But the foundation molecules, the GLP-1 or olinigliperon, our amylin those monotherapies they're really for the masses, the large numbers.

Great. And maybe you could also talk about the direction of travel for pricing is that's been a key area of focus as these new drugs have come to market. Yes, June, you're the money guy.

Yes. So this is a rapidly evolving space, as you can imagine, and price has been coming down. But the opportunity for us on small molecules is cost of goods are are really low, right, where cost of goods are going to be traditionally where small molecules are, and that gives us a real big advantage with respect to pricing. It's going to be different for oral peptides because their cost of goods are just going to be much higher and they're going to need more dosing to get the same level of efficacy on top of the fact that they got to formulated as an oral in order to work as a peptide.

Great. All right. With those kind of big pieces in mind, maybe we could talk about your individual programs. So starting with the linaglipraand you have demonstrated Phase II efficacy across a couple of studies now. Maybe you could just walk through the highlights from that program and compare now versus a broader set of oral obesity medications as you mentioned, after the data earlier this week. .

Yes. So we shared back in December, it was access and access to data. So access went to 120 milligrams, in access to went to 180 and 240 milligrams. So what we've seen between the December data release and the March data release is we've seen up to 16% with no signs of plateauing. So again, best-in-class profile in terms of efficacy. What we've also shown is keep in mind, in Phase II, it's there to really explore. And so we know that we do not want to start at 5 milligrams. We do see some tolerability challenges. When we go to 2.5 milligrams, we see the tolerability significantly improves. So again, our starting dose in Phase III is going to be 2.5 milligrams. So that's another sort of learning that we've had. We've also done -- I think we've done more Phase IIs than even the big pharmas. And 1 of the reasons why I sort of point that out is we've really figured out how to work with. So the 2.5 milligram start, the once every 4-week titration step -- we have additional studies going on in body composition, for example, how exactly do we do those studies in the Phase III setting. And then what is the maximum dose that we want to go to. Again, we've tested up to 240 milligrams. We've had our end of Phase II meeting with the FDA. And so we'll be released -- we'll start the Phase III in Q3, and we'll update further on exactly the doses. But we've really learned a lot from this that's really put us in a good position to start Phase III.

Okay. Great. Well, that's a great segue to the alignment you have reached with the FDA on a Phase III program. Maybe up to like what are the key features of that Phase III program as you kind of see it.

So the FDA, there's lots of turmoil at the FDA. We're all familiar with what's going on there. But in this particular space, obesity, we've had a really good set of interactions. They're clearly very -- they're worried about obesity in the United States, 70% plus of Americans are overweight, 46% are obese. And so they came out with new guidelines last January, January 2025. And in those guidelines, they were very specific. It needs to be 52 weeks on maintenance dose after your titration phase. It needs to be 4,500 participants, 3,000 on drug, 1,500 on placebo. They highlighted maintenance. They're really, really worried. 85% of people discontinue injectables after 2 years. 60% after 1 year. So they're really worried about what's referred to as the OU effect. People lose weight and then they gain way, lose weight, game weight. So they highlighted maintenance. I think this is where small molecule pills are really going to have a particularly important unmet need for long-term maintenance. So with all those guidelines, 1 question we get is, would a strategic do anything different than what we're doing in our Phase III. The answer is no. strategics. They have the same guidelines from the FDA. We've already seen in the other designs that others have done. So for chronic weight management and I'm specifying chronic rate management Phase III it's pretty much really dialed in by what the FDA has guided everybody towards. So it's very straightforward.

Okay. In terms of the titration schedules and top doses you're taking forward, I know you've kind of figured this out internally. What should we know about how many schedules you're taking forward? How long it will take to get to the phase or to the top dose that kind of thing?

So what we've disclosed so far is that we are going to start at 2.5 milligrams why 2.5 milligrams for us is a sort of sweet spot is for sort of 2 reasons One, the tolerability profile improved significantly when we started 5 milligrams. So it was a really big learning. Second, 2.5 milligrams is really -- we can see some weight loss. It's really important. So you may be familiar with what's going on with the placebo arm in these Phase III trials now. you know if you're on placebo within 4 to 6 weeks. If you're not losing weight, if you're not having any of the sort of GI AEs -- you know and keeping people on the trial is a real challenge. So we've had a lot of learnings from the Phase II studies on how to keep people in placebo arm on the trial for Phase III. But 2.5 milligrams is the right start. You lose a little bit of weight, so that you know that you're on drug and then the sort of stepwise 4-week titration steps. We haven't disclosed the titration scheme yet, we'll disclose that when we start the Phase III. But -- and it really depends. We'll be using 3 doses sort of a low, medium and high dose is what we're going to sort of do. And it's really excited to sort of get that started.

How do you think about what would be patient-friendly with respect to titration schedule with -- like in terms of how long it takes to kind of get to the highest doses at some.

Yes. So 1 of the things I should have mentioned at the very beginning was -- so with the data release that we had on Friday, at ADA. We also released simultaneously a paper in Nature Medicine. In the nature of Medicine, Dr. Blake Cole, our CMO, came up with this idea of using heat maps. So basically, what we've disclosed, I think it's most data, anybody has disclosed individual patient data of what exactly is the journey and dose by dose for that access study. And then 1 of the questions that we were asking was if a patient skips a dose, what happens, do they have to start to retitrate if a person has a GI AE, do they have to sort of restart or go down and sort of what exactly is it? And what we learned from this heat map, so it's in that paper. It's also in our updated corporate deck is individual skip doses all the time, and they don't have any problem, absolutely no problem at all. And life happens. You forget something you travel and you can get to sort of bring the pills -- so that was a really important finding from that access study and that nature medicine paper came out with those heat maps. So I hope that people start to include these. The cumulative AE tables that we get if I ask you, it's not fair to ask you this right now, but over the past 9 months, have you been nachos. I think almost everybody to say, yes, in the past 9 months, I've probably been notches ones. So these numbers, it's what everybody reports. But I think these heat maps of individual patient journeys really tell what's going on with the patient. And what they do, they -- everybody modifies the titration. I mean this is personalized medicine at a global scale. -- most people don't even go if I think about is that bound. I only know 2 people that have gone to the 15-milligram dose. Almost everybody that I know at least has gone to 10 milligrams at the MAX. And so we really want to give patients the flexibility to titrate kind of on their own schedule. The clinical trial will try to be relatively organized on it, but we do allow down titration. We do allow holding titration -- it's really up to the individual. What's most important is that they have a good patient experience and they follow a titration scheme that they're comfortable with. And when we were doing our own research on this 5 years ago, I remember going to a clinic outside of Boston outside of 128. And we ask the physician, what do you want the most in next-generation obesity medicines. She was very clear. She said, "Look, my phone is ringing nonstop. I don't want my phone sort of ringing nonstop. I need flexibility. I need to be able to give my patients simple instructions, I need to give them flexibility. So if they want to cut a pill in half, if they want to hold the titration up and down, I need to give them that flexibility. And that's the way we try to design the drug.

You mentioned the trial conduct challenges, particularly with respect to discontinuations across both placebo and treatment arms largely because people know they're not on drug, and they could go get drug from many, many options. [Audio Gap]

Thing. It's really about you've modified your eating habits, smaller portions, your gastric emptying has sort of regulated even the sort of effects of food noise and everything have sort of settled down -- so this is the biological hypothesis being able to go over seamlessly to the same dose of oral but we need to do this experiment. So we're doing that right now. That will read out in Q4, and that will set the stage. We think that this is part of a significant go-to-market strategy. how exactly do we sort of enter the market and switching from injectables over to orals is 1 of several different paths.

Would you think about a registrational program like with that kind of setting or cohort of patients? And is that as well defined in terms of what I would need to look like?

I'd say let's stay tuned on that. Right now, what we're laser focused on is there is the foundation. The FDA has their requirements you have to meet. So that's what we're sort of focused on. And that is the sort of longest study. Again, the 52 weeks on maintenance that's defined by the FDA. These additional studies are a subset of that. And so you can imagine a series of Phase IIs.

Okay. Perfect. And you did mention that you have the funds sufficient to complete a Phase III weight management program, but can you be a little bit more explicit about what that kind of cost you anticipate being SP1 Yes. Yes. I mean it's going to be a pretty typical Phase III 4,500 patients -- and it's going to be in the range of $300 million to $500 million, right? We have $1.5 billion in the bank, and we will be able to complete that registrational Phase III study.

Okay. Great. Maybe let's talk about ACG2671 or the AML program that you referenced earlier. Maybe start with just the data you shared at ADA. What do you think people should be most excited about or take away from the. I think -- so first, this is a non-human primate. So I just want to sort of set that it's still a preclinical set of model. We have a Phase I going on right now that will read out next quarter. So that's a human single ascending dose, SAD sort of study. The data that we shared was we see significant weight loss, both as a monotherapy and in combination with GLP-1. So that was sort of 1 important thing. Nonhuman primates in this class of medicines really is the best animal to study in terms of human. So that was, I think, sort of really good to see. The second thing is we got additional PK data, in particular, 1 of the things that's been a topic of conversation. The half-life is in nonhuman primates, more than 60 hours, and so typically in humans, you'll see even longer for the half-life. This opens up real differentiated profile. Alenigliperon clearly dosed once a day, we saw best-in-class efficacy. So the 8-hour half-life is not an issue. But this opens up additional sort of dosing sort of regimens that I think, again, will create a potentially differentiated profile. So that was -- we got lots of questions, had lots of really good conversations and then what it also does is it sets the stage. I think of structure has been traditionally, most of our value is really in aleniglipron. We haven't gotten a lot of credit for amylin itself. And it's still a little bit early on amylin once we release the human data, that's more, in particular, the proof of concept. But we also, by -- in Q4, we'll go into human trials for the combo and that's our GLP-1 plus our Amylin. And to me, so we're going to go from a one-product company to a 3-product company in the second half of this year.

Great. SP-6 Maybe 1 of the -- you mentioned earlier, 1 of the things you mentioned earlier was that there was a symposium on Amylin at ADA. I guess, as you think about the role that Amon,but particularly oral Amlin could play in the market. Could you just contextualize that for us? SP1 I think the rules are going to be very similar to the GLP-1 space. Is there a mark in this was a question just 6 months ago, end of 2025. Is there really a market for oral GLP-1 pills?

Clearly, the answer is 14% of the market in 5 months million pent-up demand, 80% growth of the market. Clearly, there is a large market for oral pills. It's going to be the same with amylin. An amylin the hypothesis is potentially better tolerability, potentially better selective weight loss, that over lean muscle. So there's all those pieces. So I think the same rules are going to apply in terms of oral pills versus injectables. And what's great is this is really about giving patients different options. I think that's an important part of that. It's my understanding that it's like relatively challenging technical endeavor to design an oral amylin. Maybe you could talk a little bit about why there's technical challenges exist and how you're able to overcome them with the design of ACG-2671? Yes. So I'm miles I'm going to sort of geek out a little bit sort of on this. Amylin are more complicated. It's got a protein called ramp that binds to calcitonin receptor that then create amylin receptor. There are 3 different ramps. So there are 3 different amylin as well. Business debate in the field about DACAs versus Saras as well. What's the right sort of molecule it has a bigger binding site, a more complex binding site. So we're really proud. I mean I'm incredibly proud of the Discovery team, many people. I have many friends in the different pharmaceutical companies and their like an array. They know that I've been focused on GPCRs for 30 years, but you can't make a small molecule to that. and the team did it. And not only did they do it, but we released back in January, our dosing for our SAD, the dosing scheme is 1, 2, 5, 10, 20 milligrams. It is a potent molecule. And so that's also really important as well. And then with this half life, even more with a big binding site with the complexity. So it was a tremendous, I think, scientific accomplishment to get there. Now that we're there, we know that there's a lot of competitors that are coming at us now that the patents have started to publish. And this is where I'm also really proud of our IP strategy. It's worked in the GLP-1 space. we have more IP than anybody else on GLP-1 small molecules. Our amylin strategy is GLP-1 strategy on steroids. We've really done a lot -- we've made a lot of molecules. We have our discovery in Shanghai, China. It's where we started the company from the very beginning. So we take advantage of that chemistry resources there in discovery. So a lot of IP in order to maintain our first-in-class position for us.

You mentioned the Dacraversera debate. I guess what do you think is the important debate in terms of how Amlon are going to perform SP-7 In patients?

Yes. So last ADA, Lilly announced a molecule called Loralentide that showed some really, really good sort of properties. So it was really impressive. And that's where I think this heated debate get really sort of going over the past 12 months. whether really or SAR is the ultimate or DACRAs. This ADA, there was a symposium Friday afternoon, 1 of the leading authorities in the field highlighted, he actually likes the ACOs because the calcitonin really shows opportunities in bone health and particularly with sort of weight loss when you're talking about lean muscle, 1 of the questions is, particularly in older population, is bone health, a factor. And so the hypothesis is hitting the calcitonin pathway, you can really improve bone health. So the debate is continuing to go. It's not going to get resolved, I don't think anytime soon. I think the amylin space really is the early innings still early stages. We're going to see a lot of -- we continue to see a lot of molecules. We know that DACRA mechanism is very safe. Cagrilintide has been in thousands of patients or participants in the clinical trial. So we know it's safe. So it's going to be an exciting field. The debate isn't anywhere near resolved. From a structure perspective, we have 2671 that's now in Phase I. It will go into a Phase IIa next quarter. So excited about that. That will be a 12-week study. We also have another molecule going into the clinic in Q4, 35, 35. That's a different chemical scaffold. We're making sure that we want to win in this amylin space. So we will put multiple molecules in the clinic, not that there's anything wrong with our current molecule. But we're going to put multiple ones, and we'll put both DACRA and Cerus into the clinic from a small molecule perspective, while the peptide field continues to really educate us as to what's going on. I'm really grateful to the peptide field. They taught us so much and we learn as we make small molecules, what's the best target product profile for a small molecule. Are there other features that you think will be important other than DacRatera? It relates to like drug-like properties, et cetera, that you think will play a role in how Amylin perform I think that the same rules are going to apply that we applied to GLP-1. It needs to be a once-a-day drug. We don't think that there is really the sort of market for a twice-a-day drug. So that's part of our TPP. Safety is going to be up there is going to be -- again, these are molecules medicines that are being used by millions of people, safety, the buyers I think combinability is really important we think about early on. So we thought about from day 1, we want this to be combinable with other medicines. And then the fourth one, and this is something everybody uses this word access, accessibility, during 88 for the last 5 days that we were sort of in New Orleans. And but they're really not talking about accessibility in terms of price. Cost of goods, so we spend a lot of time on manufacturing. We're really proud of our synthetic route of our manufacturing process. the people that really need these medicines the most are the people that don't -- they can't afford insurance. There's a -- and we're talking about a global market as well. So it's really about numbers. This is really a volume play is how we look at it. And so we spend a lot of time, and we're really proud of the manufacturing work that we've done to make sure these medicines truly are accessible. It's not just a word that people are using. -- they really are both affordable, no refrigeration, no requirements and costs comes from that. That's an important piece for us as well.

Okay. What benchmarks do you think investors should have in mind ahead of Phase I data, both monotherapy and combination settings?

Yes. So again, I want to manage expectations. In a Phase I, we give 1 pill. You take 1 pill. Again, we're doing 1 25, 10, 20 milligrams. So what we're looking for, first of all, safety. Is it safe? Was there any sort of issue with it? Second, PK. We're looking for the -- we have to have those PK numbers to design the 12-week multiple ascending dose study. So that's critical. -- weight loss, people should not set any expectations. If I give you just 1 pill, don't -- let's not go there. But if I take lessons from the GLP-1 space when we did the SAD study, we went to the highest dose we did see some of the gastrointestinal AEs. If you go straight to a high dose, yes, you should see some of those. So that's another piece that we can start to see at the higher doses.

Okay. In terms of investing further behind the program, I guess, what should we anticipate with respect to additional studies, both on the monotherapy and again on the combination side over the near term?

Yes. So I think the combinations are going to be fascinating. We're really excited to get that started in -- the -- 1 of the scientific questions that we have is, is this -- is the combination mostly Amlin with a little bit of GLP-1 or mostly GLP-1s a little bit of ambulance. We got to work that out, that's a scientific question that will go into the combo design. What's the perfect molecule. The perfect molecule is very tolerable with good solid weight loss and having the right sort of range. So you mentioned Lilly didn't attain maintained study. And that was a good -- they did a really good study. Littles 1 beautiful work. In that study, though, what they showed was fair was okay relative to semaglutide. But relative to tosepatide, step-bund, people regained weight. So ofoglipron gives you 11% weight loss, that's the MAX. -- can we achieve -- we're up to 16% right now. We still have more room, we haven't plateaued. So I think can we maintain more of that mid-teens level of efficacy, the best-in-class profile that we have to date can that be maintained in a combo a switch in a maintenance long-term maintenance.

So I think that's where we'll continue investigating. What is your hypothesis with respect to the balance that you'll need to hit between GLP and Amylin? Do you have any I do.

I -- the bet that I'm putting on the team, but we are debating this across the board. I think that it's more with this long half-life of Amylin, what I'm excited about is, and how would achieve steady state, it's probably going to be sort of more Amylin with a little bit of GLP-1 kicker. But that that's my bet. The team is pushing back. And bottom line is we don't know. We just don't know. We need to do the experiment. -- are no good models on tolerability. Yes. How long are the studies that you'll have to run in terms of like number of weeks on drug or whatever to really kind of dial in the I think that the 12-week studies, the Phase IIa studies, you have to still titrate relatively fast. It's still not a lot. We want to spend 6 months on that maximum dose. That only gives us 6 weeks to get to the titration phase. And so part of the reason we're skipping the 4-week study, we don't get anything meaningful out of a 4-week study. Most of the weight loss is water. It makes -- it gives a point where investors get some data, so they sort of like that. But it's not that informative -- so we're going straight to the 12-week study. And then getting to the 36th week is really where we get the once every 4 week titration, we sort of learn. We've seen a number of companies now that because they're trying to catch up, they're skipping some of these steps. That's -- I think that's dangerous. So we'll do the 12-week, the 36 that really educates us on how to then do the Phase III. Because at the end of the day, there'll be some volatility as we learn in Phase II volatility of, say, the stock. But the data that really matters at the end of the day, there's 1 piece that day that matters the most. The end of Phase III, what goes on the label. That's what matters the most. And so we're optimizing for that.

Okay. Maybe last question for me and our final 1 here is just you talked about having the cash on hand to run as -- but as you think about the broader development programs we just talked about, and you provided an update on cash runway and the specific activities that you have embedded within that guidance.

Yes, absolutely. So the latest guidance is again, $1.5 billion cash as of the end of the first quarter. It will fund the registrational Phase III study through the end of 2028. We'll deliver data on that. We also have our portfolio, including the AML the 35, 35 programs that are in the clinic, 5 will go into the clinic later this year. And with 2,671, we'll be able to fund through the 12-week MAD study. and that will start in the third quarter as a described so Well, that brings us perfectly to time.

I appreciate all the time and conversations after this morning, guys. And thanks everyone who joined us here and online. Great. Thanks, Cary. Thank you very much for -- and good luck.