All right. Good day, everyone. Welcome to day two of Cantor's Global Healthcare Conference. For the next session, we are very excited to host the team of Structure Therapeutics. From Structure, we have Raymond Stevens, CEO, and Jun Yoon, CFO. Gentlemen, thank you for joining us today.
Thank you, Prakhar, for having us.
You had some very exciting updates earlier in this week, so we will definitely touch on that as well. Maybe to level set expectations, Ray, just provide a brief overview of the company and some of the key priorities for the company over the next one-two years.
Yeah. What we have, we are really laser-focused right now on clinical execution. We have started our phase III ACCOMPLISH-1 and ACCOMPLISH-2 studies. That is a global study. That is now initiated, and we are focused on recruit to retain, make sure the quality of that phase III study is as good as possible. Dr. Blai Coll, our Chief Medical Officer, he is leading that. That is our oral GLP-1 small molecule. That is right now looking at potentially best-in-class profile. Quite excited about that. The other program that we have now entered phase II-A is our amylin. That is ACCG-2671. That has now started a phase II-A 12-week study and multiple ascending dose. We have that. We have a couple of data readouts coming up. We just had a data readout on Tuesday of this week. That was both on our amylin program and on our aleniglipron GLP-1 program.
We have additional data coming out in Q4. That is our body composition, our type 2 diabetes, and our switch study from injectable. We will also enter the clinic with our second amylin molecule by the end of this year, our combination GLP-1/GIP. Then in the first half of next year, we will read out our 12-week MAD study on our amylin ACCG-2671. So a lot of activity in the next 12 months in addition to the phase III that will read out at the end of 2028.
Okay. That is a great overview. Maybe, before we dig into the pipeline, I wanted to get your thoughts on the landscape, especially for oral drugs and obesity. This year we have seen the uptake of two oral drugs, oral Wegovy and Foundayo. Both drugs have launched pretty well, especially oral Wegovy. So I guess, how has that played out versus what you were expecting?
Yeah. First of all, what I think is great, I was telling somebody earlier, it was a year ago that we were here at the Cantor conference. I was talking with you, and the debate was, is there really room for an oral GLP-1? The injectables are just fine, is what many people are saying. Now, first of the year, we had the oral Wegovy launch, and then in April, we had the Foundayo launch. Those two medicines have already taken up 17% of the market. They have already sort of taken in the GLP-1 space. 80% are new entrants, are the naive patients, so they are expanding the market. So what we are seeing is, from the market, there is a huge demand. It is expected oral GLP-1s will take up 50% of the market by 2030. So a lot has changed just in the past year. The oral GLP-1 market has really grown and expanded, and I do not see it slowing down anytime soon.
Yeah. We have not even seen the uptake in the ex-U.S., which is a big market as well for these drugs. Maybe on the small molecule versus peptide, because there are a lot of companies that are developing oral drugs using peptides. Your entire focus is on small molecules. What are the pros and cons?
Yeah. The reason why we started Structure Therapeutics is around accessibility. I am going to look at there is only roughly 10 million people, or 11 million -1 3 million, I think is the latest number, of people that are getting access to this class of medicines today. That is a small percentage. Only 1% of the market is currently being penetrated. There is such a demand and there is a lack of access to this class of medicines. Part of this is when I think about accessibility, it is affordability, cost of goods, it is cold chain requirement, the shipping and everything. There is a lot of different features to it. It is oral. Think about global. Not everybody wants a needle. Patients want options.
What was fascinating at JP Morgan, one of the things that just resonated with me so much was so many people were telling me, "Oh, my father can finally get on a GLP-1," because he did not want a needle. He was waiting for the pill. I am seeing somebody nodding their head yes. Exactly the sort of the case. I think that with small molecules, those are all the advantages, cost of goods, manufacturing, scalability, no cold chain requirements. There are so many advantages to small molecules. Small molecules will eventually dominate this space.
Okay. You had some important updates this week for both of your assets. Maybe for you, what were some of the key highlights?
I am going to start with our amylin. A lot of excitement around that program. This is the first human clinical data for an oral amylin small molecule. First of all, one of the highlights, six-day half-life. This gives us opportunity both for daily dosing as well as potential for weekly dosing in a more long-term maintenance study. The safety profile, very clean safety profile. Really pleased with that. Then we had three different levels of target engagement. First, at our 1 and 2 mg dose, no AEs. Really clean. Is the drug working? At our 5 and 10 mg dose, we saw a target engagement. The second level was weight loss. Again, this wasn't done as a weight loss study, so this was purely exploratory. When they come back in for final check, we weigh them.
We saw 3.3% weight loss at the 10 mg dose. Then third, something that we are quite interested in is since this is a DACRA, a dual amylin and calcitonin receptor agonist, bone health. Bone health is important, so we measured CTX-I, which is a peptide, as well as we looked at bone alkaline phosphatase. What we saw was they both moved in the direction of we are seeing improvements in bone health. Those three levels of target engagement from those biomarkers really gives us even further conviction the drug is working, it is active, and we are very excited to move into the 12-week, multiple ascending dose study.
Okay. The drug has a really long half-life, as you said, of six days. What was the rationale to design the molecule like this to have such a long half-life?
I would like to sit up here and say, "Yeah, we designed it exactly this way." It was the observation from the molecule. That is the truth to it. Once we realized, though, that it had a long half-life, we realized the opportunity that was in front of us. The way I like to think about this is, many questions are about the titration. By dosing at a low dose, because it is also very potent. It is a really potent molecule. We tested in the SAD study 1, 2, 5, and 10 mg. We will see a level of accumulation, and that is almost like a self-titration within the body. But we did not design it to be six-day half-life. But as soon as we saw that we had this feature, we are taking advantage of it.
Got it. One question we get, coming back to the long half-life is, with the long half-life drug, how do you get comfortable on the safety profile, especially some of the off-target effects, given it's a small molecule?
Yeah, absolutely. As a chemist, it's one of the things I always think about. It's always top of our mind. We've completed the three-month tox study, so that's finished and done. Very clean profile. As we reported on Tuesday, no SAEs, no liver tox signals at all. So very clean profile, so very pleased with that. We've initiated our six and nine-month tox study, so we're carefully monitoring that. It is something that we're aware of and we'll monitor. I think given the low dose combined with the half-life, it's almost like the perfect combination that we want for something like this.
Right. During the update, you showed some weight loss data, but I felt that some of the great data that you showed on the PK, as well as the biomarker data, that was probably more relevant for an update like this, rather than maybe weight loss in the SAD trial. One thing that's interesting is how potent the drug is, right? If you do some calculations around potency, what you showed in the preclinical data, you can get to 3 - 5 mg dose as really potent. You did test up to 10 mg dose as well. Do you really need to go to 10 mg given the profile that you're seeing with the 5 mg, as well as the self-titration that you talked about?
This is something that we're going to explore in the multiple ascending dose study. It's the perfect format for that. We know what we got out of the SAD data. We know where to start. At 1 and 2 mg, there were no AEs at all. We've got our starting point, and we will explore. I think about this with our GLP-1 program. When we did the SAD study, we went to 90 mg, and then in the 12-week, we went to 120. Then when we went into the 36-week, we went to 180 and 240. It's something that we want to explore. We have the safety window to explore higher dose, so that's something that's important. We will evaluate this in the MAD study. How high do we want to go?
Okay. On the weight loss, there is obviously signals of weight loss as well, despite this study not being designed as a weight loss trial and in healthy volunteer patients. You did see weight loss at the top dose as well as 5 mg. Maybe just one clarification. It was at day 24 and day 17, so very different time frames. Was the study always designed like this, and did you measure weight loss at earlier time points?
Yeah. To take your questions backwards, we did not measure sort of time points of weight loss. This was not intended as a weight loss study. The reason was we knew the half-life. As we reported at the American Diabetes Association meeting this past June, in non-human primates, the half-life was 60 hours. So we knew we had a long half-life, so we needed to measure for an extended period of time the PK properties. So our intention was to go to 17 days. Once we started the 1 and 2 mg doses, we realized the half-life is even longer in humans than in non-human primates, which is not unusual. You see that. So we amended the protocol for the top dose, the 10 mg dose, to go out to day 24. That's the reason for that.
Right. So you did not measure weight loss for that?
We measured weight loss at the beginning and at the end of the study.
Okay.
Just as part of.
Got it.
Typical physical.
Got it. As we think about the MAD trial, which you have already started, and this is probably a nice problem to have, but how do you figure out the titration schedule for a drug that is self-titrating if you're giving it a daily dose, or you maybe just do a weekly dose from the get-go?
Yeah. We're going to explore both daily and weekly. Again, the weekly will be exploratory. Also, keep in mind, this is a 12-week study. In 12 weeks, there's only so much we can do. Again, I think about our experience with GLP-1s that have been very successful. We can only titrate for a few weeks at a time. We can't do four-week titration steps either. We can only do two-week at max titration steps. That is going to be one of the limitations in a 12-week study. I ask myself the question, what do we want to get out of the 12-week study? It's proof of concept. We want to look at efficacy, but we're also balancing tolerability as well. It's not going to be the perfect profile. We need to learn.
Right.
Each of these steps, we need to learn and balance those two together.
Right. Will you have the adaptability in the trial to modify the different dosing of schedules and the titration as you go and as you learn more?
Yeah, absolutely.
Okay. Got it. Because you have such a long half-life and you have a daily oral GLP-1, obviously, combination is a big differentiator for your portfolio as well. How do you figure out the dosing there? Because aleniglipron will be dosed daily, takes away the meaningful convenience advantage of a weekly, is there a regimen that you think could basically help both molecules differentiate?
Yeah, this really gives us a lot of optionality as we look at it. We get to steady state faster with the amylin, and so that might help with tolerability at the initial stages to build that up as we bring in the GLP-1, or vice versa. There is a number of different questions that we need to answer in the MAD study as well as in the combination studies as well, to really optimize this. We are looking forward to doing those studies, because we think both the monotherapy medicines, whether it is our amylin or our phase III aleniglipron, those are molecules for the masses, really. We can manufacture it at a very large scale, great cost of goods. The combinations are more for specialty markets. We will continue advancing those programs in that way as part of life cycle management.
Okay. You have a portfolio of all the amylin drugs. You had a backup DACRA as well. Based on what you are seeing with ACCG-2671, is there a need for a backup?
Yeah. I do not like calling it a backup. I am sensitive to this. It is our second DACRA molecule. We are not trying to solve for anything, to be really, really clear. We want to make sure that we win in this space. We have a unique advantage of first movers advantage in terms of we are the first oral amylin small molecule, so that is important. Our structure-based drug discovery platform allows us to visualize and see the binding site so we can design molecules. We have invested deeply into the chemistry of making a number of molecules. So it is really about making sure that we win. It increases our probability of success. Think about the small molecule GLP-1 space. There was danuglipron, there was orforglipron. There is actually two other scaffolds out there. You never quite know what is going to happen in drug discovery.
We think that by having multiple shots on goal, it is going to increase our probability of success. ACCG-2671, we like this molecule. It is quite unique.
Yep. Absolutely. What about selective amylin oral small molecules? Are you working on that as well, and what is the status there?
Yeah. We continue to work on our SARA program. We are working on both DACRAs and SARAs, and to take this back, there is a lot of really exciting encouraging data from eloralintide as well. We continue to monitor that. We are also quite intrigued with the calcitonin component of the DACRA in bone health. We are going to continue parallel processing both DACRAs and SARA small molecule drug discovery.
Okay. You build a really strong IP portfolio for the oral GLP-1. Maybe if you can just talk about the IP portfolio that you are building for the oral amylin as well, because obviously you are ahead, but competition in a large market is inevitable.
Yeah. Jun, you want to take?
Sure. On the IP portfolio, I will repeat what Ray said before. The amylin IP portfolio is GLP-1 portfolio on steroids. What we have done in the GLP-1 space in using our structure-based drug discovery platform is build the broadest IP chemical library, chemical scaffold, for the small molecule GLP-1. We have been able to monetize that with a recent deal earlier in the year with Roche. We have the same capability, and we have done that with the amylin side of things. The DACRAs that you see, the SARAs, there is a broad portfolio with respect to IP and small molecule chemistry.
Right. In terms of competition, we do have the peptides on the amylin space. We have Novo's amylin drugs as well. An oral GLP-1, the competition came up really fast. In terms of the small molecules, you are leading the pack here, but things that are happening in China where we may have limited visibility, what are you seeing in terms of the oral small molecule amylin space?
Yeah. Go ahead, Jun.
Yeah, no, in terms of the oral amylin space, we know there's a lot of people working in chemistry here. They're trying to move into this space. We're the only ones that are in the clinic with a small molecule, and the reason why we have a robust IP portfolio is we're putting flags down in all the different chemistry. So that's going to provide us with a moat and potential barriers of entry as others work in the space.
Okay.
I'm a big fan of the book, "Only the Paranoid Survive." That's how we feel about the amylin space.
That's great. Maybe we can talk about aleniglipron as well, which is in phase III now. So there are only three molecules in phase III on the oral GLP-1 space for orforglipron-like molecules. We have AstraZeneca, we have Ascletis, and you have aleniglipron as well. So I guess, what are you highlighting as what differentiates aleniglipron versus some of your peers?
We're the best. No, sorry.
That seems a good short and sweet answer.
Yeah. No, but if you actually look, what we're seeing is on most of the oral GLP-1s, and they're good molecules. We have a lot of respect for orforglipron. You're seeing this 11%- 12% is where they're all starting to go, in that anywhere from 36 to 60 to 75 mg dose range. Aleniglipron, we're showing 16%. And think about our 16% number. That's after eight weeks at the top dose, only eight weeks. Wait until we get our top dose after 52 weeks. We're really excited about sort of seeing that level of efficacy. So I think what we're seeing is, we're seeing a separation from the pack of aleniglipron in terms of efficacy, is just much, much better. And I think that's really important. I'm a big fan of, you don't need to be first in class, but you need to be best in class.
Got it. You've tested various titration schedules for aleniglipron right now. Phase III is testing a slower titration schedule with a low starting dose as well. I guess, what are the key data points that are now driving your conviction that the safety tolerability profile in the phase III will be very manageable?
Yeah. Dr. Blai Coll, our Chief Medical Officer, I think has done a phenomenal job. I think he's probably done more phase II studies, I think, than anybody else in characterizing. Our dynamic range goes from 2.5 mg, where we see a little bit of weight loss. We know that we're getting target engagement, the participant knows that they're getting drug, and then they continue that. That linear slope we think is really important. That's what the physicians tell us that they want to see. I think that's important. The studies that he's done, open label extension, or there's a challenge in the field with placebo groups and knowing that they're not on drug pretty early on and what happens there.
The open label extension that Blai did was a tremendously innovative idea to retain those participants, to get them to continue on to the full study and follow the instructions. Blai's use of heat maps, I thought, that we published in Nature Medicine this summer at ADA. Those heat maps show each individual patient journey. I hope other companies start to do these same heat maps and share that level of detail. That shows the confidence we have in our data. You can see every individual participant. And one of the questions was, well, what if you skip a dose? Do you have to re-titrate? Nope. We can see sort of within these heat maps, we can see the episodes where they skipped a dose. They were perfectly fine as they went on the journey. Some people adjusted.
I think Blai has done a phenomenal job in the clinical trials and continues to be very innovative at applying all those learnings. The phase III, we have a lot of confidence in the phase III execution, particularly for chronic weight management.
You do have few readouts in 4Q as well for aleniglipron. What are you hoping to learn from those readouts?
The first one is the body composition study that'll read out in Q4. The second one is the type 2 diabetes, and the third one is the switch. Body composition, we're looking at fat versus muscle, when you're on this class of drugs. It's an important question that's being evaluated, and that's now required by the FDA. we want to make sure that we know exactly the sort of right way to optimize for these studies. Type 2 diabetes is really part of the ACCOMPLISH-2 study. That's for individuals who are overweight with type 2 diabetes. then the switch study is, again, we think that this is a potential opportunity for go to market in terms of, we know the injectables, 85% discontinue after two years.
With that in mind, do you have to re-titrate, if you go from an injectable over to an oral for long-term chronic use? can you go from X dose of an injectable over to Y dose of an oral? That's the question that we're asking. we'll read out that data next quarter.
Got it. in the phase III, you are testing a 24-week titration schedule. I think in the open label, it was a 36-week titration. I guess as we think about the safety tolerability versus the speed of weight loss, especially at the initial phase, how do you balance that, and how important is some of the speed of weight loss as well as you think about patient retention?
Yeah. I think what's really important, and again, what we get from the sites, what we get from the KOLs, what we get from physicians is what they really want is they want a linear, a gradual They need to see weight loss near- term. In that first four to eight weeks, they need to see some weight loss. That's why the 2.5 mg was really the sweet spot to get started. They see a little bit of weight loss. as they go through the journey, they need to continue seeing weight loss week- to- week to week. The exponential, the people that have very fast weight loss in the first four weeks or eight weeks, most of that's water. It's not even sort of meaningful, and it's probably not healthy.
We've been listening to the community, particularly to the physician community, about what they think is best, and they want linear weight loss. They think that's healthy. They think it's sustainable. It's the right way to go on the patient journey. And again, as we look at heat maps, it's the right way to have the journey. It's not to have rapid weight loss.
Okay. On the safety tolerability, people still compare some of the nausea rates that you have shown in phase II, with other trials as well, which I think is apples to oranges because you do an eDiary, which asks people to report the nausea, and if you ask people five times if you have nausea, you'll probably report a nausea. Are you doing eDiary in phase III as well?
Yeah. And again, this is an important question. We're one of two that did ediaries in phase II. We think those ediaries are incredibly helpful. Again, we like as much data as possible. We learned a lot from those ediaries, tremendous amount from the patient journey. But in phase III, it's not the right setting for, in the phase III, we don't need those e-diaries. We learned in phase II what we needed to learn.
Ediaries were also helpful in figuring out if patients are compliant on the drug as well. How do you ensure that patients stay on the drug in a large global phase III?
Yeah, and this gets back to, we have a number of different sort of mechanisms that Blai's implemented from his learnings. this is a competitive space, so we're not going to disclose all of them. one of the areas is the open label extension by giving people an extra year of drug plus healthcare really resonates really well for them. They're thinking about this. It's not just a clinical trial. I'm taken care of for another year after the trial. That's important.
Got it. Okay. the other piece is.
They have to be compliant.
Right.
To get that.
Right. The other piece is how do you ensure that placebo patients stay in the trial because they do have.
Yeah.
Options outside the trials?
It's the same exact answer. The open-label extension was really helpful. If I look at the 2.5 mg open-label extension that we just did, our discontinuation rate due to AEs was 2.6%. Again, it's because of individuals, they really were compliant. Back to your question about placebo rate, particularly, again, if they know that at the end of the trial they're not going to get anything.
Yep.
They'll be like, "I joined this trial because I want to lose weight. I'm just going to go and take a compounded material." Something that we saw at ADA this year from other clinical trials.
Yep.
If they know that after the trial they're going to get a year's supply of drug, they're going to get a year of healthcare, additional benefits, they want to help with the trial. We found the open label extension to be a very powerful tool for compliance for both placebo and those on drug.
Got it. Maybe, Ray, just broadly longer term, obesity is still a pretty big undertaking in terms of as we get closer to commercialization. You've talked about maximizing the value of oral GLP-1, as well as your obesity portfolio now because you have an oral amylin as well. What's the latest thinking around strategic options for the company?
Great question. I'm going to give this to Jun.
Sure. With respect to strategic partnership, those are dialogues that we continue to have. We know that this is a space that strategics are all interested in, but they are figuring out how to play in the space, how to enter in the space. What we have from the standpoint of our portfolio is aleniglipron. We're doing chronic weight management. We're open, and we're looking at strategic partners to help us think about phase III and type 2 diabetes and other indications to maximize the opportunity, as you said. Those are discussions that we continue to have, and we pursue them.
There's a lot of interest. Obviously, amylin is on the top of a lot of people's minds. Again, differentiation is something that's obviously sort of on strategic minds as well. How do you differentiate in this space?
Right.
With the portfolio, as Jun said, amylin, GLP-1 combinations, other combinations outside of incretins, there's a lot of opportunity with a very broad portfolio and indication expansions.
Our focus is on the right partner, and the right partner that helps us think about the portfolio.
Right. is the portfolio more important, or is the oral GLP-1 getting into commercialization more important? Just how do you think about asset versus.
It depends on the partner, because some partners already have GLP-1s, and so we're not in the mindset of doing individual type of deals. This is a space that's moving into combinations.
Okay.
Amylin now enables us to think about a different modality that can be combined with an oral GLP-1.
Got it. maybe in the last few minutes, just on the balance sheet, how much cash do you have right now, and what trials does it cover?
Yeah. we got a great balance sheet, $1.3 billion in cash as of June 30th. That will enable us to complete the phase III ACCOMPLISH-1 and ACCOMPLISH-2 clinical trials, and we'll deliver that data at the end of 2028, which is our runway. we have the ability to complete the phase II-A MAD study. That's a 12-week study that we're currently undertaking for the amylin program, the ACCG-2671. We've got the ACCG-3535 molecule, the second DACRA, that's going to start into the clinic at the end of the year. we're in a great spot to be able to deliver a number of these value inflection opportunities.
Maybe, Ray, lastly, you presented the data earlier this week. Anything that you feel that investors missed or underappreciated or maybe just are underappreciating about Structure story right now?
Yeah. I think there was obviously a reaction to the stock. I think it was really our sort of postmortem sort of analysis. The data was great, but there was a fixation on the 10-mg dose of the amylin having high AEs. we reminded people, look, this is single ascending dose. We want to look at a low dose, a medium, a high dose, and we expect to see AEs. If we didn't see them, people would say, "Well, your drug's not working." I think that was something that, as we've talked with investors over Tuesday, yesterday, and then today, we've met with a lot of investors all day today, it's one of the questions on top of people's minds.
As soon as we sort of educate them on look, on whether it's a GLP-1 or an amylin, a peptide, or a small molecule, all of these, with a single ascending dose, you will see AEs if you go straight to a high dose. Your body needs time. You're slowing down gastric emptying, and so your body needs a little bit of time to digest. The KOL say, "Start low, go slow." we're really excited about going into the MAD, the multiple ascending dose, 12 week. We can titrate. I think that's going to be really important. I think that's something this week, there was a bit of a reaction to that. as people digest the data, and again, it was a lot of data that we released, both on two very big programs, and that takes time to digest.
Once you digest it's really impressive data.
I thought so that too. Thank you so much, Ray. Thank you so much, Jun. We're out of time, but I really appreciate.
Thank you.
Thank you very much for having us.