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Perfect. Thanks. Everyone who's joining us here at the Goldman Sachs Annual Healthcare Conference, thrilled to have Ray Stevens from Structure Therapeutics here to join us. Maybe you could just start with a quick overview of the business. I would love to kind of get started there, and then we'll dig in.
Absolutely, Corinne. Structure Therapeutics is really built around accessibility, plain and simple. In the obesity space, what we see is a real healthcare inequality. The really great news that we sort of see is that patients are really going to have a lot of options at the end of the day. We think that oral small molecules, which is where we're focused, our platform is structure-based drug discovery. Think of any biologic peptide drug. Using structure-based design, we can convert it into an oral small molecule. In the obesity space, GLP-1s, this is a sort of perfect spot for us. I've been working on GLP-1s for about 15 years. At Structure, what we've been able to do is we've been able to create an oral small molecule called aaleniglipron. Aaleniglipron is the second most advanced oral small molecule GLP-1. Orforglipron is ahead of us.
Alendagliparan is right now in the middle of a phase II B, two different phase II B studies called AXS and AXS2, where we'll be testing 120 mg dose in the AXS study, and then for increased weight loss, 180 and 240 mg dose. In addition, we probably have the broadest small molecule portfolio with an amylin, as far as we know, the only amylin small molecule. We have a GIP small molecule, a GCG small molecule, as well as an Apelin small molecule. What we think the future really, at the end of the day, is all about fixed dose combinations. What we like about small molecules is we can combine these in different ways for different needs to give patients even more options.
Yeah, you alluded to some of this in your last answer. At a high level, can you just talk to us about how you think about the current kind of and future state of play within the obesity market? How do you think orals versus injectables will fit? Where do you see the opportunity for the new opportunities or new agents to kind of play a role?
Yeah, the really, really good news is patients are finally going to have multiple options. The injectables, this is a convenience to them, no question. The once-a-week injectables, once-a-month injectables. We're eventually going to get to once-every-six-month injectables. We think that that's important for convenience. We also know, based on our research, there is a significant population that would prefer a once-a-day pill. They want to have their, they want to get their coffee, take their pill, drive to work. This is all about giving patients options. I think that's where the field is going. I think the other piece is obesity is finally now being acknowledged as it is a disease, and it's a pandemic. It continues to grow. We're seeing all these indications that expand from obesity into chronic kidney disease, liver, cardiovascular, CNS.
We're learning this excess weight that we have on our bodies, how it can have a pronounced effect on us. That's just going to increase the opportunities in the field or the need in the field to continue giving patients more and more options.
Yeah, so within the suite of options that you expect patients to have, you're operating specifically in the oral class of therapies. Maybe you can talk to us how you think within that oral class, what are some of the most important things? How do you balance things like efficacy, tolerability, convenience?
At the end of the day, you have to have efficacy. The drug has to work, no question. With small molecules, one of the things as a chemist that we worry about is safety. And I'm talking about off-target safety. With this class of drugs, we think about the off-target, and then there's the GI tolerability, which is more of an on-target safety. But we think about safety. And so we put the bar, we're in the fortunate position where we go after very validated targets. GLP-1 as a target has been validated. We just passed our 20th year anniversary for the first GLP-1 on the market back in 2005. And so safety is there. We also think about manufacturing. Today at Structure Therapeutics, we have the ability to manufacture 6,000 metric tons. What does that mean in terms of patients?
That means we have the ability to make enough material for 100 million patients per year. That is with Structure Therapeutics, with one manufacturer. Small molecules have the ability to scale at a global scale. We know the need is a billion now, and it is going to grow through 2030. Manufacturing is really important. The last one is we think that the future, I mentioned this fixed dose combinations. It is really about, you think about semaglutide as a selective GLP-1. Tirzepatide is a GLP-1 plus a GIP. We are hearing about triple Gs. With small molecules, we have the ability in the test tube to combine GLP-1 with an amylin, like a CagriSema, except in the small molecule, we can really play with the ratios, one to one, two to one, one to two, five to one in a fixed dose combination in a single pill.
We have more flexibility to design the next generation of drugs that are out there. It is one of the things I like about small molecules, more flexibility. The last piece on this really is what we hear from the KOLs, the physicians, they want flexibility. They do not want to get calls in the middle of the night saying, "I have this nausea" or "this side effect." They want to be able to tell the patient, "Cut the pill in half" or "Change the dose day by day to really learn how to go on these drugs." Most people discontinue these drugs after a year or two. We think that that flexibility between the patient and physician relationship is really important. This touches on the last point, which is in maintenance, long-term maintenance, we think is another advantage to the small molecules.
All right, let's talk about the specific assets then. aaleniglipron, as you mentioned, is your lead program. It's an oral GLP-1. And you've described the asset as having best-in-class potential within that landscape. What does that mean in your view, and what are the key metrics we should use to judge best-in-class within the oral?
Yeah, so everybody's going to be comparing, first of all, efficacy. I believe that the small molecules have to be as efficacious as the peptides. We're going to see this. We're already starting to see this with orforglipron versus semaglutide. I think our right comparator is probably going to be orforglipron. We have a lot of respect for orforglipron as a drug. That's one level. Tolerability is another level where you have to be as tolerable. We put, coming back to the comparators, safety. Again, we spend a lot of time making sure the off-target safety is at a really high level with a sort of small molecule. It gets back to combination, combine ability with other medicines, and not just other ingredients. We're really excited about the possibility of combining a GLP-1 with an SGLT-2, with an oral PCSK9.
There's a lot of opportunity for growth once we have these backbones. aaleniglipron is our first backbone. Then we have our amylin as our second backbone.
Okay. Maybe you could spend some time talking about the key design features of aaleniglipron that provide that profile you just described, things like beta-arrestin bias, half-life. How do all of these kind of compare, and what do you think the translation into the clinic could be?
Yeah, so first of all, the biosignaling, we are big believers in biosignaling, where you do not hit beta-arrestin signaling. Primarily, you're going through this cyclic AMP pathway. We think that that's important. We like to leave the receptor on the cell surface to get that maximum effect. We think that's important. I think the field is starting to show that more and more sort of consistently. That's one design principle. We've already talked about safety as being really important. Put the bar at a really high level for a drug that's going to be taken by 100 million plus people per year is really important. Coming back to combine ability being an important component as well. How do we exactly sort of mix these medicines together into a single pill, fixed dose combination? That's also going to be an important feature.
Okay, great. You have some ongoing phase II studies. I guess, what is the kind of trial design for those phase IIs, and how are they designed to showcase the features that you're just describing?
Yeah, so there's two different trials that are ongoing right now, two different phase II Bs. The first is AXS, and then the second one is AXS2. We're asked frequently, why did we have to do these as two separate studies? The answer is we did not feel comfortable in a 12-week study where we do a once-a-week titration scheme. We did not feel comfortable going up to 180 or 240 milligram dose. We didn't think that would be well tolerated by other participants. We felt 120 milligrams was the maximum dose we could go with a weekly titration. That's why we have AXS study itself is 120 milligram. That study will answer the question. We think that's likely to be equivalent to orforglipron. We have the opportunity to go up in dose further because we have not seen, we have preclinical data.
We know we have not saturated the receptor. We still have room for receptor occupancy. Based on our clinical data, we're still seeing dose proportionality. We can go up higher in dose. That sort of begs the question, why didn't you go higher in dose in the phase II A, the 12-week study? Again, we did not think we could go to 180 or 240 in that study. Now is the right time. Now that we can finally get to this once-every-four-week titration steps with a 36-week study, we have the time to titrate slowly. The mantra in the field, start low, go slow. It's what the peptide field has taught us for now 20 years. It's taught us your body needs time to titrate. You want to sort of have that titration scheme.
That's what we're excited about between the ACCESS and ACCESS II studies. We believe the tolerability will come down dramatically, as we've seen from orforglipron. Orforglipron, from their 12-week study to their 36-week study, they saw a pronounced improvement in tolerability. Now to the phase III data that they recently announced, top-line data, and we'll see more information in 10 days at ADA in Chicago. We've seen that the tolerability gets even better. We expect the small molecules, it's still the early days in the small molecules. Peptides, we saw this history of titration schemes. Now we're going to see it with the small molecules.
Okay, so maybe let's be more specific and start with AXS. How many different dose cohorts, how many patients, and which dose do you think is kind of like the one that we should be comparing versus orforglipron?
Yeah, so with AXS itself, it's a 36-week study. It is 220 participants. We are looking, again, we're going up to a maximum dose, 120 mg. And we think that's equivalent to orforglipron's 36-week, 45-mg, sorry, their 36-mg, 45-mg dose. And we think that's the right comparison is the orforglipron 36-week data of their phase II B.
Okay, so then what does the win look like in terms of efficacy and then tolerability?
I think similar efficacy and similar tolerability for that AXS study.
Okay, so then AXS2, you mentioned you're going to higher doses. I think that there's a couple of different titration schemes included. Could you walk through the different cohorts?
Yeah, absolutely. Again, there's a sentinel cohort that's there as we evaluate. Then we go up to 180 mg, and then we go up to 240 mg. The 180 mg participants are only on for eight weeks. The 240 mg, they're only on that top dose for four weeks. A common question we get is, are they really on drug long enough to really see efficacy? It's a fair question. What we're really looking for is directionality. We're looking for, first of all, is there any adjustment in tolerability at this sort of higher dose? Second, do we see directionality changes in terms of efficacy? We're not looking for the ultimate sort of weight loss number. If we see an indication of directionality that it's going in the right direction, that we can go to a higher dose, that's really informative to us.
At the end of the day, the purpose of a phase II B study is dose range finding. We use it to educate ourselves, what is the best plan for phase III? We simply want to know the question. We know 120 mg works really well. Should we in the phase III include a higher dose at 180 or 240 in that phase III?
Okay. I guess that does kind of beg the question of what directionally sounds nice, but what does that really mean in practice? And if we're kind of interpreting the study from the outside, what would we want to see to say, okay, there is best-in-class potential here? What's fair, I guess?
Yeah, absolutely. First of all, I think what's fair is, I think showing equivalence. I think the bar really is orforglipron. Again, a lot of respect for orforglipron. We think that's where the right bar is. Coming back to your best-in-class, again, we believe based on our preclinical models, off-target safety, we have that potential for best-in-class. In terms of efficacy, to me, one of the things that I appreciate the most when I look at the data is the shape of the curves. One of the things we're really looking forward to 10 days ADA is the shape of the curve. Are you seeing plateauing, or are you sort of seeing it continue to go down?
As we look at the data, the 180 and the 240, are we seeing a change in the slope of the curve that's going to give us the encouragement? For me, a win, if we're as good as orforglipron, and then we can do this in combination with so many other medicines, that's a win. If we can get even more efficacy with a higher dose, that's an extra bonus win. That's how we're looking at it.
Do you think about next steps then? You're going to get these results, and you're going to move forward towards presumably a registrational trial. I guess, how many doses do you think are going to be appropriate to take forward into the phase III program? How would you determine kind of the best doses to take forward?
Most likely, we'll go into three different doses in phase III, a sort of low, a medium, and a high. That's again where in the phase II B study, we're really asking ourselves, how high can we go? That's the big question. Again, 120 is likely to be one of those doses. That'll probably be the sort of potential sort of medium dose. We're also asking ourselves the question, maintenance dose. We think that, again, long-term chronic usage, we think a real opportunity for small molecules is in maintenance. What is that maintenance dose? We want to sort of learn about that. You've asked about sort of more top doses. One of the other things that we're also continuing to learn on is what is the right starting dose? In the phase II B, it's really about pushing the upper limit.
In the phase III, we have the ability to go down even further in dose because, again, we believe what the people have been telling us all these years, start low, go slow. We started at 5 mg, both in ACCESS and ACCESS II . We have the ability to go lower in dose if we want to.
Okay. In terms of phase III programs, I guess the agency has been relatively clear about what the scope and scale of those need to be. How are you thinking about the phase III program? What does that need to look like?
Yeah, so with all the chaos that we're sort of seeing right now with the FDA and everything, there was good news in January. In January, the FDA came out with very clear guidance in obesity. That guidance was, first of all, for chronic weight, they acknowledged chronic weight management is a pandemic. Second, the chronic weight management direction would be 4,500 participants, 3,000 on drug, 1,500 placebo. The other piece, there were two other pieces that we sort of picked up in their January release, and they had not updated their recommendations. I think 2007 was the last time they updated. It was a long time, and a lot has changed. The other two things that we picked up on, there's no cardiovascular outcome required. That's significant.
Other indications, and we certainly would like to explore that, but for chronic weight management, given this obesity pandemic in the U.S. and globally, there's no cardiovascular outcome study needed. Lastly, they used the word maintenance six times, which was for the FDA, we do not usually see that word a whole lot used. It was in reference to titration phase, where you titrate up and then maintenance phase as well. Again, they are seeing this discontinuation rate being a potential new health crisis where people take these drugs, they lose weight, then they stop, they gain weight, and what we sometimes refer to as the yo-yo effect. They do not want to see the American public go through a yo-yo sort of mechanism. Maintenance is something that they are acknowledging is really important.
Okay, you mentioned the outcome study, but what about adjacent indications? Are there other indications you think are important?
Absolutely. This is where we've been clear in terms of one of our common questions with investors is partnering conversations.
That was going to be my next question, but go ahead.
In that regard, we feel comfortable with chronic weight management. Again, it's very defined, and it's a straightforward path. There is so much opportunity. I mean, again, type 2 diabetes is one obvious sort of direction, but we're seeing sleep apnea, we're seeing chronic kidney disease, we're seeing liver disease, cardiovascular disease. As a biotech company, one of the things that we would really like to consider is doing more than just chronic weight management. That's where potential strategic partnerships come in. Strategic partners have the ability to do multiple phase III studies. That's one of the reasons. The other reason is, again, what we have over the kitchen sink, making medicines accessible to all. We now feel comfortable. This is a molecule. This is a drug that is going to make it to market.
We don't have any doubt on that right now. To commercialize this, to really get this to meet our mission statement of accessibility, we would like to have a partner for commercialization to make sure that we can really get this drug to all the people, all the patients who are waiting.
Okay. So that does kind of bring up a question of timing. What's the right time to seek a partner and get a partner involved? Is it pre-phase III, pre-commercialization, mid-phase III?
We started having these conversations about a year ago. It was when we had our phase II A data release. It is one of the reasons we actually could not attend the Goldman Sachs Meeting last year. We were in a period where we were right on the heels of releasing the data. That sort of kicked off the process of starting to have the conversations. We continue to have those conversations. There is interest both in our aaleniglipron as well as our amylin small molecule that will enter the clinic at the end of this year, as well as our GIP and our GCG. Again, we probably have the broadest portfolio of small molecules that hit all the incretins and combinations with other medicines. When exactly do partnerships get finalized? It is a process. We continue having the conversations. We continue to set the priority.
We want to be measured by the people that get access to our medicine. We think that's the right place, the right way to be measured. That's best done with the right partner. That could take place before phase II B data. That could take place right after the phase II B data. That could take place during phase III, all that period. I think one of the questions that we get asked again a fair amount is, what are strategics looking for? I think part of it is de-risking. This is a significant investment. There's lots of activity of people looking at partnerships in China, where we have our research base. We're very familiar with what's going on in China. We look at it as having the second most advanced. We are the most de-risked GLP-1.
Our amylin small molecule, with all the amylin data that's going to be coming out, amylin is becoming more of a de-risked target that helps, but we will have the most de-risked amylin small molecule. Long-winded answer to a lot of conversations, a lot of interest. We'll continue having those conversations. What we're really focused on in 2025, we always knew 2025 was a year of execution. We are laser-focused on really, I'd say two things: access, access to that data readout. We really need to make sure that we do as flawless execution as possible. The amylin small molecule, we're really excited about that as a second backbone. We're also laser-focused on execution for that.
That's going to be a great segue to my questions on the amylin and the pipeline. Before we leave the partnership conversation, I did want to follow up on something, which is just to understand how important to you is it that you find a partner that understands sort of the portfolio you bring to bear versus being focused on a single agent?
It's important because I think in this space, the future is fixed dose combinations. Again, we've been saying this for multiple years, is we like the monotherapies. So aleniglipron is a really good monotherapy. Our ACCG 2671, our amylin small molecules are really good monotherapy. We're in the fortunate position of being successful at all these different incretin and amylin small molecules. It really is the sort of combination of all of these together.
Okay. That's great. Let's talk about the amylin. Maybe let's start with the design features of 2671. What are you optimizing for when you were designing and discovering this agent? How do you think about the target product profile for this kind of?
From day one, we use cagrilintide as kind of our benchmark. Cagrilintide is a DACRA, a dual amylin calcitonin receptor agonist. The reason why we chose cagrilintide, again, we started working on this. We got the structure in 2016, so over 10 years ago, we've been working on amylin. Cagrilintide really has the latest set out there from Novo Nordisk. We like cagrilintide. It's got some challenges with mixing and stuff. We have our other favorites now in the amylin field. It was really the best data set that was out there. It was our benchmark. Just like with GLP-1, we had to have efficacy similar. Similar in our cell-based assays and everything, a binding potency, even in animal models. The second criteria, just like with our aleniglipron, safety. We put the safety bar really high, off-target safety.
Making sure that we did not see any liver tox signals or anything at all. We're really, again, proud of the preclinical work that we do in terms of safety. Just like with aleniglipron, we looked at combinability. Are these molecules really combinable with each other? Again, not just GLP-1 with amylin, for example, but an amylin with an SGLT-2 or a PCSK9 that are starting to come out. Combinability was important. The fourth sort of pillar that we call it is manufacturing. Can we make this? Can the cost of goods be at the point where we can make this at a scale where it's available to 100 million people per year? Those were all our design principles that went into our amylin molecule, which was the same design principles with the aaleniglipron
You mentioned this is a dual agonist. There is also a selective agonist that you've talked about. Where are you on the kind of debate between which is more advantageous, a DACRA versus a selective agonist?
My blunt answer is we do not know. One of the things that we are really excited about, again, next Friday at ADA in Chicago is an amylin symposia. We are going to see more data from both SERA's selective amylin and DACRA's. We think that the big question in the field is, what is the calcitonin signaling component doing? Is it a liability or not? Is it adding some feature? Our approach is we have the ability to develop both. We are developing both a DACRA and a SERA. It just happens DACRA was first because we use cagrilintide as our benchmark. It really has helped to educate us on hitting both, but we are actively working on the SERA as well.
Okay. You being kind of the first small molecule amylin agonist in development have the opportunity to set benchmarks the way that orforglipron has for the GLP-1 space. What do you think is the right way to think about targets for an amylin, like a small molecule amylin analog?
I think amylin is more complex. I think with orforglipron or the GLP-1s, it was sort of selective. So there were fewer questions. The biggest questions in the field was, what could a small molecule be as efficacious and tolerable? That's been answered. But it's simpler. With amylin, it's just the reason why I say it's more complex is, as you mentioned, it's a combination of amylin signaling and calcitonin signaling. There's an equilibrium between these two receptors. There's also, I think as the field is evolving, we're seeing, again, we think a lot about combinability. So how combinable is this with, for example, a GLP-1? We start to look at the complexity there a lot more as well. It's more complex. It's why it's taken longer. The field is moving. I mean, there's five clinical readouts in 2025 that we're seeing with injectable peptides.
We're going to learn a lot. Not directly to your question, but one of the other things that we've learned is the IP space, the intellectual property space is very crowded in the GLP-1 space. We're seeing this IP, patents are coming up and people are getting scooped left and right, particularly from assets from China that we're seeing. We think amylin will be very similar. Our strategy has been from day one, what I love about structure-based drug design, we get to visualize, we can actually see the binding site. We can see all the molecules that are actually binding in there and fitting into the knobs and the grooves. We have more IP than anybody, even than Pfizer or Lilly in terms of GLP-1. We also have more IP on oral small molecules for amylin.
I mean, there's not a lot out there right now. We have been very aggressive at really trying to understand this binding site and all the chemical diversity and scaffolds that fit there.
Do you think there's a role for a monotherapy amylin analog, a small molecule in particular? Or do you think this is more about the combination strategy?
I think absolutely there's a role for it as a monotherapy. The diagram that we have in the office is a aleniglipron and ACG 2671 are both monotherapies. I think that is good for the team's weight loss. Those are good monotherapies. The hypothesis around amylin is potentially better tolerability and potentially better selective weight loss. Based on preclinical models, we see more fat loss than muscle loss with amylin. We think that's important. What we like is the ability for more significant weight loss as a combination. That's kind of how we view it as a leni, 2671 are monotherapies, combos we can do for different indications.
Okay. So what are the next steps for 2671?
Right now we are completing the one and three month talk studies. That is progressing. That will be in the clinic by the end of this year. We are feeling very confident on that. In parallel, we are always quick to sort of mention, because we are the first, do not expect this to be the last small molecule that sort of enters the space from us. We expect to have multiple DCs. We expect to enter multiple molecules into the clinic. Because there is more, as you asked earlier, there is just less known on amylin. We really want to sort of explore with different scaffolds, with different properties, different molecules to really be able to pick the winner. We are largely driven philosophically within Structure Therapeutics around the statin story. The statins, it was Mevacor and Zocor were first and second.
It was Lipitor, 10 years later, sixth-generation statin that won at the end of the day. We approach the GLP-1 space and the amylin space in the same way. We're taking a multi-generational approach. We think this is the early innings in this space. There'll be a lot more activity on amylin in the near future.
You have a number of other small molecule candidates that are in kind of discovery stages. When could we anticipate additional INDs?
The other small molecules that we have in development, we have a GIP, a small molecule. We do not see that as a monotherapy at all. We see that in combination with an amylin or with a GLP-1. In our GCG, same thing, a glucagon receptor agonist. Also, we see the same thing, that is really in combination. We have the ability to do triple or whatever other combinations that we want. We have an apelin receptor agonist that has completed phase I. We are evaluating this. We are in the very fortunate position, the apelin receptor agonist is for selective weight loss in combination with GLP-1. We are in the fortunate position we have two different molecules, an apelin and an amylin, that are really good at selective weight loss.
We're doing a number of studies to sort of figure out which is the right one to put forward. If we can do it just with amylin, we kind of like that sort of path forward. Apelin is currently in development. Back to apelin, it is phase II ready. GIP, we downprioritized it a bit because we really wanted to prioritize amylin. That's what we've been doing. GIP is in the sort of second slot. GCG is in the third slot.
You sort of are alluding to it then. In terms of prioritizing, you could obviously do a lot in the clinical side with aleniglipron. You've got all of these other molecules coming through. How do you prioritize your spend across the more advanced pipeline versus the early pipeline versus discovery efforts?
Yeah, we were faced with this question a year ago where we asked ourselves, we were doing both type 2 diabetes, which we think is a really important patient population, and chronic weight management. We concluded at the board level, the unmet need, the urgency is to get these drugs in chronic weight management. Again, coming back to even the FDA sort of gave their guidelines that came out in January about the urgency of chronic weight management. Right now, we are laser-focused on chronic weight management. That's our number one priority. This comes back to partnership discussions and going into other indications. There are a lot of other indications. The overwhelming unmet need is chronic weight management.
Okay. You kind of are answering this, but I'll ask it specifically. You've got another asset in development for IPF. That seems kind of like one of these things is not like the other one. How does that fit into your portfolio? Where is the prioritization?
Yeah, it's a fair question. When we started the company, gosh, really sort of 10 years ago, we looked at a number of different targets. And our GLP-1 molecule, we made a it's a really nice molecule. We love it. And so we started a phase I study, essentially to sort of de-risk it. But you're completely correct. It does not fit in with everything else. We're focused on metabolism and obesity. And so we will be looking for potential partnering opportunities.
A way to monetize it.
Yeah, a way to monetize it that can help sort of offset some of the burn in the metabolism obesity space. It is a great molecule.
Yeah. Okay, then Cash Runway, last question. What's your current Cash Runway and what activities are embedded within that?
Cash Runway, as of the end of Q1, I think the number was $837 million. We are well capitalized. We have runway until the end of 2027. That includes all of the studies, all of our different programs. That includes phase III readiness. All the activities, making API, drug product and everything, getting everything ready for the phase III and all the associated studies, but does not include the phase III study itself.
Okay. Great.
We're in good shape financially.
Perfect. That brings me to the end of questions and basically end of time. I really appreciate you joining me today, Ray. Thanks to all of you who joined us here and online.
Thank you very much. Pleasure being here.