Right, well, good morning, everybody. I'm Seamus Fernandez, one of the Senior Bio-Pharma Analysts here at Guggenheim Securities. This is our SMID Cap Biotech Conference, and I'm really pleased to be joined here by Structure Therapeutics. Many folks actually know Structure as the sort of a pioneering company in the small molecule obesity space, and I'm really pleased. To my immediate right is Dr. Blai Coll. Blai is the Chief Medical Officer of Structure, and then to his immediate right is Jun Yoon, the CFO, Chief Financial Officer of Structure. So maybe just to start us off, if you guys wouldn't mind giving us just kind of a high-level overview of the company, the mission, and what really sets Structure apart from other companies in the obesity space, but also maybe remind us about your sort of GPCR-related mission, because that's your ticker symbol.
Yeah, absolutely. Thanks, Seamus, and it's great to be here. So from a high-level standpoint, Structure Therapeutics, just to remind everyone, our mission and vision is about accessibility, making medicines accessible to all. How we do that is making oral small molecules. We use our structure-based drug discovery technology to build our portfolio. We've got what we believe is the broadest and deepest portfolio of oral small molecules targeting metabolism, particularly GPCRs. So starting with GLP-1, we've got a small molecule, GSBR-1290. It's now known as Aleniglipron. That's a new name that is official now, so it's currently in two phase II studies that we'll talk about. We also have an amylin agonist. It's a small molecule. We announced the development candidate late last year. We're moving that as rapidly as we can into the clinic later this year.
And then we've got a pipeline of new small molecules targeting GIP, glucagon, apelin, and really everything in one shot. And so what really sets us apart is having this portfolio, that the space is dominated by peptides, and we know that the single biggest problem with injectable peptides is accessibility, the ability to scale, manufacture, deliver these medicines in oral formulation. It's a significant endeavor. And so the recent data that we've seen is 65% of patients are not able to stay on GLP-1s after a year. That number goes up to 85% after two years. So the ability to really deliver small molecules and provide that sort of sustained weight loss is going to be important. And then for 2025, what we want to remind everyone is we think this is going to be the year of the oral small molecule GLP-1.
You're aware that Lilly is going to be having their first phase III data for orforglipron. We think that's going to be incredibly validating for the oral landscape. That's going to be followed up by our data with the aleniglipron at the end of this year. It's two phase II studies, ACCESS and ACCESS-2, 36 weeks, monthly titrations. We're excited about delivering that data, reading that out at the end of the year. And then lastly, on the amylin side, GSBR-2671 development candidate, we'll be moving that into phase I studies. And that really gives us two clinical stage backbones in the oral small molecule space.
Great. And there's a rather than sort of just isolate to obesity, can you just update us on progress around the LPA1 as well? I know that falls a little bit outside of this, but just interested about other areas. And you mentioned the apelin. What are some of the areas that you're focused on with apelin? What needs to be sort of established in order to kind of move that forward into the clinic?
Yeah, absolutely. I can start on that, and maybe Blai can chime in, so on the LPA1 program, that's a program that's currently in phase I . It's in a single- and multiple-dose study, healthy volunteers. It's targeted for idiopathic pulmonary fibrosis. We're going to be finishing that phase I study and provide data on that later this year, and then on the apelin program, that's a clinical stage molecule that we're currently doing long-term chronic tox studies on. It's a six- and nine-month GLP tox studies. We want to make sure this molecule is super, super safe as we think about combination studies. It's a mechanism of action that we're particularly interested for selective weight loss. Blai, I don't know if you want to add anything else.
Yeah, on the LPA1 for IPF, we believe there's room for potency and improving the efficacy based on what's in late-stage development from other companies. And our molecule is a biased molecule, and we see a lot of potential there. So as Jun mentioned, we'll complete the SAD and MAD studies during this year.
Great. And so maybe let's go to Aleniglipron.
Yep.
Did I get it right?
A leniglipron.
Aleniglipron. I'm not going to call it 1290 any longer. So you're now in the phase 11 b trials. Just talk about the differentiation from other small molecules. You mentioned the importance of bias versus lack thereof, and how it differentiates from either orforglipron or AZD's in-licensed 5004.
I'll take that. So Aleni is differentiated from multiple aspects. Bottom line, safety. We have ample safety margins for off-target effects, and that's one element that we pay a lot of attention to in the design of the molecules in early development. So that's one element of differentiation. The second element of differentiation is the potential to go up in dosing. And it's kind of related to the safety, but as well, we've demonstrated proportionality and exposure compared to other molecules in the field. And so that's why in ACCESS-2, we're exploring 180 and 240 milligrams. So higher dosing of 120 that we know it's competitive with the most advanced small molecule out there, phase III. And so these are the two elements that are potentially differentiating Aleniglipron from the other small molecules.
Of course, we're very excited about 2025 and the two phase II programs and studies reading out towards the end of the year, in which we'll be able to establish and fully characterize the dose response from 45 to 240 milligrams. We've designed that study to have enough time to titrate so we can optimize that tolerability and also maximize the efficacy on higher dosing. So that's the bottom line. Safety, front and center, improving and optimizing the tolerability with the titration and the possibility of the upside to go higher in dosing. So maximizing the efficacy are the three elements that can differentiate Aleniglipron.
Great. And then maybe just remind us what we saw in the phase IIa data sets that really informed the strategy, not just the dose titration scheme, but also, again, that ability to kind of press the dose higher.
Yeah, so three aspects there. We didn't see any off-target effects. This is up to 200 participants dosed to 12 weeks, which is a sizable sample size and long-term duration, so no off-target effects. In terms of tolerability, we saw GI tolerability, and this is a sign of target engagement. But the important thing is that we saw that trend downwards as we up-titrated the participants, so there's indirect signs of building the tolerability there, so that's the other learning, and then coupled when you extend the titration, you improve the tolerability, and that informed that start slow and go slow on the phase III and the phase IIb, and that's why we're starting at five milligrams and spending four weeks on each one of the titration steps.
In terms of efficacy, we saw up to 6.9% placebo-adjusted body weight reduction up to 12 weeks, and that's also at 120 milligrams. As we've mentioned, we go to 180 and 240 in one of the phase II with the upside of maximizing that efficacy.
Great. And in terms of just, there's been a lot of debate over half-life versus sort of the, I guess, receptor occupancy on a relative basis, and there's PK characteristics, Cmaxes, all these things. What do you think is the most important sort of profile contributor from Aleniglipron, and how does it differentiate from the other programs?
Yeah, we wish we had that silver bullet that could inform and predict the tolerability and the level of efficacy. It's a combination of factors, right? And I think PK is important, but also the way we design the studies, it's also important. The starting dose, the titration scheme, it's really, really important to optimize that tolerability. We know we have a one today because we've done the studies up to 12 weeks, and the profile is competitive. And we don't just look at the half-life. We also looked at what's the minimum concentration within the dosing interval, and we're way above the maximum insulin secretion dose that we identify in non-human primates. So we feel confident in terms of the half-life and the level of efficacy that we've demonstrated.
In terms of tolerability, of course, PK has a contribution, but also we need to factor in, as I said, the titration scheme and the starting dose.
Great. We're going to see the orforglipron data starting in the second quarter, and maybe I'm definitely not finishing in the second quarter, but the two key data sets are anticipated to maybe read out in the second quarter and third quarter of this year with orforglipron. In terms of the bar that you would see that setting and how there would be a potential compare-contrast of aleniglipron versus orforglipron, can you just help us understand where you think the orforglipron profile is likely to shape out and how aleniglipron might differentiate or be similar?
You want to take that?
Yeah, why don't you go ahead.
So the first data set from orforglipron will be in type two diabetes participants. And so I think what we've heard from Lilly is that they're expecting a Ozempic-like level of efficacy, both in terms of HbA1c and body weight reduction in type two diabetes, that we know it's always 25%-30% lower than in non-type two diabetes. So that's the expectation. They've not been very explicit about the tolerability profile. There's a lot of speculation out there. And as we all know, they are transitioning from one to three weeks titration to four weeks in phase III. We think this will be tailwinds for us. We're expecting positive results out of orforglipron. And the way we looked into this for us are 36-week data, and the right benchmark is orforglipron at 36 weeks.
That's the New England Journal of Medicine publication back in 2023 in non-type 2 diabetes. How we're benchmarking our results towards the end of the year will be on their phase IIb.
Okay. And there's also a little bit of a hyperfocus, not just on tolerability, but this sort of small molecule dialogue around safety specifics, particularly LFT fluctuations. Anything to sort of focus on there? Very limited LFT changes in your own studies, very limited with orforglipron, but there have been a couple of GLP-1s that have fallen by the wayside, oral GLP-1s that have fallen by the wayside because of that. How do you sort of tease out that type of data? And your conviction that the phase II is likely to show robust safety?
Yeah, it's an important question, of course, with everything related to a small molecule. When we go back to all our preclinical and clinical data, we know that from an in vitro perspective, aleniglipron is GSH negative. So that's the first thing. From in vivo in preclinical, we went all the way to 1,000 mg/kg/day in rodents and 30 mg/kg/day in non-human primates. We haven't seen any signal in terms of liver tox. And then in the clinic, we haven't seen any case of DILI up until now. And we went to 120 milligrams up to 12 weeks. There's fluctuation in liver enzymes. That's going to happen. And these are participants with comorbidities. These are participants with other medications that can also cause that elevation in liver enzymes. But there's no direct sign that we have a liver tox.
And that may be similar in terms of the orforglipron scaffold. There's the programs that you're mentioning. These are most likely a different scaffold that may have some liability in terms of liver. But we feel confident with the three pieces of data that I mentioned that we don't have any signal in terms of liver. Of course, we'll continue monitoring, but it's just the clinical routine monitoring.
Okay, great. And you mentioned a GSBR-2671. So sort of a next asset for you to advance into the clinic targeting amylin. We've gotten a lot of sort of data and speculation around data very recently around amylin. What are your thoughts around the amylin mechanism and the opportunity that it presents? And any thoughts on some of the recent CagriSema data that were presented, including I'm still a little confused by the charts that were presented this morning and still trying to figure those out. So maybe you can help us.
Yeah, we're excited about the mechanism of action. I think we have two extensive data sets, both from CagriSema and Amycretin, validating the modulation of the amylin receptor for favorable weight reduction. I think it also offers the possibility to a selective weight loss, and the question that remains out there is whether by adding the amylin receptor, you can improve on the tolerability level of the classic incretin. And so these are the aspects that we're looking in. It's validated. It has the potential of selective weight loss, and it also has the potential or the upside of improving the tolerability. There's so much speculation on the CagriSema. I think it's still early to tell. It would be good to have more visibility on the data, and the news from this morning adds more confusion rather than clarity.
But bottom line, we looked at this as an opportunity for us to continue advancing on the program on the amylin small molecule with the idea of also combining with the GLP-1, right? And I think that's the beauty of our platform that will allow us to combine those different mechanisms of action for synergistic effects.
Great. And in terms of just sharing a little bit about the discovery approach and more so your initial effort is very DACRA-focused, so kind of the dual-acting kind of amylin-calcitonin approach, very similar to cagrilintide. Just walk us through a little bit of what differentiates your approach and actually how far ahead you are. To our knowledge, you're the only oral amylin that could advance into the clinic next year. At least so far to our knowledge.
I'll start.
You start, Jun.
Yeah, go ahead. Yeah, so again, we've got a great platform. And the platform using Structure is what enabled us to get to a molecule. We were able to demonstrate that with GLP-1. We've now done that with the amylin. The amylin receptor is complicated, right? It's a calcitonin receptor that with the ramp proteins will go back and forth to becoming an amylin receptor. And so we targeted a dual amylin-calcitonin receptor agonist as the initial molecule. We've got potentially another development candidate that will be following on. We're also looking at the selective amylin receptor mechanism as well. That's all in the works. And it's something that's very active and we're excited about. It's still a relatively new space, being a first mover trying to develop a small molecule in the space. But Blai, feel free to add anything else.
Yeah, just to add a couple of comments. The decision to go after a DACRA dual amylin-calcitonin was intentional because the most solid ground is based on cagrilintide, and so that was the initial thought. Of course, whether we can get efficiencies in terms of additional weight reduction or improving tolerability by going after a SARA, that's something that we want to keep our options open, and that's why we will maximize our platform to also advance in that regard, and then the second thing that we want to also mention is that we're the leaders in the small molecules targeting amylin, and we want to continue being the leaders, being very aggressive on the IP, and having both the DACRA and the SARAs can allow us to perform that strategy well.
Got it. Great. And if there are gating factors, what are the gating factors now to really getting the product into the clinic? And what do you hope to sort of learn along the way?
So we're in IND enabling GLP-tox studies during this year. We're on track to start first in human towards the end of the year. And that will be single ascending dose, multiple ascending dose for 2671. And we're very excited about this program. And we'll continue informing as we move along.
Any sort of preclinical data that you have so far that would inform the efficacy or combination efficacy of 2671?
Preclinical and DIO model is similar efficacy to cagrilintide. We also see additional effects on top of semaglutide in terms of both food reduction or food ingestion reduction and also body weight reduction within 28 days. That's the data that we're using to continue solidify the program. We'll get more data during the year from a preclinical perspective, but that's the data that we have so far.
Okay, fantastic. And just in terms of the sort of tox breakpoint where you feel really confident that we're advancing this molecule into the clinic, is there sort of a particular point in time or is it IND gets through or middle of this year? We're at six months. We're feeling really good. What are sort of the breakpoints for the molecule itself?
Yeah, up until now, we feel very good in terms of the selectivity of the small molecule. And that's one important variable. We'll do the GLP-tox all the way till three months, and that will give us a lot of information in order to decide what's next steps. And we want to do these three months GLP-tox because then you open the door for the first in human to just not be limited to four-week exposure, that it's always you need to raise the titration in order to get to a dose that theoretically is efficacious. So we want to do the 12-week data from a GLP-tox that will allow us to spend more time in the titration in the clinic.
Perfect.
Yeah, and that's one of the things we're doing differently this time than we did with the GLP-1 where we did a serial approach on one month and three months. We're doing this all in parallel.
Got it. Okay. So basically meaning that your first data set would actually have kind of full 12-week weight loss in the phase I.
After the single dose.
After the single dose.
Then from a parallel perspective, kind of continuing to six months would be happening at the same time. Then you'd be able to have an extension to that phase I, or would you sort of restart from there?
I think it will depend on the dose estimation that we will have, and it's still early in the game. If we have a very good understanding of the dosing, we may be able to transition. If that's not the case, then I think it would be much better to have separated studies.
Got it.
It's still early to tell.
Yep, understood. And let's talk a little bit about apelin. There was a disappointing announcement from a potential competitor, BioAge. I assume that there's an opportunity to learn something from those data sets and perhaps we'll capture something from that. If you were looking for data or validation from that combination data set, which was Azelaprag, which unfortunately had to stop early because of liver safety events, what would you hope to see in that data set to really validate an opportunity to move forward should your own apelin be proven safe in the GLP-tox studies, the six and nine-month data?
Yeah, a couple of comments there. These are different molecules targeting the same mechanism of action, but these are different molecules. And they may bring different liabilities. The other thing that we don't exactly understand is any potential for DDI on that program. And that's something that it's always difficult to speculate without knowing the data. But essentially, these are two things that we would be interested in knowing. The mechanism of action is interesting, is appealing, not on its own in terms of body weight reduction, but in combination with any of the incretins, whether it's amylin or a GLP-1. So we're interested in continuing pursuing that. The current program is still in long-term tox, as Jun was mentioning in the beginning. And we want to make sure that the mechanism of action is safe and there's no liability from a mechanism of action perspective.
Great. And Jun, as we just sort of think about the strategic positioning of Structure at this point, lots of competitive molecules out there, molecules emerging out of China, things like that. But how are you thinking about the opportunity for either a partnership or other sort of strategic decisions as it relates specifically to, oh God, I already forgot the name.
Aleniglipron.
Thank you. I almost said 1290, but Aleniglipron, as well as sort of the amylin opportunity and the broader portfolio of assets that you guys have.
Yeah, so in terms of partnership, that's a process that's been ongoing. We know for sure we want to have a partner for commercialization. The space is very large. The opportunity to really provide medicines and make it accessible, we're going to need a commercialization partner. So the discussions are ongoing. From our standpoint, we're laser-focused on delivering our 36-week data. In addition to that, we started the manufacturing of our registrational products. So we want to be truly phase III ready so that by the end of the year, we're going to be in a very good position with regards to having 36-week data, being phase III ready, being in the clinic with an Amylin receptor agonist small molecule, and then really building this portfolio to a place where we've got multiple mechanisms of action. It'll be truly attractive to have everything all in one shop.
So from a strategic standpoint, we're positioning ourselves to be in a good spot to be able to transact with a partner at the right time, with the best partner who shares our vision in this.
Great. Well, unfortunately, we have to wrap up, but it was great having you both here with us today. Thanks to Structure for joining us at another one of our February conferences. Hopefully, we'll see you at our November conference, and really looking forward to all the data that you guys are generating in the back half of this year for sure.
Thanks for having us.