Structure Therapeutics Aktie

So thanks for joining us. I'm Terence Flynn, Morgan Stanley's U.S. Biopharma Analyst. For important disclosures, please see Morgan Stanley's Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

Very pleased to be hosting Structure Therapeutics this afternoon, or this morning, I guess, we're still in the morning. We have the company's CEO, Ray Stevens. Ray, thanks so much for joining us. Really appreciate the time today.

Yes. Thank you, Terence.

So again, I think we'll focus a lot on some of the recent pipeline developments. Obviously, you guys had some data out for both aleniglipron and your oral amylin. So maybe first, just to start on aleni, obviously, the obesity market is growing rapidly here. We're seeing the first two orals enter the market and seeing market expansion. As you think about the profile of aleniglipron that you guys have generated so far, what are kind of the key features we should think about on differentiation?

I think one of the big key differentiators is our dynamic range. So we can go from 2.5 milligrams to 180 milligrams. What this really translates into is potentially best-in-class efficacy. So the data that we showed last week was up to 16% weight loss. So we're starting to see a separation of the pack where many of the competing molecules are in that 11% to 12% range, and we're out at 16%. And that 16% is after only 7 to 8 weeks median on the top dose.

So I'm excited about the Phase 3 when we've been out to 52 weeks, hopefully, we'll see even more efficacy. But I think dose range and potentially best-in-class efficacy is really what separates aleniglipron from everybody else right now.

Great. I kind of alluded this in my opening remarks, but as we look at the launches of the existing orals, what have been your kind of impressions of what we've seen so far just from a high-level takeaway side?

So it was about a year ago I was on stage with you, at this same conference. And a year ago the conversation was, is there room for oral GLP-1s? People were still debating this a year ago. Fast forward only a few months, it was January, J.P. Morgan conference, oral Wegovy came out. And then in April, we had Foundayo come out. Now, it's only been 7, 8 months of data that we have. The orals have already taken 17% of the market, and it's still ramping up. The -- I think the number is 80% are new entrants into the market. That means that it's all about expansion.

So what we're seeing is with the orals coming on, there was a big pent-up demand. We're seeing really good launches. Big question we get is with Foundayo, has the launch been slower? My attitude is, give it time. I think it's just -- let's keep in mind this has only been a few months. So they've been fantastic launches. The estimate is market analysis by 2030, 50% of the market is going to be oral GLP-1s.

Great, and maybe talk to us about scalability. I know that's something else that you guys have highlighted. So as we think about not just the U.S. opportunity, but also as a global opportunity and why scalability is so important.

Yes. And this is somewhat of a sort of reminder to the previous question, in this space, in GLP-1 class of medicines, one of the other things that's really starting to be appreciated is the ex-U.S. market is just as big as the U.S. market. We're really seeing that this is unique from, I think, a lot of other medicines. Now, to aleniglipron, we designed this molecule at the very beginning. We thought about manufacturing, cost of goods. We thought very carefully about that.

Our tagline for the company is making medicines accessible to all. So when we designed the molecule, obviously efficacy, safety, tolerability was top of mind. But what was also on our mind was manufacturing. Could we make the manufacturing as streamlined and as simple as possible so we could truly get the cost of goods down as low as possible so we could address a very large global unmet need? And I'm really proud of the -- our CMC team. They've done a phenomenal job at really making these medicines at the right point.

Great. Maybe we'll pivot to some of the recent data that came out. So you had the 72-week ACCESS open-label extension data. Maybe just give us kind of the highlights from both an efficacy perspective, durability, but also safety, tolerability, as, again, particularly at the 2.5 mg data.

Yes, so I'll start with the purpose. We've done more Phase II studies than I think anybody else has done in characterizing particularly for an oral GLP-1. Dr. Blai Coll, our Chief Medical Officer, again, has just done a phenomenal job there. We're really, really happy with the 2.5 milligram dose. Starting at that dose, we saw a 2.6% discontinuation rate due to AEs. This is the lowest discontinuation rate that we've seen with any of the GLP-1s. So first of all, in terms of that aspect, fantastic job.

The 2.5 milligrams start, we also wanted to see what the physicians are telling us is that what they want is gradual weight loss. They don't want to see that sort of rapid weight loss. So could we have a sort of linear profile, a linear shape to the weight loss, that's important. And we're able to see that. We see weight loss in the first 4 to 6 weeks. That's really important. Otherwise they think it's not working, they'll give up. So we think that's an important component, but that linear shape of the line is really important.

And then -- so that's the 2.5 milligram start and the start low, go slow. Really, really works well. And then the question is in that data, 72 weeks of data, safety. What I'm really pleased with is, if we look at these sort of liver tox, ALT, AST, we did not see any issues at all. So we've been in over 800 participants, 72 weeks, this is a very safe drug. So that's really, really important, the safety profile itself. And then in terms of efficacy, again, after only 7 to 8 weeks at the top dose, 180 milligrams, we're seeing 16% weight loss. That's significantly above all the competition out there. And I think it's only going to get better from there.

So we're really pleased with the aleniglipron data that we shared last week. And talking to the KOLs, what they've highlighted is, again, we're separating from the pack and we're able to maintain that solid weight loss.

Great. I think there's a couple more readouts coming up here in the fourth quarter. So you have a body composition study, you also have a SWITCH study, and so maybe just remind us kind of what we're hoping to learn from those two studies in the fourth quarter.

Yes. So next quarter, there's actually going to be 3 studies. The body composition will read out. This is where we're looking at fat versus muscle. This is an important question. This is now required by the FDA in this class of medicines. And part of it is really making sure that we do these studies optimally. We're also starting at 2.5 milligrams and we'll go to 180 milligrams in that study as well, 44 weeks.

The second study that will read out is type 2 diabetes. Are individuals with type 2 diabetes who are overweight. And here, in our previous type 2 diabetes, we only went to 90 milligrams. Now we'll be going up to 180 milligrams. So we think that's an important readout also. That will help us to inform the ACCOMPLISH-2 study, Phase III study, that's now underway.

And then the third study, the SWITCH study, we know that those on injectable GLP-1s, the discontinuation rate is 85% after 2 years. Most people stop taking injectable GLP-1s after 2 years. And so one of the big words in the recent FDA update was maintenance, long-term maintenance for this class. What the FDA wants to avoid is what is often referred to as the yo-yo effect. People lose weight, gain weight, lose weight, gain weight. And so we wanted to ask the question, could you switch from an injectable GLP-1 over to an oral? Do you have to re-titrate? Or can you start at dose X on an injectable? And can you seamlessly go straight to a similar dose of an oral? That's the question that we're asking in that SWITCH study. So all 3 of those will read out next quarter.

Great. Maybe just a couple follow-ups on the SWITCH study. I know Lilly had some data for Foundayo from ATTAIN-MAINTAIN. Any key differences in terms of design for your trial versus their trials as we try -- everyone's going to do these cross-trial comparisons, but anything we need to be mindful of there?

Yes, and I think Lilly did -- for Eli Lilly, I think that was a very well-executed study, but orforglipron can achieve 11% to 12% weight loss. They compared it to tirzepatide, a GLP/GIP, and that's putting the bar pretty high. And so what we're doing is, we're looking at -- with GLP-1s, we think that, first of all, aleniglipron is showing currently 16% weight loss. So we have potentially best in class in terms of efficacy, GLP-1.

Can we maintain that weight loss or can we possibly get additional weight loss as well if you're on a GLP-1 or can you maintain to a GLP/GIP? So I think it's really the biggest difference is we have potentially better in class molecule. Can you maintain that?

And so just to be clear, so you aren't doing the tirzepatide transition, you're only doing GLP?

Yes, we haven't updated. What we've stated is that we're doing GLP injectables. It may be a combination.

Okay. And what -- just remind us the size, like how many people are going to be in this?

I don't have the exact number off the top of my head.

Okay. But it's fairly -- it's like a decent sized trial?

Yes.

Okay. Okay. Great. And then on the type 2 diabetes side, again, you mentioned you previously went up to 90, now you're going to up to 180. I'm assuming you're going to gather not only weight loss data, but hemoglobin A1C data. So maybe just remind us what you guys saw before at the 90 mg dose.

Okay. Yes, so at the 90 mg dose, what we saw, I think it was around 3.5% weight loss, and so for those individuals living with type 2 diabetes, they typically see less weight loss than those without, that are not living with type 2 diabetes. So it was also at a lower dose. So we want to sort of basically test at a higher dose, can we see further improvements in hemoglobin A1C?

And that's really the main driver is hemoglobin A1C for individuals living with type 2 diabetes. We've recently seen some very encouraging data on Foundayo, in type 2 diabetes, and so we think this is an important question to ask.

Okay. Okay, great. Maybe now you alluded to this, but you guys have already moved into the Phase III program. So maybe just high-level level set us kind of the scope of that Phase III program that's started and then how to think about additional trials and other indications?

So we have 2 different studies going on, ACCOMPLISH-1 and ACCOMPLISH-2. This data will read out at the end of 2028. There are individuals that are on maintenance dose for 52 weeks, this is the FDA guidelines. Approximately 5,000 participants total. There will be 3 different cohorts going up to 45, 90, and 180 milligrams. The starting dose will be 2.5 milligrams. Again, what we've learned from all the studies is individuals are very happy at that 2.5 milligram start and start low and go slow. Titration steps once every 4 weeks. Again, we know that is the right sort of titration step both for tolerability, but also that linear weight loss that we're trying to achieve.

So those are the rough parameters of the -- and then one other thing I'd say is I think, again, our -- Blai has done a phenomenal job at doing additional studies to help us do the best optimal sort of Phase III. So one of the experiments that he did in Phase II was what we called an open-label extension. One of the challenges in the field are placebo groups in this space. And so Blai wanted to ask the question, if you do an open-label extension where you can extend for basically in the Phase III for an additional year. Does this help with the clinical trial execution? It certainly helped in the Phase II study. We believe it will help us in the Phase III study.

The use of heat maps, again, Blai's been very creative.

He was the first to use an open-label extension in obesity. First to use these heat maps, where we look at the patient journey. What happens if you skip a dose? That has also really helped us understand how to do the titrations, how to do the steps, and how to have the best possible patient experience as they go through titration phase all the way through maintenance. So all those things combined give us the confidence that the Phase III will be very well executed.

Great. Anything else on baseline characteristics about this population you're enrolling versus maybe the Phase II trial?

No, it will be very similar Phase II to Phase III.

Okay, great. And then how do you think about the rate of discontinuations due to AEs that would be competitive? I mean, maybe just frame for us that, and then, again, you mentioned the 2.6% I think you guys saw in the latest cut of the data. Is that right level to think about here from the Phase III program?

Yes. That was a smaller study in a shorter period of time, so I have to sort of factor that in. We need to be competitive. At the end of the day, we got to be competitive in all the different categories in terms of efficacy, tolerability, and we do think discontinuation rate. At the end of the day, what really matters? Individuals are taking the medicine and it's working. And that they don't discontinue. So that 2.6% rate I think was -- we're really proud again, I think best in class in the field. But that was a smaller study.

I'm not going to give a specific number, but we need to be competitive with everybody else.

Okay. Great. And then the second part of my question was just on the other comorbidities you might consider. We've seen Lilly, Novo lean into some of these other indications like sleep apnea, for example. So how are you guys thinking about that next cohort of potential trials?

For this particular, the way that we analyze the field, the foundation is chronic weight management. This is the biggest market opportunity. It's also the market that's becoming direct pay in terms of growth. And so we are laser-focused on chronic weight management as the primary foundation.

We're also doing individuals who are overweight with type 2 diabetes because we think that that's also a really important as well. That's where we're focused for the Phase III. That's ACCOMPLISH-1 is individuals who are overweight, ACCOMPLISH-2 is individuals overweight with type 2 diabetes.

Okay, great. Latest thoughts on potential partnership for aleni? Like where are we at? Any time lines?

We continue having dialogues. We enjoy interacting with everybody in the industry. We're laser focused on execution as the strategics still understand this space. This is uncharted territory. It's consumer product together with the pharmaceutical market. It's a field that's growing really, really fast.

What we think with our aleni data being best in class, it's highly differentiated. The dose range, 2.5 to 180 is differentiated, all the different properties. And so we think that this is going to be a really great molecule. We're focused on execution, strategics. We'll continue having dialogues, but we think it's significantly de-risked with this latest data.

Okay. Okay, great. Maybe we'll move on to your second program, 2671. This is the oral amylin. Again, an update about a week ago from the SAD portion of the Phase I. So maybe just talk to us about the highlights for those that didn't see that data, and then we'll dig into some more.

Yes, so this is a molecule, many of my sort of friends at other companies used to say, Ray, you can never make a small molecule to amylin. It's just too challenging. This is -- these are peptide receptors. And this particular amylin is a complicated biological system. So first, I'm really proud of the chemists and the biologists. They did a great job at coming up with this molecule.

The highlights from the data release that we had last week, first of all, it is an oral small molecule. Second, it has a half-life. We shared PK data, a half-life of 6 days. This is right in line with the peptides. This is -- again, this is something that we knew it was going to have a long half-life. We shared data at the American Diabetes Association meeting this summer, in New Orleans, 60 hours in human primates. So we're quite pleased. It was actually even longer than we thought in humans. That 6-day half-life gives us the opportunity to do a once-a-day dose daily or a once-a-week dose. So that's something that we're going to explore in the MAD portion itself.

We also were very pleased with the -- we had three different levels of target engagement to show that we really do have a drug that works. The first was, if you go to a very high dose, do you feel adverse events? If we didn't see anything, people would have said your drug doesn't work. So we viewed that as something that was important. So at the 1 and 2 milligram dose, no AEs, 0, 5 milligrams, you start seeing AEs. 10 milligrams, you see AEs. So it was right in line with what was expected.

Second, we did see, even though this was not a weight loss study, we give people a single pill, but after 17 or 24 days, we saw weight loss. So that was also another sign of target engagement.

And then the third, this was very exploratory, in the amylin space, there's a debate between DACRAs, dual amylin and calcitonin receptor agonist; and SARAs, selective amylin receptor agonist. And we wanted to ask the question, the calcitonin component, is there a possibility that this class of medicines could be important for bone health? This is an important segment of the population. And so we evaluated, we looked at CTX-1 as a bone biomarker, and we were very pleased to see that we saw target engagement with CTX-1 as well as with bone alk phos.

So three levels of target engagement in an SAD study, all the information that we needed to educate us on how to do the MAD portion as well as possible. So we will be starting in the MAD, obviously, at 1 or 2 milligrams, no AEs. We will titrate like everybody else does in GLP-1s and in amylins, and excited to see that data in the first half of next year.

Great. Great. Maybe just remind us, like, what is the benchmark there from some of the early injectable amylin studies? Like, what should we -- when we look at the data, what should we compare it to, I guess?

So if we look at the DACRAs, there's petrelintide, there's cagrilintide, those were kind of our benchmarks when we originally sort of designed the molecule. There's some additional molecules that have come out more recently. We think those are the right benchmarks for the DACRAs.

And as a reminder, we have both DACRA and SARA, small molecules. But for the right benchmark for this, we think the DACRAs are the right benchmark.

Okay, and this is a -- it's going to be a 4-week or 12-week MAD study?

Yes. This will be a 12-week multiple ascending dose study with titration steps starting in the 1 to 2 milligram range.

And it's a 4-week titration, I'm assuming?

We can titrate roughly for half the time. So -- and that's actually a really important sort of clarification point, Terence, is because it is only 12 weeks, we can only titrate for half of that, 6 weeks. We can't do the titration steps once every 4 weeks. So this is an accelerated roughly once every 1 to 2 weeks titration steps. So that's an important distinction. If I think about our aleniglipron program, when we went from our SAD study to our MAD study, 6 weeks was titrating, 6 weeks on maintenance.

When we switched to our 36-week study, we were then able to switch to once every 4 weeks, which we know is the right point we want to get to. And we're also able to go to higher doses as well. So with aleniglipron, SAD went to 90, we went to 120 in our 12-week and then we went to 180, 240 at our 36-week. So there's a lot of -- we have a really good path for how we're going to execute the amylin program.

Okay. Do you think that you have enough time or you'll get up to doses where you can show equivalent efficacy to the injectable amylins in those benchmarks? Is that a fair comparison just given some of those dynamics you walked through?

Yes, I think that we have to see. Again, I'm going to use the analogy with the aleniglipron where we only went to 120 milligrams in our MAD study, 12 weeks, because we could only titrate so much. In a 36-week, we could titrate in steps of 4. We have longer time. We could go to 180 and 240, where we've really seen -- where we've really been able to separate from the pack. From everybody else having this full dose range opportunity.

Okay. And the other area, obviously, is combinations. I mean, I think that's the end game for most of these, is you've got a GLP backbone, you add on another pathway, whether it's an amylin, a glucagon, as everyone knows. And so we've seen a lot of that in the injectable space. Obviously, this is an oral now, so it gives you that flexibility. So talk to us about what the combinations strategy is and time lines for when we might see some -- I know you guys have preclinical data about time lines for clinical data.

Yes, so I view aleniglipron and our amylin as monotherapies. And these, I think, are great monotherapies by themselves. We will be starting next quarter, combination trials. Well, actually we've already started in the MAD portion, we have an add-on arm where individuals that are stably on an injectable GLP-1, we give them 2671, and we're asking the question, do they have additional weight loss by giving them 2671? So I think that add-on, already -- so this is already part of the MAD study, is currently in progress.

Next quarter, we'll combine two different oral molecules, and we'll look at GLP-1 plus amylin, and that's for increase in efficacy. And then we also have a GIP small molecule, and our glucagon small molecules, we start to get into those combinations as well as other non-incretin. We've always viewed this as life cycle management. Again, monotherapies, two different backbones, those are molecules for the masses, for the large numbers of people. Then the combos are more specialized molecules for different disease subtypes.

Okay. And so that -- the MAD, you said some data, first half '27, is that going to include the injectable add-on data?

That will include the injectable add-on data, correct.

Okay. And those people I'm assuming will have had to be stable on a GLP-1 for some certain amount of time.

Stable on a GLP-1, stable tolerability, everything, and then if you give them 2671, what is the effect?

Okay. And when is the -- what's the expectation for when we could see some data from an oral-oral, like a GLP-amylin combo data for oral-oral?

So the plan is right now to start that in Q4, next quarter. And then we'll have updates in 2027 on that program.

So probably second half is more likely?

Yes.

Okay. Okay. Great. And then just remind us there, so you are for your -- the GLP, you're going to be using aleni. Is that right? Is that...

We haven't updated on that. We have multiple molecules, GLP-1, just like we have multiple molecules for amylin.

Okay. So TBD. Okay. And then you mentioned this a few minutes ago, but DACRA versus SARA. So just give us an update in terms of how you're thinking about the pros and cons of both of those and then the time line for your SARA.

Yes. We're very intrigued by the eloralintide data. We think it's very good data, and we're excited at EASD, we're going to get an update of eloralintide together with tirzepatide. So that's going to be interesting to see.

The way that we sort of look at this is -- and it's why we're exploring bone health. The difference between the DACRA and a SARA is calcitonin. That's the simplest distinction. And with the DACRA, is there an opportunity there for bone health? So we view them as two different products, is how we look at it. We don't look at it as an either/or, so we're developing both.

Okay. And kind of similar strategic question, like how do you think about maximizing value from the oral amylin program at this point? Like what are the next steps and how do you think about, again, retaining it further through development versus potentially partnering it?

Yes. So at Structure, we're in the very fortunate position. We have a portfolio. We have our Phase III, aleniglipron. We got our amylin 2671 that's now in Phase II, Phase IIa and the other molecules as well in the combinations starting to sort of emerge. We know there's been a lot of interest in the amylin. It continues to be a very exciting space. We're going to see other data from other companies in the injectable peptides. That's going to further validate and clarify the field.

So we think that we're in a really good position. Your question about strategics, I think many have been looking forward to this data, and we were excited to release that data last week. We have -- we'll continue now with the MAD underway. That will generate additional data. And we're going to stay laser focused on execution for these while we continue dialogues with strategics.

And just that IP goes out with 2040s, I imagine.

Correct. And we've been very -- the benefit I think of our platform, our name, Structure Therapeutics, structure-based drug discovery, by being able to visualize, see the binding pocket, we're able to really cast a wide net in terms of intellectual property, patenting of molecules. This clearly was an opportunity for us in the GLP-1 space with doing a deal, somebody having to come to us to license molecules.

Our amylin strategy is very similar, so I view this as we protect the castle, our main molecules, but we also create a moat to make sure we've made these molecules because we've been exploring the space because we can visualize the binding site computationally. We want to make sure that we win in this space. And this gets to a common question I get, Terence, why do you have a second amylin going in? It's a different chemical scaffold. It's all about winning in this space.

Great. And just to remind us, you mentioned a GIP and a glucagon. What -- how long did it take you to get the amylin program like to lead into the clinic, all that kind of stuff? So as we think out for time lines for these other targets, like is this 2 years, 3 years?

Yes, I'm sort of calculating in my head sort of -- we had the big breakthrough, I would say, in this whole space, we had the big breakthrough in the class B G protein-coupled receptors. 2015, we got the structure of GLP-1 and glucagon. Those were the first two. It was 2018 that we got the three-dimensional structure using cryo-electron microscopy for the amylin receptor. And that was with different peptides that we were able to see.

We made a decision a couple years ago that we saw the importance of amylin, and our GLP-1 program was well underway. So we basically shifted all the troops to focus just on amylin for a period of time. I don't have the exact sort of answer in terms of time line, but we put a heroic effort, which we continue, on amylin, again, to make sure that we win in that space. It did come at a cost of us slowing down our GIP agonist program, but that is now -- I think, that has gotten some good steam, and we hope to, next year, have some good updates on both GIP and glucagon.

So it sounds like the troops are back on GIP.

We've been able to expand the troops. We've been able to recruit more troops. It's an army. We're at war. And so we're -- I would say we're expanding. We're not shifting.

Okay. Got it. Great. Well, thanks so much, Ray. Always a pleasure, and best of luck.

Absolutely. Thank you, Terence.

Thank you.

Good morning, and welcome to the Structure Therapeutics conference call. [Operator Instructions] Please be advised today's conference is being recorded.

I would now like to turn the call over to Jen Robinson, Head of Investor Relations for Structure Therapeutics.

Thank you, and good morning. Earlier today, we issued a press release providing data updates from ACCG-2671, our oral small molecule dual amylin and calcitonin receptor agonist, and aleniglipron ACCESS open-label extension results. A copy of the press release and the presentation accompanying today's call are available in the Investor Relations section of Structure Therapeutics' website.

I would like to remind everyone that some of the statements we will make on this call and information presented in the slide deck may include forward-looking statements, which you see here. These forward-looking statements involve a number of risks and uncertainties that could cause actual results to differ materially. Please refer to this slide as well as our SEC filings for a more detailed description of the risks and factors that may affect our results. Please also note that these forward-looking statements reflect our opinions only as of the date of this call, Tuesday, September 8, and we undertake no obligation to update such statements to reflect events that occur after such date, except as required by law.

Now I will turn the call over to Ray Stevens, the Chief Executive Officer of Structure.

Good morning, everyone. On behalf of Structure Therapeutics, thank you for joining us today to discuss the important progress we are making across our oral small molecule portfolio for chronic weight management and to make medicines more accessible to all. We have 2 significant updates to report today, both equally exciting and important to addressing the unmet needs of patients' accessibility in chronic weight management. Following my opening remarks, Dr. Blai Coll, our Chief Medical Officer, will review both clinical programs in detail. After Dr. Coll's presentation, I will make some concluding remarks about the exciting opportunities in combination treatments for quality of life improvements and then turn the call over to Q&A.

Obesity treatment has advanced significantly, but the scale of unmet need remains extraordinary. Today, fewer than 1% of the addressable global population is receiving a branded anti-obesity medication. That means the overwhelming majority of people who could benefit from treatment are still not being reached. And this is not just the United States market, we are seeing significant importance of outside the U.S. market as well. Access is a major part of the challenge. Patients also have different treatment goals, tolerability needs and journeys through long-term weight management. No single medicine will meet all of those needs.

The next phase of the market will be oral medicines, which will be more accessible globally, provide more flexible treatment approaches and support patients at different stages of their journey. The early response to oral GLP-1 medicines reinforces the level of demand for convenient oral treatment. Since oral Wegovy launched in January 2026, oral GLP-1s have grown more than 1.4 million U.S. patients and approximately 17% of the anti-obesity medication market, and that share continues to rise. Importantly, approximately 80% of total prescriptions are coming from treatment-naive patients. This suggests oral medicines are not simply shifting patients from one treatment to another. They're expanding the market and bringing new patients into treatment.

Based on our market research, oral therapies could represent approximately half of the market by 2030. For a global population measured in the billions, scalability matters. We believe oral small molecules offer the manufacturing scale, convenience and access needed to reach far more patients and support chronic treatment over time. We have the platform based on oral small molecules to offer manufacturing at the scale needed.

With that unmet need clearly laid out and as we stated we would deliver in Q3, today, we will focus on 2 very exciting programs that demonstrate the productivity and breadth of our structure-based drug discovery platform, our amylin ACCG-2671 and our GLP-1 receptor agonist, aleniglipron. Choosing which program to present first was not an easy decision, reflecting both the strength of these programs and our enthusiasm for their potential. On the left side, we'll begin with ACCG-2671, a first-in-class oral small molecule amylin receptor agonist now in a Phase I/IIa multiple ascending dose clinical trial.

This is an extraordinary molecule as we are the first to report clinical results of an oral small molecule amylin agonist. In the first-in-human single ascending dose study, we observed approximately 6-day half-life, providing the potential for convenient daily or once-weekly dosing. ACCG-2671 demonstrated a clean safety profile with no serious adverse events or liver signals and a clear dose response with the expected on-target gastrointestinal tolerability. Additionally, we observed encouraging exploratory effects on weight loss and bone health biomarkers as additional indicators of target engagement.

On the right side, aleniglipron is our oral small molecule selective GLP-1 receptor agonist, currently dosing in 2 global Phase III trials. Today, we report the results from the ACCESS open-label extension study that is now completed. We observed a potential best-in-class 16.2% body weight loss at 72 weeks, with room for potential additional weight loss with longer 52-week exposure at the 180-milligram dose as designed into the Phase III program. Importantly, this potential best-in-class efficacy was accompanied by improved tolerability with the 2.5 milligram start, very low, less than 5% adverse event-related discontinuation rate and no off-target safety signal seen in over 800 participants across multiple dose levels up to 72 weeks.

For a medicine that may be taken by millions of people around the world, safety is paramount, and we are very pleased with the very attractive safety profile of aleniglipron. We are excited to have initiated our Phase III ACCOMPLISH-1 and ACCOMPLISH-2 trials that are now underway and expected to read out in the second half of 2028. Together, these programs highlight the ability of our platform to generate differentiated oral medicines across complementary mechanisms while giving us meaningful optionality in combinations as we build our oral small molecule portfolio for chronic weight management.

With that context, let me turn the call over to Dr. Blai Coll, our Chief Medical Officer, to present details on our amylin and GLP-1 oral small molecule data.

Thank you, Ray, and good morning, everyone. I will begin with ACCG-2671, our oral small molecule amylin receptor agonist. I'm excited to share the first clinical observations from the single ascending dose study. To understand why we believe this molecule is differentiated, let me start with the receptor biology. Amylin signaling is mediated through the calcitonin receptor combined with different receptor activity modifying proteins or RAMPs, creating the amylin-1 through amylin-3 receptor subtypes.

Amylin biology extends beyond modulation of appetite alone. In the central nervous system, it influences satiety, leptin sensitivity and energy expenditure, contributing to beneficial effects on body weight regulation. It also affects the GI tract, adipose tissue and insulin and glucagon secretion. In addition, the biology of a dual amylin and calcitonin receptor agonist, or DACRA, provides potentially positive effects on bone turnover via the calcitonin receptor.

CTX-1 is a marker of osteoclast activity that promotes bone resorption and is associated with potential deleterious effects in bone mass. Inversely, bone-specific alkaline phosphatase is a marker of osteoblast activity and its increase is associated with bone production. Dual amylin and calcitonin receptor agonists have been associated with a significant decrease in CTX-1 and correlated with an increase in bone-specific alk phos. This broader biology provides several opportunities to explore target engagement, including early changes in body weight and bone resorption biomarkers that will be addressed in subsequent slides.

2671 was designed as an oral small molecule with broad activity across the human calcitonin receptor and all 3 amylin receptor subtypes, which characterizes it as a full dual amylin and calcitonin receptor agonist or DACRA. It demonstrates high binding affinity and functional activity in vitro together with robust reductions in food intake and body weight in rodents. Additionally, as you can see on the right-hand side of the slide and presented at ADA this summer, the preclinical activity established a clear dose response reduction in body weight. These were important results since they achieved significant levels of activity and supported advancement into clinical development, as described in the next slide.

We evaluated ACCG-2671 in a Phase I single ascending dose study in adult participants with BMI below 30, where 31 were randomized across the 1, 2, 5 and 10-milligram cohorts with a 3:1 allocation to active treatment and placebo. The primary objectives in this first-in-human trial were pharmacokinetics, safety and tolerability after a single oral dose with exploratory assessment of changes in body weight and bone biomarkers.

Let me reiterate here that the main objective of the single dose is to understand the PK, safety and tolerability across a wide range of doses and inform the design of the multiple ascending dose. In the single ascending dose, the follow-up extended to day 17 for the 1 through 5-milligram cohort and day 24 for the 10-milligram cohort. We were pleased to not need to evaluate the 20-milligram cohort since the emerging clinical data and PK modeling supported moving directly into the Phase IIa.

Let me now provide the characteristics of the participants included in the analysis. The single ascending dose cohorts were generally comparable. All participants receiving 2671 completed treatment in the study. Mean age ranged from approximately 34 to 44 years. Mean BMI was between 26 and 27 kilograms per square meter, indicating healthy participants not living with obesity and women represented 50% to 80% of the active dose cohort. 7 out of 8 pooled placebo participants completed the study.

Let's now review the pharmacokinetic properties of 2671. The pharmacokinetic profile of the molecule is well suited for further development. We are sharing 2 PK curves here. On the left is the linear 2671 concentration time profile following single oral dose administration across the dose range of 1 to 10 mg for the first 24 hours and illustrates the rapid absorption of 2671, with maximum concentration reaching approximately 1 to 1.5 hours. On the right-hand side of the slide is the log-2671 concentration time profile over the whole sampling time to 504 hours for the 10 mg cohort and shows the similar elimination profile of 2671 across this dose range.

Additionally, exposures were consistent with dose proportionality and remarkably, 2671 shows a terminal half-life of approximately 6 days. Taken together, we're very encouraged by those properties since the data provides flexibility to evaluate both once-daily and once-weekly dosing schedules for Phase II. Linked to the long half-life is very relevant to assess what was the impact on safety and tolerability. So let's review the data in aggregate.

There were no serious adverse events, no treatment-emergent adverse events leading to study discontinuation and no cases of drug-induced liver injury. As expected, gastrointestinal events became evident at the higher doses. At 5 milligrams, nausea and vomiting were reported in 80% and 60% of participants, respectively, and at 10 milligrams, all 6 participants reported nausea and vomiting. Both events were mild to moderate in severity and vomiting events occurred the day of the dosing for most participants and nausea persisted for a few days. This is an observation commonly seen in single-dose studies with amylin receptor agonist, where potentially highly efficacious doses are used without the advantage of a previous titration.

By design, we used a wide range of doses to achieve our objective of elucidating the upper range of tolerability and the appearance of gastrointestinal events in a dose-dependent manner and also see indications of target engagement at various doses. We achieved the objective of the single ascending dose trial that informed our ongoing Phase II study. It is important to highlight the value of the data at 1 and 2 milligrams where the absence of gastrointestinal events provide valuable information on the appropriate starting dose of titration regimens to explore in Phase II.

With the PK properties and the tolerability of 2671 described, we want to spend a few minutes reviewing exploratory markers of target engagement. We are pleased to observe an early body weight signal after a single dose of 2671. At doses from 1 to 5 milligrams, mean body weight change ranged from 0.1% to minus 1.2% and could be attributed to physiological variability. Interestingly, in the 10-milligram cohort, mean body weight decreased by 3.3% below baseline at day 24. This study was not designed as a weight loss efficacy study. It is a single dose in participants with an average BMI between 26 and 27, so we should not overinterpret the magnitude of weight changes observed. However, the timing, direction and the persistence of the change provide encouraging signs of early target engagement and provide strong rationale for evaluating weight changes over 12 weeks in the Phase IIa study.

Let's turn now to the exploratory bone biomarkers. As previously introduced, CTX-1 and bone-specific alk phos are markers used with previous DACRA to assess bone health. Interestingly, by day 2 after a single dose, mean CTX-1 had decreased by approximately 60% in every dose cohort of 2671, while the placebo group showed a slight increase. As you can see in this spaghetti plot on the right, the response was rapid and broadly consistent across all dose levels of 2671 with values moving back toward baseline at later visits after a single administration. Additionally, the participants dosed with 2671 also experienced a 10.7% increase in bone-specific alk phos at day 2. At this stage, we view both CTX-1 and alk phos as evidence of biological activity across all dose ranges and together with the observation of body weight reduction, provide further evidence of target engagement. Collectively, the single ascending dose data strongly supported the transition from the single-dose study to the multiple dose study that I will now describe.

The Phase IIa study has already begun dosing participants with obesity and has 3 objectives. First, to establish the safety, tolerability, pharmacokinetics and body weight profile across repeated oral doses starting at low dose that in the single ascending dose study showed signs of target engagement but were not associated with gastrointestinal events. Second, to optimize the dosing regimen by comparing daily and weekly schedules and by testing a slow titration across a broad dose range as has been the norm in developing medicines for obesity studies. And third, to explore bone biomarkers and explore the profile of 2671 as an add-on to current standard of care GLP-1 medicines. The findings we have shared today reinforce our excitement about ACCG-2671 and its potential to become the first-in-class oral small molecule amylin receptor agonist therapy, expanding the range of treatment options available to patients.

With that momentum, let me turn to our most advanced clinical program, aleniglipron, our oral small molecule GLP-1 receptor agonist currently in Phase III. We're equally excited to share the final 72-week results from the ACCESS open-label extension. As published in Nature Medicine in June of this year, the ACCESS study enrolled 230 participants, starting at 5 milligrams of aleniglipron and reaching a top dose of 120 mg. A placebo-adjusted 11.3% body weight reduction at the end of the 36 weeks of the double-blind treatment period was achieved. Additionally, the study also reported significant improvements in health-related outcomes beyond weight loss, such as blood pressure and hsCRP.

To inform our Phase III program and explore alternative dose and titration regimens, we were particularly interested in setting up a long-term open-label extension study of up to 72 weeks, an approach that we believe makes this dose range finding program the most comprehensive and innovative Phase IIb study to date in the small molecule field of obesity medicine. The ACCESS open-label extension enrolled 151 participants from 36 sites who completed the study and consented to continue with a high participation rate of 87% of the eligible population.

The 3 aleniglipron cohorts of the ACCESS study continued dose escalation and ultimately transitioned to 180 milligrams starting at week 60 or later. The placebo cohort of ACCESS shown in the bottom of the schematic crossed over to aleniglipron at week 36 and began at 2.5 milligrams instead of the 5-milligram starting dose of the ACCESS study, followed by titrations every 4 weeks up to the highest dose of 180 mg.

Let's now review the baseline characteristics of this OLE cohort. The participants in the ACCESS trial in the 45, 90 and 120 mg arms included 28, 42 and 43 participants, respectively, and the 2.5 of aleniglipron crossover included 38, and this group enrolled the lowest number of female participants, 47%. Mean baseline BMI ranged from 33.9 to 39 kilograms per square meter with the crossover group starting at the highest mean BMI and body weight.

Let's now review the results on the primary efficacy endpoint of the study. As you can see in the plot, there is continued body weight reduction through 72 weeks. At the 72-week point, when all cohorts had been transitioned to 180 for some time, model-estimated mean body weight reduction was 11.6% in the 45-milligram arm, 14.4% in the 90-milligram arm and 16.2% or 40.5 pounds in the 120-milligram arm that later transitioned to 180 milligrams. The 2 highest dose cohorts showed the greatest weight reduction and encouragingly with no evidence of plateau at week 72. I want to highlight that the protocol was amended to escalate the dose of aleniglipron to 180 to inform our Phase III program so that the participants started to transition to 180 from week 60 onwards.

We're also pleased to see the substantial body weight reduction observed in the placebo crossover cohort achieving a 9% or 22.7 pounds after crossing over to aleniglipron for the period of 36 weeks, also observing a lack of plateauing and providing consistency and validation to the previously reported body weight reductions. Compared to the arms starting at 5 milligrams in the ACCESS study, the participants starting at 2.5 with a slow titration reached numerically comparable body weight reduction figures at equivalent doses, but at later time points, while the tolerability was optimized as we will review in subsequent slides.

This is an important slide, so let me summarize 2 key points before advancing. One, the purpose of a Phase II study like our ACCESS program, including the open-label extension, is to have a full characterization of the dose range, and we are very pleased to have explored 2.5 milligrams all the way to 180 mg that informed the design of the Phase III. Number two, achieving a 16.2% weight loss at week 72 positions aleniglipron as potentially the most efficacious small molecule GLP-1 receptor agonist, a level of efficacy that could be further improved with the current design of the Phase III with longer duration at maintenance doses.

I want to draw your attention now to the next slide, where we show the median time of exposure at maximum doses for the different arms. In the left, we summarized the median time at 120 and 180 for each arm in the study. On the right, you can see the body weight reduction achieved at week 72, where the data indicates the longer the time of exposure at the higher doses, the greater the body weight reduction. Also, I want to note the relatively short period of time that each cohort received the highest dose of 180 in the open-label extension study, a median of only around 8 weeks in each cohort.

In our ongoing Phase III study, we set the maintenance dose period to be at least 52 weeks. So we expect more participants to have substantially more time at the highest dose of 180 than participants in our ACCESS open-label extension study. This design feature encourages us to believe that our ongoing Phase III study has a strong potential to further reinforce the already best-in-class efficacy profile of aleniglipron. Mean weight reduction describes the overall trajectory, but it's also clinically relevant to look at the responder analysis on the next slide.

We are very encouraged by the responder analysis results. In the Y-axis, we represent the percentage of participants achieving the different thresholds of body weight reduction shown in the X-axis and color coded by the different groups of participants. In the ACCESS study 120-milligram cohort that transitioned to 180, 76.7% achieved at least 10% weight reduction, 59.6% achieved at least 15% and 36.3% achieved at least a 20% body weight reduction at week 72. Those results are highly impactful clinically and demonstrate the depth of response across the cohorts.

Additionally, I want to share with you other important aspects of the exploratory efficacy analysis of aleniglipron beyond body weight reduction. On this slide, you can see the change from baseline in key cardiometabolic risk factors with clinically highly relevant reductions in systolic blood pressure ranging from 6 to 12 millimeters of mercury and diastolic ranging from 2 to 6. Additionally, participants on aleniglipron also experienced a clinically meaningful reduction in waist circumference and up to 64% reduction in highly sensitive C-reactive protein. As reported in the body weight reduction slides, higher exposures to aleniglipron were associated with higher reductions in those cardiometabolic risk factors that can potentially be translated to improvement in health-related outcomes for the ongoing Phase III program.

Having established both durability and depth of efficacy, I will now turn to the participant journey through the heat map plots as we reported back in March and published in Nature Medicine this summer. This participant level view focuses on the original 120 mg cohort, and we view this as a better characterization of the participant journey and a closer look to the real-world use of the medicine compared to just the aggregate incidence tables. Each row represents one participant and the orange markers indicate vomiting events.

The different color-coded cells from left to right indicate the different titration steps starting at 5 mg and titrating every 4 weeks to reach 120 milligrams and the dashed green line indicates the open-label extension period of the study, where ultimately participants were receiving 180 mg represented by the darker cells. There are a few observations I want to draw your attention to. Overall, in the study, we observed an 88% of participants completing 72 weeks on treatment.

Vomiting was episodic and relatively sparse during the study without an increased incidence during longer exposure at higher doses. Interestingly, some participants had interruptions in dosing represented by the gray cells without a clear rebound in vomiting when aleniglipron was reintroduced. Third, the majority of participants were able to progress through titration and remain on treatment through the end of the study.

And lastly, I want to bring your attention now to the far right end of the slide, where the dark cells indicate 180-milligram doses of aleniglipron. We did not observe an increase in vomiting events. In other words, the majority of participants were able to continue dosing at 180 and complete the open-label extension study at target dose. And as indicated in the efficacy slide, the duration at 180 was relatively limited, which should be taken into account in interpreting the results.

To determine whether this pattern was consistent across different dose and titration strategies, let's turn now to the participant journey of those starting at 2.5 at week 36 instead of 5. The gray section on the left represents the first 36 weeks on placebo, followed by the open-label extension titration starting at 2.5 and titrating up to 180 on the right. As you can see, the occurrence of vomiting events, again, in the orange dots, is less frequent with a lower 2.5 starting dose titration regimen, and there is no association with the achievement of higher doses of aleniglipron.

As described in the previous slide, we also observed drug interruptions, interestingly also occurring during the administration of placebo. And when on drug indicated on the right of the slide, there was no accumulation of vomiting events. And lastly, as designed, we had a limited time of exposure at 180 described in the efficacy slide, but importantly, and a key message from this slide, continuous efficacy from 180 came without an increase in the incidence of vomiting events. Taking these 2 panels together, these data support the chronic tolerability of aleniglipron and reinforce the value of starting at a lower dose and allowing adequate time to reach target top doses.

We want to provide now the summary of the aggregate open-label extension safety data that, as you will see, is consistent with the participant level view. Treatment-emergent adverse events leading to permanent drug discontinuation were below 5% in every original randomized arm. Interestingly, the lowest rate of treatment discontinuation was observed in the 2.5-milligram crossover group at just 2.6%, which followed a lower starting dose and slower titration steps. Gastrointestinal events remain the most common adverse events. Nausea ranged from 16.3% to 26.2% across the original active arms and was 50% in the crossover cohort. Vomiting ranged from 14.3% to 21.4% with 18.4% in the 2.5-milligram aleniglipron crossover cohort.

This tolerability pattern deserves a closer look, and we want to share with you in the next slide some of the insights that largely inform the design for the ongoing Phase III. This comparison illustrates the clinical impact of the revised start low and go slow titration strategy. In the ACCESS study, the 120 mg cohort during weeks 0 through 36, shown by the light blue bars, participants started at 5 milligrams and titrated to 120 within 20 weeks. Nausea occurred in 65.1%, vomiting in 31.7% and treatment-emergent adverse events led to discontinuation in 11.1% of participants. In contrast, in the 2.5-milligram crossover cohort of the ACCESS OLE study shown by the dark blue bars, participants started at 2.5 and titrated gradually for at least 32 weeks.

You can see the substantial reduction in all 3 tolerability parameters with 15 percentage point reductions in nausea, almost half the vomiting events and the lowest AE-related treatment discontinuation rates at only 2.6%. We acknowledge that this is a contextual comparison across different cohorts and study periods, not a randomized head-to-head test. However, the direction and magnitude of the differences support the start low and go slow approach incorporated into Phase III. Having addressed on-target gastrointestinal tolerability, I will next turn to an important off-target consideration, liver safety.

The longer-term 72-week liver safety profile also remained highly favorable. Across 151 open-label extension participants, there were no cases of drug-induced liver injury, no cases of Hy's law and no ALT or AST elevations at or above 10x the upper limit of normal. 6 participants had ALT elevations of at least 3x the upper limit of normal and 2 of them reached at least 5x. One participant had AST of at least 3x the upper limit. Importantly, all aminotransferase elevations resolved without treatment discontinuation. Taking all this together with the durability, best-in-class efficacy and titration learnings, this safety profile provides the foundation for the ACCOMPLISH Phase III program.

We are very pleased to share the design details and current status of the ACCOMPLISH Phase III program, where both trials have already begun dosing participants. ACCOMPLISH-1 will enroll approximately 3,600 participants with obesity or overweight and a weight-related comorbidity. ACCOMPLISH-2 will enroll approximately 1,100 adults with obesity or overweight and type 2 diabetes. The program evaluates 45, 90 and 180-milligram maintenance doses beginning at 2.5 with 4-week titration steps. Participants will receive treatment for 76 weeks with at least 52 weeks at the maintenance dose.

The current open-label extension data with a short exposure at the highest doses and achieving a 16.2% body weight reduction gives us confidence for the prospects of the Phase III, where the periods at the maintenance doses are targeted to be at least 52 weeks. The primary objective of the program is percent change in body weight versus placebo, supported by responder thresholds and secondary endpoints among many others. We are very excited about the ACCOMPLISH program and wanted to share some additional insights with you all.

We have conducted the most comprehensive Phase II development program in obesity medicine with different patient populations, titration schemes, different doses and importantly, having the longest time of exposure up to 72 weeks from the open-label extension study with the best results among the oral small molecules reported to date. Additionally, we have dosed more than 800 participants with aleniglipron to date, and we are very pleased with the continued safety profile of the drug.

Based on those learnings, we have designed the Phase III studies agreed with regulatory agencies and are now focusing on flawless execution to prioritize a recruit to retain approach with unique retention strategies based on the Phase II and executing on balancing speed with appropriate guardrails to maintain high quality and data integrity. With all those parameters in place, we want to extend a note of appreciation to all the clinical trial sites, collaborators and especially to the hundreds of participants that have already put their trust in the program. We, at Structure, look forward to continuing the partnership to provide the highest quality data at the end of the registrational Phase III.

With that, let me turn it over to Ray for his concluding remarks.

Thank you, Blai. The progress we have shared today represents more than 2 individual program updates. It provides a view into the future we at Structure Therapeutics are building in chronic weight management. Our oral small molecule, ACCG-2671, has demonstrated a very encouraging early clinical profile, while aleniglipron is getting closer to the market and for patients who are waiting. Our strategy is to translate deep structural and GPCR metabolic science into oral small molecule medicines that can be scaled broadly, made accessible to more patients and provide greater treatment choice. That is the ambition behind our portfolio and the pipeline on the next slide shows how we are and will continue to deliver.

Our wholly-owned portfolio is organized around 2 complementary oral small molecule backbones, supported by a growing set of combination programs. Together, they give us multiple opportunities to address the scale and diversity of the chronic weight management market. Aleniglipron is our GLP-1 backbone and most advanced asset. The ACCOMPLISH Phase III program will evaluate participants receiving the 180-milligram dose for 52 weeks of maintenance compared with only 8 weeks at the dose in ACCESS II. Our second backbone is our amylin agonist portfolio. Our first-in-class ACCG-2671 is now in a Phase I/IIa MAD clinical trial.

We have a next-generation amylin oral small molecule, ACCG-3535, with a different chemical structure that could offer a differentiated TPP that will enter the clinic later this year. We also continue to make significant progress in our SARA amylin drug discovery program. Beyond these 2 oral small molecule backbones, our combination programs bring together other mechanisms with our GIP and glucagon receptor oral small molecules with our backbone oral GLP-1 and amylin receptor agonist. These combinations allow us to create differentiated treatment profiles for an even broader range of patient needs.

And this road map shows how we are accomplishing this very important goal. We have a catalyst-rich plan across all our portfolio, supported by approximately $1.3 billion in cash as of June 30, 2026. We expect this capital to fund projected operations and key clinical milestones through the end of 2028, including costs related to the ongoing aleniglipron registrational Phase III ACCOMPLISH clinical trials, the associated aleniglipron clinical trials and the ongoing ACCG-2671 multiple ascending dose clinical trial.

Our next wave of catalysts begins in the fourth quarter of this year with 3 important aleniglipron data readouts expected, body composition, type 2 diabetes and SWITCH. The body composition clinical trial will help us better understand the quality of weight loss by assessing the effects of aleniglipron on body fat over 44 weeks, starting with 2.5 milligram and going up to 180 milligram. These data will complement our overall weight loss findings and provide a more complete picture of aleniglipron's clinical profile. The clinical trial in people living with type 2 diabetes and obesity or overweight will further characterize aleniglipron in this important patient population. The findings will provide additional context for ACCOMPLISH-2 and inform our broader development strategy in type 2 diabetes.

The SWITCH clinical trial addresses a different and highly relevant patient journey, transitioning from an approved injectable GLP-1 therapy to a once-daily oral aleniglipron for long-term weight loss maintenance, a very important area of high unmet need given the high discontinuation rates observed with those on injectable GLP-1s. This study could help us understand the potential role of aleniglipron for patients seeking a convenient oral daily option after beginning treatment with an injectable GLP-1. Beyond aleniglipron, we're rapidly advancing our amylin portfolio. We expect to report 12-week multiple ascending dose top line data for ACCG-2671 in the first half of 2027, representing an important clinical readout for the program.

These results should provide our first assessment of repeat dosing, daily and weekly regimens, titration strategies, tolerability and body weight effects over 12 weeks with a first-in-class oral small molecule targeting the amylin mechanism. The study should also generate early clinical read-through for combining an amylin with a GLP-1. We also anticipate initiating the Phase I single ascending dose study of our second oral amylin, ACCG-3535, later this year, followed by multiple ascending dosing in 2027.

Finally, we look forward to initiating our first amylin and GLP-1 combination study at the end of 2026 with initial top line data anticipated in 2027. This program represents an important step towards our goal of building beyond monotherapy and offering fixed-dose combination treatment approaches for different patient needs. Together, these milestones provide multiple opportunities to create value across our portfolio while we continue advancing aleniglipron towards Phase III top line data in 2028 and potential NDA submission thereafter.

Let me close with our mission, making medicines more accessible to all. Chronic weight management is not a one-size-fits-all and patients' needs can evolve over time. We believe the future requires multiple convenient oral medicines across complementary pathways, giving patients and providers greater flexibility to match the right treatment at each stage of the patient journey. This is what our focused pipeline is designed to deliver greater choice, broader access and meaningful long-term impact for patients. That is the future Structure is working to build and help lead. Thank you for joining us today. We look forward to discussing these exciting results with all of you further.

I'll now turn the call back over to the operator for Q&A.

[Operator Instructions]

First question comes from David Risinger with Leerink Partners.

Congrats, Ray and team, and thank you for all of the detailed commentary this morning. So regarding the multiple ascending dose trial that will be reading out in the first half of next year, could you provide a little bit more color on how you're evaluating different doses and different titration schedules and also comment on the planned additional assessments of calcitonin agonism. And then separately, Ray, if you could maybe step back and comment on the bigger picture considerations for health outcomes associated with both weight loss and risk marker reductions in light of the recent failures of the Lp(a) and IL-6 candidates?

I'll let Blai take the first half of that question, Dave, and then I will tackle the second part of your question.

Yes. Thanks, Dave. Very excited about the ongoing multiple ascending dose Phase IIa for 2671. As we've described in the call, we have different cohorts supported by the results in the single ascending dose. So we want to explore the possibility of once weekly dosing in addition to the once daily in the particularity of the program that we want to further explore. We'll fully characterize with different doses and different titration schemes, both the safety and tolerability along with the efficacy. Just as a reminder, we'll have the possibility to enroll participants living with obesity and expose the duration to 2671 up to 12 weeks. So we'll have a very strong readout there. More details as we move along in the program, but that's what we feel comfortable sharing with all of you today. Back to Ray.

And Dave, in regards to your question about Lp(a), the recent data, I think there's still ongoing studies, so we're still going to continue to learn. But I think what we're seeing is with GLP-1 medicines, you get both weight loss and potential anti-inflammatory effects. And we think that, that's a good combination of having both of those mechanisms together. And so that's why we believe GLP-1 and amylin as well is a really good mechanism for improving cardiovascular health.

Our next question comes from Evan Seigerman with BMO Capital Markets.

Congrats on both the data updates. I want to touch on your thinking about combination therapy. Clearly, the PK profile of aleniglipron and the amylin asset that you presented today are different. How do you combine the 2 of them to kind of get the best out of both targets, GLP-1 and amylin just given the differences in profiles, how do you tinker so you can maximize the efficacy, improve the tolerability and come up with a real kind of blockbuster product potentially?

Thanks, Evan. I'll take the question. We're very excited about the potential combination. We're on track to start combination of GLP-1 plus the amylin receptor agonist towards the end of the year. And thanks for raising that question on the combination based on the data that you've seen today, one common question is how are we combining a molecule with PK properties that are substantially different. And it's not unreasonable to think that, that PK property with a long half-life can be used in our advantage as part of a natural titration with that slow elimination phase that will bring that molecule to achieve a steady state later than the GLP-1 receptor agonist, which, again, for tolerability purposes that can be used in the advantage of that combination.

From an efficacy perspective, I think both mechanisms of action can be synergistic. And so we're really, really excited about the prospects of that program.

And Evan, one additional point that I want to make is on Slide 16, when we talk about our 12-week MAD study, we do have a study on there, which is focused on the effects, the add-on effects of individuals that are on an injectable GLP-1 adding on our oral amylin. We want to study what is the right way to combine these 2, and we can learn a lot from the injectables by combining our oral amylin while we pursue our fixed-dose combination studies.

Our next question comes from Seamus Fernandez with Guggenheim Securities.

Great. So Ray, just hoping or Blai, you could comment on the opportunity to really deliver the highest performance results at 52 weeks. I think you noted that being able to push to the 180-milligram dose is key. I think one question we're getting is if there are ways to optimize the dose titration to shorten it to some degree while also maintaining that starting dose of 2.5 milligrams. And then the second question really is, if I have one takeaway from your amylin data, it's that Structure has a unique ability to turn what peptides are capable of into either daily or perhaps even a weekly oral small molecule. It seems like your DACRA performs as well as any other DACRA in the space just from the preliminary data.

And also looking at the SAD, those look extremely comparable. So having the data confirming the weight loss, really confirming a DACRA profile with your biomarker data, how are you thinking about the opportunity to potentially create a SARA that may not have quite the same bone benefit, but perhaps may have a better tolerability profile as we've seen with other programs? And then maybe just a last comment on your IP portfolio on the amylin side. It seems like other players are starting to have some issues working their way around your very robust amylin IP portfolio.

Seamus, I'll start with your first question, and thanks for raising this. Yes, we are planning to start at 2.5 for the ACCOMPLISH program. We're very pleased with the efficacy that we've seen in the open-label extension, but you've also noted that the titration scheme in the Phase III is up to 24 weeks. And we feel that maintaining those 4-week titration steps starting at 2.5 and not increasing the dose in each one of the titration steps greater than 2.5 fold increasing dose, it's the right sweet spot for the Phase III. And so that's the question -- the answer to your question.

We're very, very pleased with the results in terms of the efficacy, and the prospect of maintaining that duration for 52 weeks in the Phase III already positions the program in a very highly competitive efficacy level. So that's on aleniglipron.

Yes. And on your -- so first of all, Seamus, thank you very much for your kind words about the team. I want to acknowledge our discovery team and clinical team. They've done a phenomenal job at both discovering the molecules that we've had to date and the execution, I think it's [indiscernible] execution by the clinical team. In regards to SARA, we're excited about mechanisms. At the recent American Diabetes Association meeting, there was a session on amylin, and there was a highlight about the potential importance of DACRA, in particular calcitonin for bone health. A lot of us talk a lot about weight loss and selective muscle versus fat, but we also think bone health is important.

So this is purely exploratory at this stage, but we think that that's an interesting opportunity. But we do continue to work on a small molecule selective SARA amylin molecule, and we'll be updating on that further. And then in terms of IP -- sorry, the IP question, yes, we've invested very heavily on making a lot of molecules dating back to the GLP-1 and that's really sort of panned out for us. We're really pleased with our IP position. In the amylin space because we're first-in-class, because of our structure-based drug discovery platform, being able to literally see the binding site in the pockets, we've also invested very deeply into making a lot of molecules into these binding pockets. And so we have, I think, an even more stronger IP position around the amylin.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Congrats on all the updates and the first data for your oral amylin program. Would love if you could put into context, yes, it's early data and very encouraging sort of how the product profile already looks versus other amylin programs in development? What differentiation do you see at this point? And then second question is what lessons have you learned from the titration optimization process with aleniglipron that you can actually implement to your oral amylin receptor agonist program, 2671, as you're embarking into your 12-week study?

I'll start with the answer to that question, yes. Thank you for it. And then Blai, please fill in any other details. But I think the biggest differentiator, we're talking about an oral small molecule. And the biggest advantages there is that what we hear, we've seen this tremendous growth in the uptake of oral medicines in the space. So I think oral -- an oral pill is a key differentiator in the amylin space. Second, small molecule manufacturing. Again, we've highlighted previously with GLP-1, and it's very much the case with our amylin. We're able to manufacture these medicines at a global scale that is needed. Blai, any additional points?

Yes. Very pleased, yes, with the results of the Phase I. This was the first time to our knowledge in the small molecule targeting the amylin receptor agonist. And being able to demonstrate no off-target effects, a PK profile that is really, really relevant in terms of the small molecule and that long half-life and then seeing those 3 parameters of target engagement already on a Phase I is highly encouraging, and that's part of the reason of the excitement that Structure on the ongoing Phase II.

In terms of -- you were also asking about this titration optimization, what we've learned from the GLP-1. What we know so far from GLP-1 versus amylin is that, that biology in terms of the tolerability to build that and the receptor desensitization. It's pretty comparable and pretty similar. And we're planning to do the same steps that we've done in the GLP-1. So starting at a low dose that we've already identified with 1 or 2 milligrams of 2671 and start the titration from there.

One additional point, as somebody else asked a previous question on this. We think that the shape of the curve, the weight loss curve is really important. We've always believed that a linear -- what we hear from physicians is what they care the most about is more of a linear. They don't care about this because the really rapid weight loss. So it's sustainable that they see something in the early days and that they continue seeing weight loss over time. That's what the physicians and the patients are really looking for. And so all of our learnings, the shape of the aleniglipron curves and how we'll apply that to the amylin program, I think, gives us further confidence in how the amylin program will progress.

Our next question comes from Prakhar Agrawal with Cantor Fitzgerald.

Congrats from my side as well on these very strong data sets. So maybe a couple of questions on oral amylin. If you can elaborate on the biomarker data that you showed in terms of the bone markers, why is this relevant for 2671? And how would it compare versus some of the other amylin drugs so that we get more confidence that the drug is active. Secondly, on the MAD trial, based on some of the data from Lilly's eloralintide that also has a long half-life, seems like you can titrate up amylin faster and the drug accumulation could have positive effects on efficacy for amylin without offsetting tolerability issues.

So how are you thinking about the titration schedule for oral amylin once you have the starting dose figured out? And last question on aleniglipron. I think you alluded to in the beginning as well during your prepared remarks. But what retention strategies could you deploy for Phase III to ensure that patients are in the trial or throughout?

Yes. Prakhar, thanks for your questions. We'll start with the amylin and the bone biomarkers. These have been already reported in some programs of dual amylin calcitonin receptor agonist, amylin type, amylin calcitonin, also showing in Phase I and also in patients with osteoarthritis a significant reduction in CTX-1 and an increase in [indiscernible] intent on showing those initial signs of target engagement. This is something that can potentially be highly relevant if it translates into an increase in bone mineral density and an improvement overall in bone health as we all know, especially for certain pockets of participants in patient population, this is a large unmet medical need for this patient population.

In terms of the MAD trial and how to titrate, it's still very early. We're in early days of the small molecule on amylin receptor agonist. We need to understand very well the biology. We're following the same steps as we were alluding to in the previous question in terms of we do not rush the titration. We have 12 weeks in the multiple ascending dose Phase IIa ongoing and we want to take full advantage of that. If we have an opportunity to titrate faster, we'll identify that in the multiple ascending dose that can be incorporated in the label development.

And then the last question on aleni, and thanks for raising these retention strategies for aleniglipron Phase III is we spend a lot of time internally and with our external collaborators in defining what's the best strategy for ACCOMPLISH-1 and ACCOMPLISH-2, and we feel very confident about the strategy that we put in place. Of course, we can not get into the details that we've learned a lot about the -- how to retain those participants based on the extensive Phase II dose range finding study that we just presented today. We also learned a lot from other programs, and we want to make sure that retention is the #1 priority, and that's how we [indiscernible] the program.

Our next question comes from Terence Flynn with Morgan Stanley.

Congrats on the data. I guess 2 for me on 2671. The first on the Phase II MAD study, I just wanted to clarify, it sounded like during your prepared remarks, you mentioned there might be an add-on cohort that's part of that Phase II. But then during the Q&A, it sounded like maybe it was a separate portion. So I just wanted to clarify if there will be patients on GLP-1 injectables that are part of the MAD prospectively or if that's like a later amendment.

And then the second question is, it looks like you've completed some of the food effect studies already. So just anything notable there? And then maybe provide an update on where you are in terms of drug-drug interaction studies and anything to note or think about for 2671?

Thanks, Terence. I'll take one by one. So on the add-on cohort, let me clarify, this is one of the cohort that will be explored as part of the ongoing Phase IIa study, the multiple ascending dose that is ongoing. Additionally, we're on track to start a different study combining our own GLP-1 with 2671 before the end of the year. So that hopefully will clarify. We have completed the food effect study in one of the cohorts in the single ascending dose. That was not the scope for today's presentation. The data is being [indiscernible], but what we can share today is that we are not requiring any kind of food restriction for the ongoing Phase IIa study. And then the DDI plans for 2671 are also ongoing, and we'll provide further details as the program [indiscernible].

Our next question comes from Roger Song with Jefferies.

Congrats for the data. Maybe one on amylin and one on aleni. For amylin, actually, the weight loss exceeded our expectation, seeing a very meaningful weight loss -- competitive weight loss here. So can you give us some context here? How is this weight loss in the context of some GI side effects and then in the BMI lower than 30? And then how consistent this weight loss across patients, particular for the 10-milligram cohort? And how should we think about the kinetics from 17 to 24 days? That's on the amylin.

And then on the aleni, thanks for sharing the patient journey chart again, so which give us a lot of the context for the tolerability. And then for the placebo crossover, just thinking about the read-through to the Phase III, since the titration for the placebo crossover is flexible, maybe help the GI rates. Just curious about the Phase III, how flexible the titration understanding you say titrating up to 24 weeks. And then on the weight loss part, how confident you will get to 15-plus percent just like the OLE 72 weeks to 16%?

Thanks, Roger, for your questions. We'll start with 2671 and the context of that observation and body weight loss for the 10 milligrams. As you well pointed out, that was observed at 3.3% observed at day 24. And the relationship with the gastrointestinal events, it's the right question to ask, and thanks for raising this. The nausea persisted over a few days after dosing. But importantly, the event of vomiting happened, all of them at the day of dosing on day 1 and one participant had another event on day 2. But we didn't see in that cohort any other event of vomiting beyond that point. And so again, we don't want to over-interpret that 3.3% but it's another sign of target engagement when you put together the 3 pieces, the gastrointestinal induction study at 5 milligrams, [indiscernible] body weight reduction and then the dynamic changes in the bone biomarkers are all pointing out in the direction of finding efficacious doses of 2671 very early on. So that's on 2671.

Additionally, I think it's even more impressive to see that kind of body weight reduction, taking into account the baseline characteristics of those participants and knowing that their BMI versus 26, 27. We all know that the higher the BMI on baseline, the higher the likelihood of seeing a magnitude of response that is greater. And so we look at this as a sign that is very, very encouraging. On the aleniglipron Phase III and the titration, we're planning to do a titration as you've seen, starting at 2.5 every 4 weeks and not escalating the dose more than 2.5-fold increase, we'll have some flexibility. So if there's any need from a participant perspective to down titrate, we'll allow that in the protocol.

The important point here is to make sure that the majority of participants can remain in the study. And one of the examples, for instance, from the open-label extension is that when you allow that flexible titration, you're able to complete those 72 weeks with 88% of participants on treatment receiving aleniglipron. And that's what is most important, and we're planning to execute the Phase III program [indiscernible].

And then I think you're asking a very good question about the confidence that we have for the weight loss in Phase III with the current titration and knowing the results of the open-label extension achieving a 16% just with a median time at 180 of 7 to 8 weeks, the results are highly encouraging to be continuing the lead in that small molecule field. So we're very, very confident about the prospects of [indiscernible].

Our next question comes from Jon Wolleben with Citizens.

For aleniglipron, I'm wondering for Phase III expectations, do you think there is a rate of nausea, diarrhea, vomiting that represents kind of a no-fly zone or with efficacy you've shown and what we see in the real-world use today, is there an expectation that patients will just find a tolerable dose? And then on the amylin programs, can you remind us of the differences between 2671 and 3535? And would you move both forward with differentiated profiles? Or is the goal to pick out the best of class there after the MAD data?

Thanks, Jon. I'll take the aleniglipron. We spent a lot of time during the Phase II program to optimize the tolerability. We think that the tolerability needs to be [indiscernible] at the end of the day, we need to continue improving the participant experience, make sure that the level of compliance is as high as possible so they can benefit of the efficacy of the drug. And after all these time, the learnings are very, very clear. We feel confident that have found the sweet spot in terms of optimizing that tolerability while we can maximize the level of efficacy. And with that titration step, higher rate of continuation on drugs and ensuring that we will have enough time at the maintenance dose that positions the program in a very good place. [indiscernible].

Yes. And I'll take the -- Jon, I'll take the question on amylin. So we're -- first, we're really excited about 2671. It's quite a unique molecule. And so we'll continue pushing that [indiscernible] ahead. In terms of 3535, first, it's good practice to have additional molecules in the pipeline. We're in this to win. And so we're going to put multiple molecules in the clinic. If you think about with the GLP-1, you have the aleniglipron versus the orforglipron scaffolds that have been used. And so that's our philosophy.

We continue to work on additional generation in part as we continue exploring and building our intellectual property case. And that also relays into we'll continue pursuing both DACRAs and SARA small molecules. We think that there are very important questions to be asking. So there's nothing in particular other than different chemical scaffolds between those 2 and the need to continue exploring this space aggressively.

Our next question comes from Patrick Dolezal with LifeSci Capital.

For 2671, could you give us some color on how the PK exposures achieved in the SAD portion map to some of the preclinical obese nonhuman primate data in which you saw the sort of nice deep reductions in weight over time. Obviously, I know it's a SAD data, but is there an indication that you're getting the exposures that you were targeting based on the preclinical experience?

And then the second question is, are there any internal benchmarks for success that you'd be able to share for amylin on the MAD portion? Just curious how you're thinking about TPP and what a win looks like for the program as we think about data next year and especially given this is a relatively unique asset you're pioneering and you already have aleniglipron in the pipeline?

Thanks, Patrick. I'll take the first question on 2671 and the PK that we were expecting. We were not surprised to see the level of exposure that we've seen. Also not surprised to see the dose proportionality. We were not expecting a long half-life, and that was one of the reasons why we needed to extend the single ascending dose and the PK collection. But overall, very pleased with what we reported in nonhuman primates and what we've reported today. Bottom line as well, I think it's important to reflect on what we're seeing at 5 and 10 milligrams is clear signs of target engagement that gives us all these information that we needed to design the multiple ascending dose.

I'll start with the TPP and the expectations for the multiple ascending dose and let Ray continue elaborating. We're in the initial steps of this program. We want to understand the safety and the tolerability and also the level of efficacy that we can achieve at 12 weeks. Having those preliminary results of single ascending dose is highly encouraging to have an amylin receptor agonist with small molecule that can potentially modulate the activity of the receptor and bring good body weight reduction with a clean safety and also offers the possibility to explore bone potential biomarkers and also different [indiscernible].

Nothing to add. I think a great [indiscernible].

Our next question comes from Andy Hsieh with William Blair.

So I'm just curious if you could contextualize the CT-1 bone health data for us. Just looking at REDEFINE-2, it seems like [ CagriSema achieved ] the patients experienced increases from week 8 all the way through week 20. Here, you see a pretty dramatic drop in day 2, but largely normalized by day 8. So how would you kind of interpret these results?

Thanks, Andy. We're very pleased with the results on the bone biomarkers. So one thing, think about this as a single-dose administration. And in order to interpret the rebound back to baseline, you also need to take into account the half-life of the biomarker itself. And so it's not always easy to compare those 2 dynamics at the same time. But directionally, we're moving in the right direction because we're seeing a dramatic decrease in the CTX-1 and the expected increase in the specific output, which is something that biologically is plausible based on the previous results. In terms of the magnitude of the effects, we're seeing similar reductions with [indiscernible] that have reported results and also, as we mentioned before, in [indiscernible] individuals. So that's also consistent with previously published data.

And Andy, please keep in mind, this is purely exploratory. We think this is a very important area. It's a very big unmet need. But at this stage, it's exploratory and what we believe we're pursuing as we enter into the multiple ascending dose phase.

Our next question comes from Samantha Semenkow with Citi.

This is Ben on for Sam. If I may, what does the 3.3% mean weight reduction after a single dose of 2671 imply about the weight loss potential you're hoping to demonstrate in the 12-week MAD study?

Thanks, Ben, for the question. As we've said, we looked at these body weight changes as a sign of target engagement, along with the other 2 data points that we provided during the call, the gastrointestinal induction starting at 5 milligrams and then the impact on the bone biomarkers. And so we wouldn't take that in isolation or as a proxy on what to expect in the multiple ascending dose. Bottom line is that we have identified signs of target engagement among those, the 3.3% body weight reduction that gives us dose that we then have the possibility to explore in the right patient population because we're enrolling participants with obesity up to 12 weeks, we will have then a more appropriate platform to assess the level of efficacy. Hope that helps.

Our next question comes from Annabel Samimy with Stifel.

I have a couple on aleni. So I'm just hoping you might be able to comment on how you arrived at the maintenance dose levels for the Phase III trial and ACCESS all the cohorts kept on titrating up to 180 to keep weight loss going. And I guess they were on it for only 8 weeks. And in the Phase III, you have 2 cohorts that don't go beyond 45 and 90 milligrams. So what was the thought there? And what is the longest time patients have been on 180? And then the last point in ACCOMPLISH noticed that the titration through 120 to 180 arm was skipped. So just around -- a little bit more color around that would be great.

Thanks, Amanda. So the thought behind the ACCOMPLISH-1 and 2 is to have a dose of -- a range of doses that go from the low 45 milligrams that is low efficacious dose to 90 milligrams and 180 to maximize that level of efficacy. The open-label extension as you've seen, we had a median of 7 to 8 weeks in the top 2 arms in the study. And the maximum that you could get exposure in the open-label extension was 12 weeks because the protocol was amended starting at week 60. And so that was the maximum exposure that it's relatively limited.

But despite that, you can see also the [indiscernible] starting at week 60 and not indicating any [indiscernible] after that. Thanks for raising the question about the 120, 180 in the interest of time, provided a lot of granularity on the transition from 90 to 180 versus 120 to 180. But the data that we have in hand is supportive of that transition from 90 to 180 without a worsening in tolerability. So that's the reason why we're providing the design of the study in the comp [indiscernible] on that move from 90 to 180.

And Annabel, one of the things that we've been hearing from the KOLs for many years is what's most important is at the beginning, you want to start low and dose slow. And then in the later stages, you can have different jumps. So we [indiscernible] see carefully evaluated. We jumped from 90 to 180 versus 90 to 120 to 180, and we think this is the right approach for the Phase III with that data in hand.

Our next question comes from Alexandria Hammond with Wolfe Research.

Cameron DeGuzman on for Alex Hammond from Wolfe Research. Perhaps another one on bone markers. The 60% CTX-1 suppression from a single dose was quite striking. It's being framed positively as target engagement, but with a 6-day half-life and just thinking about drug accumulation at a steady state, should we expect the chronic profile to be meaningfully higher in the MAD trial? How are you thinking about longer-term bone health monitoring there? And is there a point, I guess, in which chronic suppression of bone resorption at a steady state could become a concern?

Yes. Thanks for the question. And of course, we're spending a lot of time on there because it's an important consideration. We don't have any evidence from previous studies or any biology indicating that elimination of the resorption in adult population can bring some serious consequences in terms of bone health. But of course, this is something that we'll need to continue evaluating. We'll have the opportunity in the 12-week study and further on to complement not only on bone biomarkers, but also in bone imaging, and that's the intent of this program.

Our next question comes from Ananda Ghosh with H.C. Wainwright.

Congrats on the data. A follow-up question from the earlier CTX-1 related. The CTX-1 has been linked with low calcium level in rats. Did you measure calcium levels? Or is there a way you have incorporated these biomarkers on the MAD data as well as to kind of answer the questions on the bone health? And the second question is looking at the tolerability profile at 10 mg or 5 mg, how do you interpret the therapeutic index or the therapeutic window for the amylin drug?

Yes. Thank you. Good question on the calcium. We have not observed any clinically impactful fluctuations in serum calcium in the single ascending dose at any of the doses and that also included a full panel of PTH and also vitamin D. And so no changes in there have been observed to date. DEXA is, of course, a good tool to assess that bone health. The only limitation of the DEXA is that 12 weeks in the current 12 weeks, it's probably too short of a period of time to have a sensitive look at this. And so probably we'll need to wait for longer studies to assess the impact on DEXA.

And then in terms of tolerability, of course, we need to take into account the impact of the titration and the same biology that we've been repeating with the GLP-1 should apply here on the amyloid receptor agonist. And so tolerability index, we know at what dose -- at what first dose we've been inducing the gastrointestinal event and that's been evident at 5 milligrams. But what we need to explore now is that starting at 1 or 2 milligrams, how much improvement in tolerability we can make yet still achieving an efficacious dose. And so that's one of the questions that we have in the design for the multiple [indiscernible] dose.

Our next question comes from Hardik Parikh from JPMorgan.

I was just wondering for [ LillyAccess ] OLE in the PBO crossover arm with moderated titration, we saw improvement in vomiting, discontinuation rates as well as some improvement in nausea. And I was just wondering, when you look at Phase III, what additional levers do you have besides the moderated titration to further improve on that tolerability profile when you kind of consider diarrhea and constipation? And then one on the oral amylin. You mentioned you would do -- you would test both the daily and weekly dosing in Phase II. I'm just wondering if you could just give us some high-level comments on how you see the trade-off of efficacy versus safety when you -- or tolerability when you consider those 2 dosing options.

Let me start, and then I'll sort of hand it over to Blai in a little bit of a break. So Hardik, I think one thing to sort of consider, we've been very intentional about collecting as much data as possible. So for example, in all of our studies today, particularly all the Phase IIs, we use e-diaries. And so we collected a lot of information. We think this leads to an overreporting, particularly in nausea. So in the Phase III, we will not be using e-diaries, it's too long of a study, and it's not the right sort of setting. But in Phase II, all that data we collected, we think we'll see even more improved numbers as we go into the Phase III. Blai?

Yes, nothing else to add. I think all the learnings have been incorporated in the design. Of course, we cannot release all the details on how we're executing the Phase III. But with all the learnings, we feel very, very confident. And then again, as we mentioned in the presentation, focusing all the priorities around the retention is something that we've been very, very thoughtful and very careful about it, and we feel we're in a good place.

In terms of the amylin, the daily versus weekly with that half-life, we have the opportunity to explore what are the potential impact on both the tolerability and the efficacy that we may achieve in the 12-week study, and that's the intent of the ongoing Phase IIa. Thanks for raising the question because I think having a titration that is weekly versus daily and using different dosing there can also open the window to assess [indiscernible].

And that applies to the excitement around the combination as well. We think there's some very important combination opportunities as well as we look forward to the future.

I'm not showing any further questions at this time. I'd like to turn the call back over to Ray for any further remarks.

So first of all, thank you all for joining us today, some very positive updates on our amylin and GLP-1 programs. The world needs more accessible options for chronic weight management and at Structure, we're very passionate about creating world-class and accessible solutions to address this need for all the patients who are waiting. Thank you.

Thank you, ladies and gentlemen. This does conclude today's presentation. You may now disconnect, and have a wonderful day.

Well, good morning, everyone. Thanks for joining us here at the Goldman Sachs Healthcare Conference. Thrilled to be joined on stage today by the team from Structure Therapeutics. And it's been a really busy week with respect to obesity. So I would love to actually open up there.

We're coming on the back of ADA. What did you learn over the weekend? And how does that kind of inform your view of the obesity landscape as it stands today?

So one, we had a great ADA just coming from New Orleans. We -- Dr. Julio Rosenstock gave the opening lecture with our data, our ACCESS data. And I think what we sort of took home from that, we also had a Nature Medicine publication that came out simultaneously to the presentation on Friday of ADA.

We clearly coming out of ADA, we clearly have the best-in-class profile. We just saw data from AstraZeneca come out yesterday, and that was one of the pieces that I think the field was waiting to see. There's a tight grouping, I think, of the oral pills down in that sort of 11% to 12% range. And we've currently shown data up to 16%. So we're feeling really good about that. The other piece, I think, from ADA that was also, I think, a highlight was the amylin progress. There's a whole symposia on Friday, late afternoon on amylin.

And then we released data, a presentation on Sunday showing our -- some additional data on our ACCG-2671 on the amylin that has a very different profile than our aleniglipron. And the main thing that's different is it has a 60-hour half-life in nonhuman primates, so likely to be longer in humans. So excited about that, and we'll release that Phase I data next quarter. A lot of news from ADA.

A lot of news. Let's stay at 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, Corinne. So if you actually just go back 6 months, let's go back to December. Is there room for oral pills? No, people are sort of still debating like injectables are fine. Injectables are actually the convenience of once a week and everything. Fast forward only 1 month of Wegovy launch. It is the fastest launch 5 months later. Now 14% 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 [ Fundeo ] 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 one 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 IIa for amylin next quarter, and then we'll start our combination of our GLP-1 with our amylin in fourth quarter. We're seeing more and more of these combos for specialized markets, a combo of 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, our aleniglipron, 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 as that's been a key area of focus as these new drugs have come to market.

Yes. Jun, 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 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 formulate it 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 aleniglipron, 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, ACCESS data earlier this week.

Yes. So we shared back in December, it was ACCESS and ACCESS II data. So ACCESS went to 120 milligrams. So ACCESS II 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 one of the reasons why I sort of point that out is we've really figured out how to work with aleniglipron. 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 in the Phase III program. Maybe up top, 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 yo-yo effect. People lose weight and then they gain weight, lose weight, gain 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, one 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 weight 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 2.5 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 the 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 a 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 really excited to sort of get that started.

How did 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, et cetera.

Yes. So one 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 and in Nature Medicine, Dr. Blai Coll, 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 one 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 individuals 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 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 nauseous? I think almost everybody say, yes, in the past 9 months have probably been nauseous 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 Zepbound, 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 asked 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 a 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 the drug for many, many options. So I guess, could you be more specific about what you've learned and how you plan to manage that into Phase III?

Yes. So one of the experiments, again, what Blai did in the trial design for ACCESS is he added in -- and again, this was -- that was -- the heat maps were really creative, innovative. What Blai also did in the ACCESS study was he did an open-label extension. And what exactly that was, was after 9 months, we gave participants the option, would you like to go on drug for another 9 months? And what was remarkable was 86% of people signed up for the open-label extension. That includes a placebo arm. So people don't want to stay on the placebo arm for another 9 months. We gave them the ability after 9 months that they could go on and they would start at 2.5 milligrams. So that was really important to give them -- so our solution on part of our solution on the placebo arm with these clinical trials is giving people the knowing, okay, I'm on the placebo arm, I get drug after the end of the initial period.

And then they're going to be on drug. They're going to get sort of the care and everything, the health care, that is an incentive for them to agree to conduct the trial appropriately and to follow the guidelines because we know we just saw data this weekend at ADA There were placebo groups in some of the clinical trials where a significant number of participants on placebo were getting compounded GLP-1s. They had a 5% weight loss in the placebo arm. And the participants, they asked them, did you take a GLP-1 during the trial? And they said, yes.

Great. That's a real challenge. Okay. So you talked about the weight management studies and those being very similar across the board, whether it's being conducted by a large/small biotech. But I guess as you think about the adjacent indications and testing other long-term health outcomes, which we've seen many of these programs do, how are you thinking about a broader Phase III program? And what is your capacity to kind of execute beyond the weight management trials?

Yes. We feel -- we actually feel very confident we can do a Phase III in chronic weight management based on our experience. as good as anybody else. So we've really learned that. But our experience, our expertise does not go beyond that. We cannot do a liver sort of parallel Phase III in liver disease, MASH. We cannot do one in heart failure. This is outside of the scope of what we can do. But chronic weight management really is the fundamental. It is the foundation of this field. It's all about sort of losing weight first. And so that's where we're focused. And where -- the natural question where this sort of goes to is where does a strategic partner sort of fit in. A strategic really has that ability to go into other disease indications. And so we continue having those conversations.

Okay. As you think about and you're having those conversations, I imagine it does come up, like what adjacent indications would be the best fit for a product with this profile. I guess what would you share in terms of the adjacencies that you think aleniglipron will be best positioned to serve?

Yes, Jun, do you want to?

Yes. I mean in terms of Phase III, and we're seeing this with other programs like orforglipron and other competitors, they're in type 2 diabetes. They're in fatty liver disease. They're in osteoarthritis and sleep apnea, right? So these are all adjacent indications that can be pursued. And with a strategic, we could expand into those indications. But as Ray said, our focus is chronic weight management. We have the funds to be able to do that. We have the experience and the learnings to be able to do that. We've got the green light from the FDA to start that Phase III, and we can deliver that data by the end of 2028.

So to put a finer point on that, when do you think you would be able to start a Phase III program here in terms of timing through the rest of the year?

Yes. So we're guiding to the third quarter, right? And it was just last month that we provided an update with respect to the end of Phase II. Again, green light, we're aligned with the FDA on what that Phase III needs to look like. And when we start that Phase III in the third quarter, we'll provide an update with respect to the doses. You already understand the 2.5 mg start low dose low 4-week titration strategy. And the only remaining item is really the 3 doses that we'll provide an update, and we have that alignment with FDA on.

One somewhat adjacency is the kind of maintenance area, and you talked about it earlier. Just remind us the parameters of your maintenance switch study from weekly injectables? And what do you think the benchmarks are for weight loss and management in that kind of indication?

Yes. So we have -- right now, we have another trial going on right now that we call maintenance switch. And really, the sort of question, the scientific question that we're asking here is, do you need to -- when you want to switch over, again, we know the discontinuation rates in injectables is significant. It's a significant issue. And so do you have to retitrate if you want to switch over to a once-a-day oral pill to long-term maintenance? Or can you seamlessly go from one dose of an injectable straight over to an equivalent dose of an oral pill. So that's a scientific question.

Our hypothesis is that you should be able to seamlessly go over and maintain that sort of weight loss. That's the hypothesis. Once your body has adapted to this class of medicines, we don't think it's a molecule to molecule specific 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 an 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 of how exactly do we sort of enter the market and switching from injectables over to orals is one 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 it 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 foundational the FDA has their requirements they 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. So you can imagine a series of Phase IIbs.

Okay. Perfect. And you did mention that you have the funds sufficient to complete a Phase III weight management program, but could you be a little bit more explicit about what that kind of cost you anticipate being?

Yes. I mean it's going to be a pretty typical Phase III. It's 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 ACCG-2671 or the amylin 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 poster presented?

I think -- so first, this is a nonhuman primate. So I just want to sort of set that. It's still a preclinical sort 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 one 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, one of the things that's been a topic of conversation. The half-life is in nonhuman primates, more than 60 hours, 60. And so typically, in humans, you will see an even longer sort of half-life. This opens up real differentiated profile. Aleniglipron 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 -- 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, in Q4, will 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 product company to a 3-product company in the second half of this year.

Great. Maybe one of the -- you mentioned earlier -- one 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 amylin, but particularly oral amylin could play in the market, could you just contextualize that for us?

I think the rules are going to be very similar to the GLP-1 space. Is there a market? And 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, 3 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.

And in amylin, the hypothesis is potentially better tolerability, potentially better selective weight loss, fat 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 those technical challenges exist and how you were able to overcome them with the design of ACCG-2671.

Yes. So I'm smiling, so I'm going to sort of geek out a little bit sort of on this. Amylins are more complicated. It's got a protein called RAMP that binds to calcitonin receptors that then creates the amylin receptor. There are 3 different RAMPs. So there are 3 different amylins as well. There's this debate in the field about DACRAs 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, Ray, 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 sort of 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, the chemistry resources there in discovery. So a lot of IP in order to maintain our first-in-class position for that.

You mentioned the DACRA versus SARA. I guess what do you think is the important debate in terms of how amylins are going to perform in patients?

Yes. So last ADA, Lilly announced a molecule called eloralintide that showed some 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 our SARAs is the ultimate or DACRAs. This ADA, there was a symposia Friday afternoon, one of the leading authorities in the field highlighted he actually likes the DACRAs because the calcitonin really shows opportunities in bone health and particularly with sort of weight loss when you're talking about lean muscle, one 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 the 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, 3535. 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 DACRAs and SARAs 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 DACRAs and SARAs as 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. It's going to be -- again, these are molecules, medicines that are being used by millions of people. Safety, the bar is [indiscernible] 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 ADA for the last 5 days that we were sort of in New Orleans, but they're really not talking about accessibility in terms of price. cost of goods. So we spent 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 -- 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 cost that sort of 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 in 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, 2, 5, 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 one 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 Q4. The -- one of the scientific questions that we have is, is this -- is the combination mostly amylin with a little bit of GLP-1 or mostly GLP-1 with a little bit of amylin. So 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 did an ATTAIN-MAINTAIN study. And that was a good -- they did a really good study. Lilly has done beautiful work.

In that study, though, what they showed was orforglipron was okay relative to semaglutide. But relative to tirzepatide Zepbound, people regained weight. So orforglipron 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 in 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 it achieves steady state. It's probably going to be sort of more amylin with a little bit of GLP-1 kicker. But that's my bet. The team is pushing back. And the bottom line is we don't know. We just don't know. We need to do the experiment. [ They all ] are 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, still not a long. 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 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 36-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 one piece of data 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 in our final minute here is just you talked about having the cash on hand to run a Phase III. But as you think about the broader development programs we just talked about, can you provide 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 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 amylin 2671, the 3535 programs that are in the clinic. 3535 will go into the clinic later this year. And with 2671, we'll be able to fund through the 12-week MAD study, and that will start in the third quarter, as Ray described. So...

Well, that brings us perfectly to time. So I appreciate all of the time and conversations this morning, guys. And thanks to everyone who joined us here and online.

Great. Thanks, Corinne.

Thank you very much, Corinne, and good luck.

Good morning, and welcome to the Structure Therapeutics Conference Call. [Operator Instructions] Please be advised that this conference call is being recorded. I would now like to turn the call over to Corey Davis of LifeSci Advisors.

Thank you, Dan, and good morning, everyone. Earlier today, we issued a press release providing top line results from the ACCESS II clinical program for aleniglipron, our oral small molecule GLP-1 receptor agonist. A copy of this release and the presentation accompanying this call are available on the Investor Relations section of the Structure Therapeutics website.

I'd like to remind everyone that some of the statements we'll make on this call and information presented in the slide deck may include forward-looking statements, which you see here. These forward-looking statements involve a number of risks and uncertainties that could cause actual results to differ materially. Please refer to this slide as well as our SEC filings for a more detailed description of the risk factors that may affect our results. Please also note that these forward-looking statements reflect our opinions only as of the date of this call, Monday, March 16, and we undertake no obligation to update such statements to reflect events that occur after such date, except as required by law.

Now I'll turn the call over to Ray Stevens, the Chief Executive Officer of Structure Therapeutics, to start the presentation. Go ahead, Ray.

Thank you, Corey. Good morning, everyone. And on behalf of everyone at Structure Therapeutics, thank you for joining us today to discuss our positive top line data from 3 different studies of our oral GLP-1 pill, aleniglipron. This morning, we will present the results from the now completed ACCESS II program and the results from 2 additional prespecified interim analyses, which were conducted after median follow-up of 20 weeks on our ACCESS open label extension study and our body composition study. These data follow from the successful results reported back in December of 2025 and is the first of several additional data releases that we anticipate over the course of 2026.

After my introduction and summary, Dr. Blai Coll, our Chief Medical Officer, will review the data in more detail. At the end, we'll turn the call back over to the moderator to manage Q&A.

The new data we are sharing today continues to demonstrate that aleniglipron has a compelling and differentiated profile with potential best-in-class oral GLP-1 efficacy that is very consistent across all the studies we have reported to date.

Let's begin by summarizing the data we shared in December, starting with the Phase IIb ACCESS study. At 36 weeks aleniglipron showed a placebo-adjusted mean weight loss of 11.3% at 120 milligrams with no signs of plateauing. We observed an overall 10.4 AE-related treatment discontinuation rate in the study.

Moving to the ACCESS II study. At 36 weeks, aleniglipron showed a placebo-adjusted mean weight loss of 15.3% at the 2 highest dosages of 180 milligrams and 240 milligrams. And again, no evidence of weight loss plateauing. Following the rerandomization period at week 28, we observed 0 AE-related treatment discontinuations at doses up to 240 milligrams. For the ACCESS open-label extension and body composition studies, after a median follow-up of 10 weeks, we saw a more favorable tolerability profile by using the lower 2.5 milligram starting dose compared to 5-milligram starting dose. There was 0 AE-related treatment discontinuations.

Finally, aleniglipron showed an excellent safety profile in over 500 participants across all studies up to 44 weeks. There were no events of drug-induced liver injury, no off-target safety signals across all dose levels and no events of QTc prolongation.

Moving to the right-hand side of the slide. Today, we're very excited to be sharing the full data readout for the ACCESS II and prespecified interim analysis from ACCESS open-label extension and body composition studies. The data highlights best-in-class potential for efficacy within the oral GLP-1 pill class and approaching the efficacy observed with the injectable GLP-1 class. Starting with the ACCESS open-label extension for patients continuing at 120 milligrams and after a median follow-up of 20 weeks or 56 weeks total on aleniglipron, the study observed a body weight loss of up to 16.2% with no signs of plateauing. We observed an AE-related treatment discontinuation rate of 2%.

For the now completed ACCESS II study at 44 weeks, we saw a placebo-adjusted mean weight loss of up to 16.3% at 180 milligrams and 16% at 240 milligrams. There were no signs of plateauing. For those participants who achieved re-randomization, only 1 patient discontinued due to AEs up to 240-milligram dose.

Moving to the ACCESS open-label extension and body composition studies where patients started at 2.5 milligrams. After a median follow-up of 20 weeks, the data suggests an improvement in tolerability by starting low at 2.5 milligrams and titrating more slowly compared to the ACCESS studies. We are pleased with the GI tolerability results associated with a very low AE-related treatment discontinuation rate that remains below 4%.

Finally, for the greater than 625 participants treated across all studies up to 56 weeks at 120 milligrams and 44 weeks at 240 milligrams, we saw no events of drug-induced liver injury, no off-target safety signals across all dose levels and no events of QTc prolongation.

I will now turn the call over to Dr. Blai Coll, our Chief Medical Officer, to walk through the details of the top line data, what we believe to be the potentially best-in-class oral GLP-1 pill that can scale to meet the global demand for patients who are waiting.

Thanks, Ray. We want to share with you exciting data today from the aleniglipron program, as Ray alluded to, and review with you key questions to continue the patient journey of aleniglipron towards a chronic weight management indication. First, what is the top dose to move forward the program. Number two, does weight loss continue beyond week 36? Third, while tolerability is optimized by starting low and going slow, are there initial signs of weight loss? Number four, related to that, does the tolerability improvement associated with the 2.5 milligram start and titrate slowly persist over time? And finally, very important, does aleniglipron maintain an absence of off-target effects.

To address those questions, we will focus on ACCESS II completion up to 44 weeks and top dose of 240 mg, and we will provide additional prespecified interim analysis from the ACCESS OLE and the body composition studies.

Let's start with the first set of questions around top dose and efficacy beyond 36 weeks, reviewing the top line data from the ACCESS II study. As a reminder, you can see in next slide, the design of the ACCESS II study, where 73 participants living with obesity were overweight and at least 1 comorbidity were randomized to aleniglipron or placebo. Participants started at 5 mg of aleniglipron in 4 weeks titration steps to reach 120 mg and got rerandomized on week 28 to 120 mg, 180 mg or went to 180 for 4 weeks before reaching target top dose of 240 mg a day.

We reported 36-week data in December. And today, we will be focusing on the efficacy up to 44 weeks and the tolerability profile after rerandomization. A reminder of the baseline characteristics with age between 50 and 52 years old, predominantly female participants, 62% and 67% with a baseline BMI of 39.9 for the group randomized to aleniglipron. Per eligibility criteria, both HbA1c and blood pressure were within normal limits.

Next slide summarizes the primary efficacy endpoint based on the primary efficacy estimate showing a very clear separation of curves early in the trial that continues all the way to week 44, showing a 13.6% weight loss for the 120 mg group, 15.3% for the 180 mg and 15% for 240 milligrams. There is additional body weight reduction between week 36 reported in December and week 44 as the final data point in the study.

In the bar graph on the right, we show the placebo-adjusted estimates with a 14.7% reduction for 120 mg, 16.3% for 180 mg and 16% for 240 mg representing an absolute weight loss ranging from 33 to 39 pounds. Overall, a clinically and statistically highly significant body weight reduction at 44 weeks with greater efficacy at doses higher than 120 mg.

The categorical analysis of body weight reduction based on 5%, 10% or at least 15% weight loss also yielded clinically relevant results with 93% of participants on 180 achieving at least 10% and 61% reaching a 15% or greater weight loss. Additionally, and as part of an exploratory analysis, 32% of participants receiving 180 mg achieved a 20% body weight loss or greater at the end of the 44 weeks.

With the compelling level of efficacy, let's transition over to the tolerability analysis after re-randomization. As you can see in the top panels, we're describing the occurrence of vomiting for 120 mg and 180 mg of aleniglipron, where 1 participant in each group had an event of vomiting. For the 240-milligram arm in the bottom left, 4 participants experienced events of vomiting starting at week 37. Interestingly, just 1 participant assigned to the 180-milligram arm discontinued due to an adverse event after rerandomization.

Overall, the tolerability profile after rerandomization showed no serious adverse events and a 3.7% discontinuation due to an adverse event. Importantly, the majority of participants on aleniglipron, 70% to 100% completed the last 12 weeks in the study at target dose, defined as having a compliance rate during that period of time at least of an 80% compared to just 60% in the placebo arm. The gastrointestinal profile showed no substantial differences between 120 mg and 180-milligram arms and a higher occurrence of nausea and vomiting in the 240-milligram arm.

To summarize ACCESS II, potential best-in-class efficacy with a 16.3% body weight reduction, placebo adjusted for the 180-milligram arm. Importantly, the tolerability profile for higher doses shows a low number of AEs leading to discontinuation with the incidence of gastrointestinal events at 180 mg comparable to the 120-milligram dose. An important consideration to the patient journey is centered around the continuation of body weight reduction and the tolerability by starting aleniglipron at 2.5 milligrams and titrating more slowly.

To address those 2 questions, we will review the prespecified interim analysis from the open-label extension study of ACCESS. The design of the study is shown in this slide, where 151 participants from ACCESS completed the first 36 weeks of the study and signed up to continue for the open-label extension portion. Patients at 45 with an N of 28 during the double-blind treatment got up titrated every 4 weeks to reach 120 mg.

Similarly, 42 participants assigned to 90 milligrams in the randomized period were up-titrated to 120 mg for the open-label portion and the participants on 120 mg in the double-blind period continued on 120 mg for the remaining period of the open-label extension. The participants initially assigned to placebo in the bottom row started on 2.5 milligrams of aleniglipron at week 36 and titrated every 4 weeks and will eventually reach 120 mg. We will focus today on the analysis after a median follow-up of 20 weeks.

We will start off with the description of body weight changes, graph showing the body weight reduction in the percentage in the Y-axis for the participants in the 4 arms of the study. Let's start with the gray line depicting the placebo crossover participants with a reduction of around 1% at the end of the randomized period. At week 36, they started on aleniglipron 2.5 milligrams indicated by the blue circles and titrated up on a 4-week scheme to reach a 6.4% weight loss after a median exposure of 20 weeks.

The participants assigned to 45 mg in the randomized period shown in triangles were up titrated every 4 weeks to reach 120 mg and showed additional body weight reduction from week 36, achieving a 13.3% weight loss at week 56. And participants assigned 90 mg and 120 mg during the double-blind treatment, the 2 bottom lines in the graph were dosed at 120 mg and experienced additional weight loss ranging from 15.3% to 16.2% after a median follow-up of 20 weeks.

From a tolerability perspective, we described in the slide nausea on the left and vomiting on the right from those 38 placebo crossover participants starting at 2.5 milligrams. We observed very low occurrence of nausea and without a specific temporal pattern up to week 56, where doses of aleniglipron were approximately of 30 milligrams and no events of vomiting reported up to week 56. Overall, this slide shows the tolerability profile during the open-label period starting at week 36 and after a median follow-up of 20 weeks.

The number of treatment-emergent adverse events is higher in the placebo crossover group since this represents the first time those participants started exposure to aleniglipron. Additionally, the study shows a low number of AEs leading to discontinuations, #3 at 2% and ranges of nausea from 11.6% to 39.9% and vomiting ranging from 7.1% to 16.3% with diarrhea and constipation less, commonly reported.

In summary, from the open-label extension, the study showed clinically relevant and additional body weight reduction beyond week 36 up to 16.2% weight loss at 120 mg. Tolerability is characterized by very low numbers of AEs leading to discontinuations, 2% and the additional data reinforces the tolerability improvement by starting at 2.5 milligrams and titrating more slowly with no vomiting events and no discontinuations in that group after a median of 20 weeks in the study.

Let's now transition over to the body composition study to address the questions around the level of efficacy by starting at 2.5 mg and titrate slowly and key tolerability markers. A reminder of the study design, 71 participants living with obesity were enrolled in 11 sites across the U.S. 59 participants randomized to aleniglipron with the same titration scheme as described in the ACCESS OLE starting at 2.5 mg and titration on a 4-week basis to eventually reach the 120 mg target dose. We will share results after a median follow-up of 20 weeks corresponding to the 30-milligram titration step.

A reminder of the baseline characteristics with average age ranging from 49 to 55, predominantly female participants, 64% to 67% and BMI of 38 [indiscernible] across group. In this slide, you can see the description of body weight changes in the study with the placebo participants shown with the gray line with body weight reduction fluctuating at around 2% at week 20. Importantly, the participants receiving aleniglipron showed a consistent and differentiated body weight reduction, achieving a 6.8% weight loss after a median follow-up of 20 weeks, coinciding with the 30-milligram titration step.

In tolerability, you can see the panels on the left, describing events of nausea on top and vomiting at the bottom for the aleniglipron-treated patients and on the right, the occurrence in placebo participants. We observed fluctuating events of nausea, coinciding with the titration steps, but overall showing a tapering down over time with very low prevalence of vomiting events as shown in the lower left panel.

This data suggests a different pattern compared to ACCESS and ACCESS II, where starting at 5 milligrams was associated with a higher peak of both events during the first 4 weeks in the study. This profile is associated with a low number of AEs leading to the study drug discontinuations with just 2 participants at 3.4% happening at weeks 9 and 11, both due to gastrointestinal symptomatology.

Overall, in the body composition of study, we see very low AEs leading to study drug discontinuations with 50.8% of participants reporting at least 1 event of nausea and 23.7% reporting vomiting. It is important to highlight here that the placebo event rate of some of the gastrointestinal events is high in the study, showing 33.3% of placebo participants reporting nausea, 8.3% of vomiting and 50% of participants reporting diarrhea, data points that should be considered in interpreting the overall profile.

The increased awareness of the gastrointestinal events in the class of GLP-1 receptor agonist by clinical sites and participants, along with data capture involving E-diaries may artificially inflate the rate of subjective events such as nausea.

In summary, for the body composition study, participants starting at 2.5 milligrams of aleniglipron and titrating slowly show preliminary signs of body weight reduction, achieving a 6.8% after 20 weeks of median follow-up. Importantly, from a tolerability perspective, the data supports the start low, go slow strategy with very low number of study drug discontinuations due to adverse events at 3.4%.

To summarize the tolerability, you can see in the slide a comparison of the 2 titration strategies taking patients to 30 milligrams of aleniglipron. In ACCESS and ACCESS II, patients started at 5 mg and titrated every 4 weeks to reach 30 milligrams in 12 weeks indicated with the dark blue bar graphs. In the body composition and in ACCESS OLE patients, we followed a start low and go slow strategy of starting at 2.5 mg titrating every 4 weeks to reach 30 milligrams in 20 weeks, shown in orange. It is important to highlight the duration of the 2 sets of data are not the same with longer capture of events for the start low and go slow titration in body composition and ACCESS OLE 20 weeks compared to 12 weeks in ACCESS.

Additionally, as stated in the previous slide, the reporting of nausea may be subjective and should be interpreted with caution. Comparing those 2 sets of studies at the same dose, the data suggests an improvement in the 3 parameters: nausea, vomiting and especially AEs leading to study drug discontinuations. This further supports the strategy starting low and going slow by starting at 2.5 mg, keeping 4-week titration steps and escalating the dose not more than 2.5 fold. We are very pleased with those results that will better inform the design for the upcoming studies.

Lastly and very importantly, let's review the off-target safety profile. As reported back in December from ACCESS,, the new data from ACCESS II and interim analysis of the open-label extension and body composition studies confirms the lack of drug-induced liver injury events. There are no cases of liver enzyme increases above 10x. And importantly, all cases of fluctuations seen in both ALT, AST results while continuing study drug.

With that, we wanted to summarize the key findings from today's data readout. First, we have characterized the profile of aleniglipron demonstrating best-in-class efficacy, reaching 16.3% body weight reduction at 44 weeks for the 180 mg group and the tolerability markers between that arm and 120 milligrams are comparable. Number two, data suggests there is no plateauing effect in efficacy up to 44 weeks in ACCESS II and up to 56 weeks in the ACCESS open-label extension at 120 mg.

Three, by starting low at 2.5 mg and titrate slowly, there are initial signs of body weight reduction to achieve a 6.4% to 6.8% weight loss after a median follow-up of 20 weeks. Four, the additional data from starting slow at 2.5 mg and titrating more slowly reinforces the continuous optimization in key tolerability markers. And lastly, yes, we continue maintaining no events of drug-induced liver injury or other unexpected off-target effects.

With that, let me turn it over back to Ray for the concluding remarks.

Thank you, Blai. As we wrap up, we believe that the totality and consistency of the data presented today, together with all the data that we have presented to date on aleniglipron provides a compelling evidence that aleniglipron, our oral GLP-1 pill designed and manufactured to meet the global needs has a differentiated clinical profile to address the global obesity pandemic. 2026 will be a transformational year at Structure Therapeutics as we continue to share more data from 4 additional studies for aleniglipron throughout 2026, including the completion of the ACCESS open-label extension and data readouts for the type 2 diabetes, obesity, switch and body composition studies to further solidify a best-in-class profile.

We have an end of Phase II meeting scheduled with the FDA in Q2 and remain on track to initiate Phase III in the second half. As you'll see from this pipeline, aleniglipron is only one piece of the portfolio as we build the broadest oral small molecule metabolic obesity portfolio at Structure Therapeutics.

Next up is the amylin program, where we have 2 amylin molecules, ACCG-2671 and ACCG-3535 in development. ACCG-2671 started a Phase I clinical trial in December as the first and most advanced oral small molecule amylin receptor agonist to enter the clinic, and we anticipate data from Phase I in the second half of 2026. Given the importance of the amylin target and our first-in-class approach, we named a second development candidate at the end of last year. ACCG-3535 is our second-generation DACRA with a different chemical scaffold and will enter the clinic by end of this year.

We view aleniglipron and our amylin molecules as foundational backbones that can be used both as monotherapies and in combination with other mechanisms to address the different obesity patient segments and the various cardiometabolic indications beyond obesity. We have a preclinical program underway combining our GLP-1 and amylin backbones that we have shared previously at international medical conferences and the team continues to work on our GIP and glucagon molecules to be used in combination with our backbone molecules.

At Structure, we believe the -- only oral small molecules can scale to meet the needs of the global obesity patient population. The currently available injectable peptides serve only a very small fraction of the more than 100 million people in the United States who are living with obesity or overweight. By 2030, it's estimated that more than 1 billion people globally will be living with obesity and 3 billion will be living with either overweight or obesity. Patients need more options. The world needs more options. We believe that developing oral small molecules gives us a competitive advantage in being able to scale and make medicines more accessible to people living with obesity.

I especially want to highlight how proud I am of the work done by our chemist and manufacturing teams in preparing for aleniglipron production at the scale needed to meet this global demand.

With today's update, the positive ACCESS II data at higher doses and progress in our ACCESS open-label extension and body composition studies continue to demonstrate best-in-class potential with our once-a-day oral aleniglipron pill, a medicine designed to be accessible, scalable, combinable and represents an important solution in addressing a global health care challenge.

I will now open the call for Q&A.

[Operator Instructions] Our first question comes from Yasmeen Rahimi with Piper Sandler.

Could you maybe comment on, clearly the strategy of starting low and going slow seems to be working really well and that you're not reaching a plateau. So could you think about helping us understand if you can do any modeling to figure out orfoglipron's differentiated weight plateauing effect? In other words, can you model and see, is it 1.5 years that you reach plateau? Is it 2 years? Is there any evidence? And then also, is there any mechanistic rationale for the lack of plateauing effect? And then I'll jump back in the queue.

Yes, this is Blai. Thank you. I missed the first part of your question. I got the second part. Hopefully, I can cover everything. You're asking about the plateauing effect and the like.

If you could model it. Yes, that's right. If you could model and predict when plateauing could achieve and then what is the reason for a differentiated plateauing effect?

Yes. Thanks for your question. So absolutely, we're -- that's what we're doing right now. It's using that 44-week ACCESS II and all the way to 56 in the ACCESS OLE to inform the model that will help us predict the level of efficacy. We don't see a plateauing effect as of yet to week 44 and 56, and this is a differentiated element, and we're very pleased with the results. Potential mechanisms of action there behind that clinical observation is that, as you know, we have seen proportional exposure all the way to 240 milligrams of aleniglipron, and that can be behind that additional body weight reduction that we're seeing beyond 36 weeks. Thanks for the question. Hopefully, I covered everything that you were asking.

Our next question comes from Evan Seigerman with BMO Capital Markets.

Really congrats on the data. I wanted to touch on the difference between 180 milligram and 240-milligram doses clearly both performing the same. Do you have a hypothesis as to what's happening here? Are we getting pharmacological saturation? Is there something else nuanced in the data? Just help me parse through this very good data, but I want to know kind of the differences between these 2 dosing arms.

Thanks Evan for the question. This is Blai again. I'll take the question. So yes, as you well pointed out, we don't see differences in efficacy between 180 mg and 240 mg. The results in efficacy and body weight reduction are comparable at the end of the 44 weeks. Interestingly, though, what we're seeing is that the pattern of efficacy is very similar between 180 mg and 240 mg. But then tolerability-wise, which is always the things that we need to couple with the efficacy, the 180 milligrams behaves very, very similar to what we've seen for 120 mg. At the end of the day, I think the most important conclusion of ACCESS II is that we're getting available -- highly available data to inform the design of the Phase III to design the modeling and that ultimately will result in the identification for the top dose for Phase III.

Our next question comes from Seamus Fernandez with Guggenheim Securities.

So congrats on the data and the consistency and thanks for the robust presentation overall. Actually, Ray, I wanted to talk a little bit about the scalability of the product. I know this is something that we've talked about before, not really finding a lot to critique in the data. So I wanted to maybe provide a better understanding of how you've approached the scalability to reach 100 million patients or more. And I know that comes down to the design of the molecule, but there's a lot that goes into this. So I was just hoping you might help investors think about what it takes to get to 100 million patients in this market.

Thank you, Seamus, for the question. We were in the fortunate position. GLP-1 receptor is very well characterized. The peptides, we sit on the shoulders of giants, as they say, with all the characterization of the peptides over the years. And so we were in the fortunate position to be able to really focus on design early on at the very beginning as we're thinking about design principles, not just efficacy, not just safety, not just tolerability, but also at the very beginning, we thought about manufacturing.

So as an example, we felt it was important for manufacturing not to have any chiral centers that require chiral separation, just as one representative example. This is an important step in the manufacturing. So we were able to remove any of those chiral centers that would require chiral separation. That's one example. Again, as I highlighted in my closing remarks, the chemist and our manufacturing team, they've just done a phenomenal job at the synthetic route at optimizing based on the molecule itself, the entire process to really make -- to really allow us to be able to scale this to the global needs that are required.

And our next question comes from David Risinger with Leerink Partners.

So congrats on all of the disclosures today. Could you please provide some color on how you're thinking about the go-forward start low and go slow strategy for Phase III? Specifically, what period of time do you envision titrating patients from 2.5 mg at day 0 to 180 milligrams in Phase III?

Blai you can start?

Yes. So good question. Thanks, Dave. So the plan is based on the data that we've released today and back in December, as we've communicated, starting at 2.5 milligrams is the most optimized starting dose for aleniglipron. We plan to keep the 4-week titration steps. And as released today, we're not planning to titrate and escalate the dose every time we titrate more than 2.5 fold. This is the combination of starting at a low dose at 2.5 mg and going slowly to reach the target doses. The final doses for Phase III are still to be determined. This is currently ongoing work at Structure Therapeutics with the data we just released plus the modeling that we're actively pursuing.

Two additional comments there is that it's important to see not only that we're optimizing the tolerability, we're reducing significantly the number of AEs leading to discontinuation with these current titration steps, but we're also seeing early signs of body weight reduction. And this is the 2 factors that we're laser-focused on. We know contacting with clinical investigators and data from the market research that it's -- of course, it's very, very important to optimize tolerability while you're also seeing effects in terms of body weight reduction. And this is what the data is pointing out right now.

And Dave, you and I have had this conversation before about the titration schedule and how long a titration schedule should be. Based on our research, what we found is what's most important is that patients will get bored if they do not see weight loss after 4 weeks or 8 weeks. And so that's something that's really important to consider. What I really like about the data that we're showing today and back to the December data is that we are seeing weight loss at the starting dose of 2.5 milligrams. And even better, what I like is we're seeing this very nice smooth linear weight loss from the very beginning, starting at 2.5 mg all the way out to 30 milligrams to date. And we see similar curves with the longer studies to 44 weeks and 56 weeks.

So we think that's really important. It's better than these exponential weight losses that we see where people lose half of their -- half of their weight is due to water loss and it's very rapid. So we really like the profile that we have, and we believe that the data that we've shown patients will lose weight at the very beginning, starting at 2.5 mg and that will keep them very engaged as they progress through going on aleniglipron.

Our next question comes from Terence Flynn with Morgan Stanley.

I guess just any thoughts on where you might present the full ACCESS data? Is it likely at ADA? Or is there another venue that you guys are considering? And then any -- I would love your latest thoughts, Ray, on potential partnership discussions and what that might look like?

Ray, do you want to take the first one, and I'll take the second.

Sure. Thanks, Terence. Yes, I think medical conferences later in the year, and you're mentioning ADA, there's also an obesity week in the fall. And so we have a lot of exciting data and we'll be informing as appropriately. But yes, that's a reasonable assumption.

And Terence, on your second question, in regards to strategics, so we continue to interact with strategics.

The data that we demonstrated today and back in December shows very strong best-in-class efficacy for aleniglipron. We'll continue those dialogues. We also have the Amylin Program that will start having data readouts in the second half of this year. So we'll keep you updated as that progresses.

Our next question comes from Prakhar Agrawal with Cantor Fitzgerald.

Congratulations on this update today. Maybe one on oral amylin. It seems like the second half update will be just that. So maybe if you could talk about what will be disclosed at this update? And how are you thinking about the MAD readout timing? And where are you with the chronic stock studies with the oral amylin? And maybe just a clarification on the liver enzyme. There were like ALT, AST elevations of 5x upper limit of normal, a few cases, but if you can clarify whether these were transient and whether patients have discontinued the drug.

Blai Do you want to take this?

Sure. Thanks, Prakhar. In regards to the oral amylin, yes, we're guiding to second half results from the single ascending dose. Currently, designing multiple ascending dose, the multiple ascending dose design will largely depend on the findings on the single ascending dose.

So more to come on that end. Highly scrutinized program, of course, very excited and we're very excited about the progress of these programs so far. So more to come on that end. In terms of the ALT, AST elevations, we're not seeing a different pattern compared to what we released in December.

So all the fluctuations that participants continue on drug -- continue on study drug and the ALT, AST come back to normality. So very, very pleased to see that there's no events of DILI that the participants that experience any of those [ fluctuations ] despite not stopping study drug or discontinuing drug or reducing the dose the ALT, AST levels got back to normality.

And Prakhar, just as a reminder, back at the beginning of the year, we did update our corporate deck on the Amlin Program, and we did share the schema of the titration scheme. So that continues to be work in progress. We are right on schedule. As they say, with Phase I, no news is good news in that study.

Our next question comes from Samantha Semenkow with Citi.

Let me add my congratulations on the data as well. Another one for me for the oral amylin asset. I'm just wondering if you take a look forward, how are you thinking about what a competitive profile would look like from like an efficacy and tolerability profile for oral amylin? And if you could give some thoughts around both the monotherapy and potential combination view for that asset?

Yes. Let me give Blai a little bit of a break here. And then Blai you can add on to anything that I missed. So first of all, Sam, and Prakhar, thank you guys for asking about amylin, even though this call was for aleniglipron. We know there's a lot of interest in amylin these days. The way that we're sort of looking at this is we still believe very much in the amylin mechanism for a number of different reasons. one, the safety profile of tolerability is very strong from the data that we've seen to date. And so that, we think, is really important. Second, there is a subset of the population that do not respond to GLP-1s. And so we feel for those individuals, we think amylin is a potential option for them.

And then lastly, we have presented previously at international medical conferences, the combination of our oral GLP-1 together with our oral amylin, and we see this very synergistic effect between the 2, so for additional weight loss if one wants to go to that level. So I think in terms of tolerability advantages, we continue to be intrigued by the selective weight loss, which we think is also an important area. There's a number of reasons why we remain excited about amylin and in the combinations. Blai, anything else you want to add to that?

No. Just one comment, Sam. I think good question on the -- on how we're developing the amylin. We'll develop as monotherapy for now, but also with the intent to combine, as we've said in the opening remarks, we have the ability to have that combination of different mechanisms of action that, as Ray alluded to, can potentially be synergistic. And that's the plan that we have for the amylin program.

Our next question comes from Jon Wolleben with Citizens.

Wondering if you could talk a little bit about the differential properties between aleniglipron and orforglipron and the results you're seeing here with the clinical profiles, just to better understand what's going on mechanistically here.

Yes. I'll start at sort of a very high level. We see 4 different reasons for differentiation. Clearly, efficacy stands out. This is the most efficacious oral GLP-1 out there from the data that we've shown now. Second, in terms of off-target safety, very pleased with the profile. We think that in terms of tolerability, similar in regards to tolerability. Third, manufacturing, something that was asked earlier on, really, really proud and pleased with the manufacturing that we've been able to accomplish for aleniglipron. That is a distinct advantage. The lower cost of goods and scalability is quite significant.

And then fourth, combinability. The differentiation with combinability, we -- not only did we design this molecule to be efficacious, safe, manufacturing at scale that's needed, lower cost of goods, but we also designed it so it was very combinable with other molecules, whether it's other incretins and weight loss or non-incretin molecules as we look forward in life cycle management. So those are the 4 different reasons why we believe it's highly differentiated.

Our next question comes from Roger Song with Jefferies.

Congrats for the data. Really like the consistency, as you said, Ray. Very quick two from us. So the first one is, we already see the 2.5 mg starting dose all the way to 20 weeks for the tolerability. Just curious about the expectation about longer follow-up. Do we expect to see some late incidence of the GI AE, particularly from those new patients versus the existing patient will change the profile?

And then very quickly on the Phase III design, knowing you will have diabetes and then potentially the SWITCH maintenance data coming up in the second half. I understand it's not gating factor for the Phase III start, but how those data will inform the Phase III and how much you will change the Phase III with those data?

Thanks, Roger. I'll take the question. So on start of 2.5 and up to 20 weeks, yes, we will see more incident events. And what we're seeing right now, and this is also consistent with what orforglipron saw, it's more of a random effect over time. There's no a temporal trend anymore when you find the right starting dose and the right titration steps as we've been showing with starting at 2.5 mg and going all the way to the 30 milligrams with those 20 weeks. And so yes, we will be seeing most likely an increased incidence there. But the most important thing is that we are keeping the number of AEs leading to discontinuations very, very low. And so this is the hardest endpoint or the most robust endpoint, and we're very pleased with that data.

Number two, on the Phase III design, there's nothing gating. We're collecting information on the SWITCH, but we don't see that as a key factor for informing the Phase III. And the type 2 diabetes Phase II, we need to get that data and having the exposure at higher doses than 90 milligrams for type 2 diabetes, but it's not gating. We're all ready. We have all the data ready to have the interactions with the regulatory agencies.

Our next question comes from Andy Hsieh with William Blair.

Just a quick one on Slide 16, for the 90-milligram open-label study, you see kind of a precipitous drop from week 52 to week 56. I'm just curious about what's happening here. And also at the bottom, you said no statistical model applied. So if you can just kind of clarify for us what that means in terms of plotting out the chart.

Yes. Thanks, Andy. This is Blai. I'll take the question. So the 90 milligrams in OLE, you see that drop between weeks 52 and 56. Taking into account that at these 2 different time points, we see different patients. And so this is probably the reason why we're seeing such a dramatic difference. This is an open label, it's interim and not all the patients have completed week 56. So that's one of the reasons why we see some differences that most likely will stabilize over time. At this point, though, after 20 weeks of median follow-up in the open-label extension, we will see potential differences in the final numbers. But directionally, I think we're very, very strong in the levels of efficacy.

And then the second question in regards to the nature of this data, this is descriptive. It's not modeled. There's no LSM or MMRM statistical approach here for multiple reasons. One, it's -- because it's an interim and it's an observational study, and that's why we don't have any modeling applied yet.

And Andy, one follow-up on that. The 90 milligrams is going to 120 milligrams. So those 2 curves, the 120 milligrams, they should converge at some point. And I think we're starting to see that in addition to it is a median 20 weeks. So we're getting a range of participants at different levels.

Our next question comes from Corinne Johnson with Goldman Sachs. [Operator Instructions]

Okay. So I was just saying I know it's a work in progress and you guys are still going through it all. But could you speak to how you're thinking about determining a go-forward top dose given the weight loss you see at all 3 top doses really depending on the time point is reaching about 16% weight loss? And then also, what are the implications for the duration of the Phase III depending on which top dose you kind of go forward with given that start low, go slow titration strategy?

Thanks, Corinne. Yes, as we've indicated, we're very pleased with the characterization in the dose range finding studies from 45 milligrams to 240 milligrams. We're currently work ongoing on the definition of what will be the top dose. But I think the data is very, very consistent and very compelling in both in terms of efficacy and the tolerability management for that 120 mg or higher doses. So that's for the top dose implications on that top dose in terms of the duration. I think it's very clear that based on the FDA guidance, we'll need to do a 52 weeks maintenance once we achieve the target dose and then starting at a low dose and titrating slowly to optimize that tolerability, but it will not significantly alter the overall duration of those studies.

Our next question comes from Annabel Samimy with Stifel.

This is Jayed on for Annabel. Congrats on the great data. Just one question from us. On the body composition trial, I know the interim analysis, but were you able to get any early insights into lean muscle loss versus fat loss in these patients?

Thanks, Jayed. Unfortunately, we don't have the data yet because the collection of the [ DEXAs ] are still blinded, and we look forward to report the results at the end of the study, but we don't have that data as of yet available.

Our next question comes from Hardik Parikh with JPMorgan.

Just had one high-level one. With this update, I was just wondering internally, what aspects of aleniglipron's tolerability profile, do you still -- do you have more confidence now? And what are still kind of the major unanswered questions for you guys? Like I know the 2.5 mg starting dose, we saw some encouraging signs on discontinuation rates and vomiting, while we saw some higher rates for other GI events, including the placebo arm, as you mentioned. So just how do you think the aleniglipron's tolerability profile can still change going forward in the Phase III versus what you saw in the OLE and the body comp studies?

Thanks, Hardik. I'll take that and Ray please feel free to chime in. We're very pleased with the results of the tolerability that we're seeing starting at 2.5 mg, maintaining the 4 weeks and not escalating more than 2.5 fold. We're seeing decreases in nausea, seeing decreases in vomiting. And as we've said in the call, most importantly, we're seeing a dramatic reduction in the number of AEs leading to study drug discontinuations that at the end of the day, I think it's the key pillar for a successful Phase III program. Of course, there are learnings from the open-label extension. There are learnings from the body composition that we're including in -- or we're planning to include in the protocols for Phase III that we'll continue optimizing those results. But we're very pleased with where we are right now at the completion of the dose range finding studies. Ray, anything else to add?

Yes. This gives me the opportunity to really praise Blai and the clinical team overall. They've shown tremendous innovation and creativity in the design of these studies for example, including the open-label extension when we released the data back in December, really taught us the power of participants and knowing that they can continue on a study and seeing that really high continuation rate of people wanting to continue on aleniglipron.

So I think that was really powerful. We learned that lesson. It was kind of what I described as an experiment within an experiment. Here, we have the same situation between the body composition study and the open-label extension starting at 2.5 milligrams, Blai and the team have continued to evaluate different variables.

At the end of the day, what all this data is really for is for us to design the best possible Phase III. And I think we have probably one of the most comprehensive Phase II data sets where we've explored a number of different things to give us that very successful possibility, probability of completing Phase III with the TPP of exactly what we want.

Our next question comes from Dave Risinger with Leerink Partners.

Yes. I just had a question on Slide 18, please. So in the right column, the placebo crossover data was a little peculiar. Do you have any color on the conflicting figures, which show nausea 40% and vomiting at 0%?

Yes, Dave, this is Blai. Thanks for the question. So this is the overall incidence that we've seen on those participants that started on aleniglipron at week 36. As we've indicated that 40% of nausea, it can be highly subjective. We're not seeing any events of vomiting there. Now whether this is -- the protocols are very, very similar. This is the same protocol that we use for ACCESS. It's very similar to the body composition study.

Those participants may be [indiscernible] by being in the study for the 9 previous months receiving placebo, so highly motivated and we're also seeing some preliminary signs of sites not being very aggressive in terms of the up titrations if there's any symptomatology of nausea and those down titrations persist longer compared to the body composition.

These are learnings that we can incorporate into the Phase III. This is the most important thing in addition to the low number, very low number of AEs leading to discontinuation. As you see here, we don't see anybody discontinuing up to 20 weeks of follow-up, which is, again, as we've said, it's the most important factor.

This concludes the question-and-answer session. I would now like to turn it back to Ray Stevens for closing remarks.

Thank you all for joining us today for our ACCESS II top line data readout and ACCESS open label extension and body composition updates. We look forward to keeping you updated with multiple data readouts throughout 2026. As we advance aleniglipron forward and continue to progress our amylin in combination oral pill programs to make this class of medicines more accessible to all.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Good day, and thank you for standing by. Welcome to the Structure Therapeutics top line results from the aleniglipron Phase II Access Program. [Operator Instructions] Please be advised that today's conference is being recorded. I'd now like to hand the conference over to Danielle Keatley, Head of Investor Relations. Please go ahead.

Thank you, and good morning. Earlier today, we issued a press release providing top line results from Structure Therapeutics access clinical program for aleniglipron, our oral small molecule GLP-1 receptor agonist. A copy of this release and the presentation to accompany the call are available on the Investor Relations section of our website. Before we get started, I would like to remind everyone that some of the statements that we make on this call and information presented in the slide deck include forward-looking statements, which you see here. These forward-looking statements involve a number of risks and uncertainties that could cause actual results to differ materially.

Please refer to the slide deck as well as our SEC filings for a more detailed description of the risk factors that may affect our results. Please also note that these forward-looking statements reflect our opinions only as of the date of this call, and we undertake no obligation to update such statements to reflect events that occur after such date, except as required by law. Now I will turn the call over to Ray Stevens, our Chief Executive Officer, to start the presentation.

Thank you, Danielle. Good morning, everyone, and thank you all for attending the Structure Therapeutics Access Program top line data release. Today, we will present the results from our core Phase 2b Access program and 3 additional ongoing clinical studies. For today's update, I will begin by discussing the aleniglipron obesity market opportunity. Dr. Blai Coll, our Chief Medical Officer, will review the top line 36-week data from our ACCESS, our core Phase IIb study. After reviewing the ACCESS study, Blai will share data from 3 ongoing clinical studies that provide additional information.

Blai will then discuss aleniglipron next steps, focusing on Phase III readiness. Finally, I will review aleniglipron's role as the backbone in our oral small molecule portfolio before turning to Q&A. To begin, I want to reaffirm the mission that guides us at Structure Therapeutics to make medicines accessible to all. ACCESS to medicine is a fundamental human right, and everything we do is driven by that belief. The results that we're sharing today move us an important step closer to fulfilling that mission. As we think about how to make medicines more accessible to people living with obesity, I want to reground us in the obesity market.

The currently available injectable peptides only serve approximately 5 million people in the United States. That's a very small fraction of the more than 100 million people in the United States who are living with obesity or overweight. Patients need more options. The world needs more options. Globally, by 2030, approximately 1.5 billion people are expected to be living with obesity or overweight and could benefit from medicines to manage their weight. We know that patients need options and ACCESS and always oral small molecules can scale to meet the needs of the global patient population. We believe that oral aleniglipron, a medicine designed to be accessible, scalable and combinable, represents an important solution in addressing this global challenge.

Aleniglipron is a convenient once-a-day pill with no fasting requirements and one that can be stored and transported at room temperature. With a remarkably wide effective dose range, patients and prescribers will potentially have a great deal of flexibility on dosing with aleniglipron. And because aleniglipron can be easily combined with other oral medications, it will form the backbone for future oral combination therapies in development here at Structure Therapeutics. Turning to the results on Slide 8 and the information you've all been waiting for. The data we are sharing today demonstrates that aleniglipron has a compelling and differentiated profile and a best-in-class potential.

Based on the data we're sharing today and our comprehensive and compelling Phase II program, we are ready to move into Phase III with an update on timing after our FDA meeting in early 2026. Starting with efficacy. For the ACCESS study, our core data set for aleniglipron, at 36 weeks, patients on the 45, 90 and 120-milligram dose of aleniglipron experienced 8.2%, 9.8% and 11.3% placebo-adjusted weight loss, respectively. This data is clinically meaningful and statistically significant. In the exploratory ACCESS 2 study, patients experienced placebo-adjusted weight loss of 14.1% at the 120-milligram dose.

Notably, at the higher doses of 180 and 240 milligrams, patients experienced a remarkable placebo-adjusted weight loss of 14.4% and 15.3%, respectively. When looking across the 4 data sets that we are sharing today, we see no evidence of weight loss plateau beyond 36 weeks. In fact, we'll show evidence of continued weight loss beyond 36 weeks from the ACCESS open-label extension. Pharmacokinetics data from the study demonstrate that aleniglipron is dose proportional for doses up to 240 milligrams per day, which provides strong biochemical rationale for the differentiated efficacy data set for aleniglipron.

Beyond weight loss, we're pleased to report clinically meaningful improvements in blood pressure and blood glucose hemoglobin A1c in participants receiving aleniglipron. Moving to tolerability. In the Phase 2b ACCESS study, we saw an overall 10.4% adverse event-related treatment discontinuation rate. The GI-related AEs were consistent with other GLP-1 receptor agonists. In the exploratory Phase 2 ACCESS study, which we studied higher doses of aleniglipron, participants who achieved rerandomization to higher doses at 28 weeks experienced no AE-related treatment discontinuations at the higher 180 and 240-milligram doses up to 36 weeks. In the ACCESS open-label extension and the body composition study, the data show a clinically meaningful improvement in tolerability, dosing started at 2.5 milligrams.

And importantly, this improved tolerability persists as we escalate to 5 milligrams compared to when we start dosing at the 5-milligram dose. Furthermore, when we start the titration phase of the study at 2.5 milligrams per day, we see no discontinuations due to AEs. To date, up to approximately 10 weeks, a period when most others see most of the discontinuations due to AEs in the GLP-1 class of medicines. Now turning to safety. To date, more than 500 patients have been treated across all studies with aleniglipron. Patients have had up to 44 weeks of exposure and up to 240-milligram dosing over 36 weeks. Among all of these patients, we have seen no events of drug-induced liver injury.

I want to take a minute to pause and repeat this really important safety results. Among all these patients, we have seen no events of drug-induced liver injury. There have been no off-target safety signals across all dose levels and no events of QTC prolongation. I'll now turn the call over to Dr. Blai Coll, our Chief Medical Officer, to walk you through the details of the top line data we are sharing today in the beautiful weight loss curves.

Thanks, Ray. And I'm very pleased to share the data of the aleniglipron program today centered around ACCESS, the large Phase IIb assessing efficacy, safety and tolerability of doses of aleniglipron up to 120 mg for 36 weeks. In addition, we'll offer compelling and differentiating data insights into 3 of the most important questions for treating patients for chronic weight loss. Number one, are there any signs that weight loss is plateauing beyond the 36 weeks from our Phase 2b ACCESS study? We will provide data from the ACCESS open-label extension study to address these questions.

Number two, can we dose higher than 120? And what additional efficacy, PK exposure and tolerability do we observe? As you know, we specifically designed ACCESS 2 to explore doses up to 180 and 240 mg, and we're pleased to share the top line at 36 weeks today. And lastly, tolerability is associated with the starting dose. So we wanted to explore if a lower 2.5 mg starting dose would further improve the tolerability of aleniglipron. We explored this in 2 different studies, and we'll share data from the body composition study and the Phase 2 ACCESS open-label extension, both starting at 2.5 milligrams.

We have generated a compelling set of clinical trial data from 4 studies, the top line of which will be presented today. The totality of this data provides clear and unambiguous evidence that supports the further development of aleniglipron in a Phase III program for a chronic weight management indication. Let's dive into the data now with our core set for alenigipron, the randomized controlled Phase 2b ACCESS study. 230 participants with a body mass index equal or greater than 30 or 27-plus weight-related comorbidities were enrolled in 36 participating sites across the U.S. Participants were randomized to 3 different arms of aleniglipron with doses of 45, 90 or 120 versus placebo. The starting dose was 5 milligrams with 4-week titration steps to achieve the target dose of each cohort.

The primary endpoint was the percentage body weight reduction from baseline to week 36 based on the primary efficacy estimate, and we will also report today key secondary endpoints. It is important to note here that the ACCESS study used an e-diary, which was done to support the participants in the study. A e-diary prompts patients to report specific adverse events on a real-time basis as opposed to an unsolicited reporting of symptoms. There is a well-recognized reporting bias associated with the use of e-diaries and the team prioritized the use of the e-diary for patient support, knowing that this may have increased the risk of overreporting as has been previously described.

Because clinical sites were notified regularly of patients with symptomatology, the sites had the option to reach out to the participants and provide further guidance on diet, adjustment to the study drug or symptomatic treatment based on their response. In Slide 12, we summarize the baseline characteristics of the participants, which are very consistent across study arms. Age range from 49 to 52 years, predominantly female, 53% to 55% with a baseline BMI of 39. HbA1c and blood pressure according to the eligibility criteria within normal limits. This population, in summary, adequately represents participants living with obesity or who are overweight with weight-related comorbidities.

So let's review the key efficacy findings in ACCESS. We are very pleased to report a clinically meaningful body weight reduction in those participants receiving aleniglipron. As shown in the graph, there is a clean and swift separation of the curves starting at week 4 and continuing until week 36 with a clear dose response showing a 9% body weight reduction for the 45 mg group, 10.7% for the 90 milligram and 12.1% for the 120 milligrams. Importantly, without any signs of weight loss plateauing. These findings translate into a significant reduction in absolute body weight ranging from 23 to 30 pounds, achieving a highly statistically significant difference compared to placebo at 8.2% reduction for 45, 9.8% for the 90 milligrams cohort and 11.3% for the 120 mg cohort.

These results are consistent with the percentage of participants achieving different thresholds of weight reduction at the end of week 36, shown in the next slide. As you can see, more than 70% of the aleniglipron-treated participants achieved at least 5% body weight reduction. In the 120 mg arm, 70% of participants lost at least 10% of their body weight and nearly 40% lost at least 15% of their baseline body weight. It's also worth noting that these significant changes in body weight were associated with substantial reductions in both systolic and diastolic blood pressure and initial reductions in HbA1c in a population without hypertension or type 2 diabetes.

Taken together, the results show aleniglipron achieved a compelling level of efficacy in a dose range from 45 to 120 at 36 weeks. And I would like to review now the tolerability in ACCESS. So in the next slide, we're showing the occurrence of nausea in the last panel, which peaked in the earlier part of the titration phase of the study. This temporal aspect of adverse events is an important concept that I would ask to keep in mind for a later section in our presentation today. The Y-axis shows the percentage of participants and the horizontal axis represents time with green, orange and red indicating the severity of the events.

Each one of the panels describe the arms in the study. And as you can see, we observed the peak in nausea around 20% occurring in the first weeks when the 3 groups of aleniglipron start at 5 milligrams. There is fluctuation over time with the vast majority of events being mild to moderate. And importantly, the number of events does not increase as participants are reaching the target dose and nausea remains below 10% all the way to the end of the study. It's also important to understand the adverse events that led to treatment discontinuation as indicated by the arrows in the slide. We observed an overall low AEs leading to treatment discontinuation of 10.4% in ACCESS. And importantly, a large majority, 2/3 of those discontinuations occurred within the first 12 weeks of the study with a 4-week starting dose of 5 milligrams, then going to 15 milligrams for 4 weeks before reaching 30 mg of aleniglipron.

On the right-hand side of the slide, we summarize the events of vomiting, where you can see a scattered occurrence of events with a prevalence also below 10% throughout the study for the 3 aleniglipron arms. Consistent with the findings on nausea, we do not observe an increase in vomiting as participants complete the titration steps and reach the target dose through 36 weeks. To summarize the tolerability of aleniglipron in ACCESS, we see treatment-related discontinuations of 10.4% in the participants receiving aleniglipron. It's important to note that the vast majority of participants in the treatment arms completed the study on treatment, ranging from 73% to 78% compared to 75% in the placebo group.

The study shows treatment discontinuations due to adverse events ranging from 7.7 to 13.3 without a clear dose response, similarly to what was observed for the most commonly reported adverse events listed in the table. The lack of dose response may be due to the events accumulating in the beginning of the titration phase where the 3 arms share the same dosing. And as mentioned in the design slide, the use of the e-diary should be taken into account in the interpretation of those results. To summarize our core Phase IIb ACCESS study, aleniglipron shows compelling efficacy from 45 to 120 mg with body weight reduction ranging from 8.2% to 11.3%, respectively, without signs of plateauing up to week 36.

We have observed the expected gastrointestinal-related events as known by the class of GLP-1 receptor agonist with a manageable profile that achieved an overall 10.4% treatment discontinuation. Let's move now to the first question of the 3 exploratory initiatives we want to share data with you today. As you know, there is intense interest by doctors, payers and patients in when a particular drug reaches a plateau in efficacy. So we use the data from the ACCESS open-label extension to ask the question, is there a weight loss plateau for aleniglipron beyond 36 weeks? In Slide 19, we described the design of the ACCESS OLE, where participants in the 45-milligram arm in the double-blind portion of the ACCESS study were titrated to 60 milligrams for 4 weeks and then 90 milligrams.

The 90 and 120-milligram arms of ACCESS continue in the OLE at 120 mg and those on placebo started at 2.5 of alenglipron during 4 weeks and were up titrated to 5. The ACCESS OLE study is still ongoing and will provide additional longer-term safety and efficacy data while providing access to drug for patients. Today, we report interim data from 143 participants that represent the majority of the eligible participants at week 36 up to 8 weeks after the rollover from the ACCESS study. In the next slide, we show the summary of the efficacy observed where the participants who were on placebo in the ACCESS study started their dosing in the OLE at 2.5 milligrams and were titrated to 5 mg. They experienced a clinically meaningful 3% body weight reduction at the end of the first 8 weeks.

Additionally, and to answer the question of a plateau, participants in all dose cohorts previously treated with aleniglipron continue to experience additional body weight reduction ranging from 1.1% to 1.3%, indicating no weight loss plateau after 36 weeks. Let's now move to the second exploratory question. Can we dose higher than 120 milligrams? And what would be the impact on efficacy, exposure and tolerability. For that, we designed our ACCESS 2 study, and we're very excited to share this data with you now.

The exploratory Phase II ACCESS 2 study originally enrolled 85 participants in 2 sites across the U.S. 12 of these participants were part of a Sentinel group, which aim to provide preliminary data to the independent data monitoring committee regarding the 180 milligrams a day dose before moving to higher doses in the main study group noted in the second row of the study schema. This main study group included 73 participants, 61 allocated to aleniglipron and 12 to placebo. In ACCESS 2, the starting dose and titration steps were the same as in ACCESS starting at 5 milligrams. At week 28, the remaining participants at 120 mg of aleniglipron were rerandomized to 3 groups. One group stayed on 120, the second titrated to 180 milligrams and the third group titrated to 180 milligrams for 4 weeks and ultimately reached 240 mg.

We report data from the prespecified analysis at 36 weeks today. The study is still ongoing and will complete at 44 weeks. Slide 23 summarizes the baseline characteristics, which are comparable to ACCESS with an average age around 50 years old, predominantly female participation with a baseline BMI ranging from 36 to 39.9. In the next slide, we're excited to present that very meaningful greater efficacy was achieved with higher doses of aleniglipron above 120. Consistent with the results of our core Phase 2b ACCESS study, here, we see a clear separation of curves from placebo from the beginning of the study with body weight reductions continuing to week 36 and with no signs of weight loss plateauing.

It's interesting and very reassuring to point out that with both ACCESS and ACCESS 2 studies at 120 milligrams of aleniglipron, we see consistency in the body weight reduction at week 28 at around 10%. Let's now zoom into the box at the lower right-hand side of the graph to see what happened after the rerandomization when patients were up titrated to 180 or 240 mg. Where you can see in the left panel, the participants continuing on 120 after the rerandomization phase achieved a 13.1% body weight reduction from baseline. And the 2 groups exposed to 180 showed directional separation at week 32. Importantly, those participants that titrated up to 240 experienced an even greater body weight reduction, reaching 14.2%.

Translating this to placebo adjusted numbers, the 120 dose achieved a 14.1% body weight reduction, 14.4% for the 180 and 15.3% for the top dose at 240, which corresponds to 35.5 pounds of weight loss at week 36, highly statistically significant and clinically very relevant. Importantly, we observed proportional dose exposure with aleniglipron up to 240-milligram dose, reinforcing the dose response seen in body weight reduction between 120 and 200-milligram groups and indicating the remarkably wide effective dose range of aleniglipron observed to date. Let's transition now to the tolerability profile of aleniglipron in participants receiving higher doses. In Slide 26, in the left panel, we show the occurrence of nausea during the first 28 weeks in the study before rerandomization with a target dose of 120 mg.

In the panel on the right, we show the occurrence of nausea after rerandomization from 120 to 180 to 240 and placebo. We observed fluctuations in nausea in the first phase of the study with a slight increase in events while participants titrate to 120 mg and the events attenuate over time. As seen in the panel on the right, only 2 participants who titrated from 120 to 180 milligrams showed intermittent events between weeks 33 and 36. Very importantly, all of the discontinuations due to adverse events happened during the titration phase from 5 milligrams to 120 as indicated with the arrows, with approximately half of the discontinuations occurring in the first 12 weeks of initiation as consistent with the ACCESS study.

No discontinuations due to adverse events occurred in participants who were up-titrated from 120 to either 180 or 240. In the next slide, we're summarizing the events of vomiting that followed the similar temporal pattern with a far lower number of participants reporting events less than 15% throughout the study. And with 1 participant in the higher dose phase at 120, no patient in the 180-milligram group, top right quadrant and only 1 participant in the 240-milligram group in the lower left quadrant reported intermittent vomiting events between weeks 33 and 36. To summarize the tolerability in ACCESS 2, we observed 17 participants discontinued due to adverse events during the titration phase from 5 to 120 milligrams at 27%.

11%, 18% discontinued due to other reasons, non-adverse event related and 6 participants remain on aleniglipron at a dose lower than 120. It is worth noting here the number of discontinuations being higher than in ACCESS. As we have described, these are different studies, the presence of the OLE in ACCESS as an example, with also different clinical sites where variability can be expected. But importantly, we see a similar trend of accumulation of both gastrointestinal events and discontinuations in the first titration steps of the study. The most critical question in ACCESS 2, though, was the tolerability once participants reached higher than 120 mg doses, and the study did not observe discontinuations during the 180 and 240 dose phase, which is very promising data.

Similarly, the most commonly reported gastrointestinal events declined in frequency as participants move to the higher dose phase. In summary, we are very pleased with the results of ACCESS 2, answering the additional activity of aleniglipron at higher doses than 120, with directionality in efficacy up to 240 with 1.2% additional body weight reduction after 4 weeks compared to 120 mg associated with proportionality in exposure and very importantly, with a tolerability profile once participants reach 180 and 240, showing no discontinuations of treatment due to adverse events. And that brings us to the last question.

In next slide, will a lower 2.5 milligram starting dose further improve tolerability of aleniglipron? As you have seen from our core Phase 2b ACCESS study, there is a pattern of peak incidence for both nausea and vomiting observed in the beginning of the 5-milligram dose. And in both studies, ACCESS and ACCESS 2, the majority of treatment discontinuations occur in the first 3 titration steps up to 30 milligrams. With that in mind, we pose the question, if we started lower and went slower, dosing at 2.5 instead of 5, would we observe a further improved tolerability profile. We collected data from 2 studies in which we started dosing at 2.5, our Phase 2 body composition study and our ACCESS open-label extension study.

Next slide, we describe the designs of the open-label extension on the left, where the participants on placebo during the double-blind treatment phase transitioned to 2.5 milligrams of aleniglipron for 4 weeks before escalating to 5 milligrams. The body composition study on the right enrolled 71 participants with similar eligibility criteria to the previous studies done in 11 sites in the U.S. In this study, 59 participants have been randomized to aleniglipron at a starting dose of 2.5 milligrams compared to 5 starting dose in ACCESS and ACCESS 2 and 12 participants to placebo. We will report today the results from a prespecified analysis after a median follow-up of approximately 10 weeks.

Baseline characteristics are consistent with previous studies, participants in the mid-50s, predominantly female with a body mass index between 38 and 39. In the next slide, we describe the occurrence of nausea. We report comparable results of nausea between the 2.5 milligram starting dose and the placebo group and below 10% and also sporadic events of vomiting at the 5-milligram a titration with no discontinuations of treatment due to adverse events after a median follow-up of approximately 10 weeks.

To summarize the tolerability, in this slide, you can see a vastly lower incidence of nausea and vomiting when we started the 2.5 mg dose of aleniglipron and remarkably, and unlike our experience in ACCESS or ACCESS 2, we observed no treatment discontinuations in the first 10 weeks of dosing. We find this result very encouraging. To summarize the tolerability of the lower 2.5 starting dose versus the 5-milligram starting dose, we want to take the opportunity to put all the pieces together in this slide and walk you through the cross-trial comparison on the impact of different starting titration doses on the tolerability of aleniglipron. We plot in the graph the occurrence of nausea in the blue bars and vomiting in orange bars across the studies displayed in the horizontal axis.

Starting from the far left with ACCESS, 22% of participants reported nausea in the first 4 weeks when starting at 5 mg and 6.9% experienced at least 1 event of vomiting. Those results were consistent with ACCESS 2, also starting at the same 5-milligram dose and reporting 21.1% and 11.3% of nausea and vomiting, respectively. Conversely, when we analyze the results from the ACCESS open-label extension participants shown in the middle panel, we see minimal nausea, 5.7% and no vomiting in participants starting at 2.5 mg and no events in weeks 5 to 8 when they were up titrated to 5 milligrams. In the panel on the right, we show the results from our body composition study in which we took the opportunity to start all participants at 2.5.

We report 15% of nausea and 1.7% of vomiting in the first 4 weeks, decreasing to 6.5% and 4.3% of nausea and vomiting, respectively, when participants up titrated to 5 mg. Most important and unlike in ACCESS and ACCESS 2, there were no treatment discontinuations in the first 8 weeks of dosing. And recall that the 2.5 milligram dose is meaningfully active in terms of weight loss, as we've shown in the ACCESS open-label extension study. Based on the observations that the 2.5 starting dose is active and starting titration with the 2.5 results in further improvement of the tolerability profile, we plan to initiate the Phase III program on all future studies at the 2.5 milligram starting dose following the approach of start lower and goes low.

Lastly, we want to spend the next slide to highlight an important aspect of the program that is the off-target safety data. In Slide 36, we describe the events of liver enzymes fluctuations seen in the 4 Phase 2 studies described today. As Ray mentioned, we have no cases of drug-induced liver injury, no increases of 10x the upper limit normal and infrequent fluctuations in ALT, AST, 3 and 5x upper limit normal distributed across different arms, including the placebo without a clear dose response. It is important to remark that those participants experiencing elevations in liver enzymes, continuous study drug and ALT/AST returned to the baseline values.

For a drug that is potentially going to be taken by millions of patients chronically, we interpret these results as highly encouraging, indicating a safe liver profile with aleniglipron. To wrap up, we covered a lot of ground this morning, so I want to spend some time summarizing all the findings from our Phase 2 program. In regards to efficacy, we demonstrated statistically significant and clinically highly relevant body weight reductions achieved with 3 doses in ACCESS up to 11.3% placebo adjusted for the 120-milligram arm. Exploring higher doses up to 240 milligrams yielded directional meaningful additional body weight reduction up to 15.3% placebo adjusted for the 240-milligram arm.

Importantly, there are no signs of the activity leveling off up to 44 weeks, and we have observed clinically meaningful improvements in both blood pressure and HbA1c. We observed proportional exposure with aleniglipron, indicating a high degree of dose optionality from 45 to 240 of aleniglipron moving. For the tolerability, aleniglipron showed the expected gastrointestinal-related events consistent with the mechanism of action of the GLP-1 receptor agonist. We observed an overall 10.4% treatment discontinuations due to adverse events in our core Phase 2b ACCESS study. Despite a higher discontinuation rate in ACCESS 2 when exploring higher doses of aleniglipron, we see only slight increases in nausea and vomiting.

But importantly, those events were manageable and did not trigger treatment discontinuations in the 180 or 240-milligram dose cohorts of the study. And lastly, we observed clinically meaningful improvements in all tolerability parameters when we started dosing at 2.5 of aleniglipron and unlike in ACCESS and ACCESS 2, there have been 0 AE-related discontinuations observed to date, which critically informs the design and titration regimen for the Phase III clinical development. To complete the summary, with more than 500 participants dosed with alenglipron up to 44 weeks of exposure and top dose of 240, we are very pleased to report no events of drug-induced liver injury, no off-target safety signals and no events of QTC prolongation.

To conclude, we would like to summarize the results that position aleniglipron Phase III ready. We assessed the efficacy, safety and tolerability of aleniglipron in the ACCESS study. And based on the data to date, we answered the 3 additional questions. No weight loss plateau, dose response activity confirmed up to 240 and clear tolerability improvements starting at 2.5. Those 3 pillars robustly inform the aleniglipron Phase III program to pursue a chronic weight management indication. And as indicated in the bottom of the slide, we've already completed the API manufacturing and the drug product manufacturing is well underway for an anticipated mid-2026 FPI. With that, let me turn it over back to Ray.

Thank you, Blai, for the exciting and very strong results shared today. From the data that you've seen presented, aleniglipron is differentiated and has the potential to be best-in-class oral GLP-1 small molecule. The totality of the data presented today provides substantial evidence that aleniglipron is a compelling medicine with best-in-class potential for activity, best-in-class off-target safety and favorable tolerability with the 2.5 milligram starting titration dose. As such, we believe aleniglipron is well positioned to capture a significant portion of the growing chronic weight management market.

In particular, I'd like to highlight that according to our market research, the biggest growth opportunity for oral medicines for obesity is with the primary care physicians or nonspecialists. What they're looking for are options that are effective, convenient, flexible in dosing and accessible to their patients. Oral small molecule pills manufactured at a global scale represent a new option to meet these unmet needs for the growing number of nonspecialist prescribers. However, aleniglipron is only one piece of the portfolio we are building here at Structure Therapeutics. We have the goal to build a broad oral small molecule metabolic portfolio. In addition to aleniglipron, I'm excited to highlight the current status of our amylin program.

We now have 2 amylin-targeted molecules, ACCG-2671 and ACCG-3535 that are in development. ACCG-2671, we're pleased to announce that the IND has been cleared by the FDA and Phase I initiation is well underway. We believe that ACCG-2671 is the industry's most advanced oral small molecule amylin receptor agonist. For our second-generation DACRA, the development candidate, ACCG-3535, was selected last month. We view aleniglipron and our amylin molecules as foundational backbone molecules that can be combined with our portfolio of other oral small molecules. In addition, we have programs underway to combine these 2 backbone molecules with our GIP and glucagon receptor oral small molecules in discovery.

Beyond obesity, we're evaluating potential indication expansions for these molecules in a chronic kidney disease, NASH, hypertension, heart failure, sleep apnea, type 2 diabetes, osteoarthritis and addiction. 2025 was a very successful and productive year for Structure Therapeutics. We have a strong and broad portfolio of obesity-related oral assets. As you've heard today, we now have 5 different studies for aleniglipron. As mentioned, we anticipate being ready to move into Phase III development by mid-2026. Our lead amylin program is moving into the clinic, and we're also very excited about our combination opportunities with our GLP-1 and amylin combination pill entering IND-enabling studies and continuing progress in our discovery research on GIP and glucagon.

As we wrap up our prepared comments, I'll highlight our upcoming catalysts for 2026, building on the accomplishments from 2025. In the first 6 months of 2026, we'll have our end of Phase 2 meeting with the FDA. You will see our top line results for our ACCESS open-label extension study, ACCESS 2 extension study and our body composition study. In the summer of 2026, we plan to be ready to initiate the pivotal Phase III studies. In the second half of 2026 for aleniglipron, you will see top line results from our SWITCH study investigating the safety and efficacy of switching patients from an injectable selective GLP-1 receptor agonist to our oral aleniglipron for weight maintenance. We also expect to share top line results for our studies in patients with type 2 diabetes plus obesity at higher doses than we previously studied in type 2 diabetes to support Phase III and label inclusion.

Turning to our amylin franchise. In the second half of 2026, you'll see our initial oral amylin ACCG-2671 Phase I study results and the initiation of our second oral amylin ACCG-3535 into the clinic. As a closing remark, I want to thank all Structure Therapeutics employees for the years of hard work and dedication in developing aleniglipron as well as our clinical investigators for their partnership. Most importantly, we extend our deepest gratitude to the more than 500 participants who have enrolled in our aleniglipron clinical program to date. Their trust and commitment are essential to advancing this medicine and to fulfilling our mission of making medicines more accessible to all. Aleniglipron has tremendous potential to change lives, and we look forward to advancing aleniglipron into Phase III and beyond. I will now open the call for Q&A.

[Operator Instructions] Our first question will come from Evan Seigerman with BMO Capital Markets.

I would really love it if you could talk through how you think about the PK properties of aleniglipron and how that might have contributed to both the efficacy and tolerability that we saw today. Specifically, what do you think is driving the higher efficacy that we're seeing here versus some of the other competitors in the oral small molecule space? And maybe any nuances with the product's half-life that could contribute to higher GI symptoms, trying to optimize that access as you think about Phase III.

Thank you, Evan. This is Blai. I'll take the call. So we're very pleased with the PK profile. As we've shown in the slide and in the presentation, we are seeing proportional exposure when compared to 120 milligrams versus 180 and 240, and that's a clear differentiation element from aleniglipron. And that's also consistent with the directionality in the additional body weight reduction that we've seen with just 4 weeks of exposure to 240. So those 2 pieces of data are very closely related. We see higher and proportional exposure between 120 and 240. And with a limited period of time of doses up to 240, we see the directionality in additional body weight reduction.

So we're very, very pleased about the results of ACCESS 2 on that end. You're mentioning the PK characteristics and the half-life. I think this data set once again demonstrates that we have a once-a-day orally available small molecule, highly efficacious and a very competitive profile. Thanks for the question, Evan.

Our next question comes from Seamus Fernandez with Guggenheim.

Congrats on the data. It looks like the 2.5 milligram dose has really helped to resolve some of the early tolerability issues that you see emerging. Wanted to just get your sense of how you would hope to advance into your Phase III clinical program. Is it obvious -- it seems obvious to us that 2.5 milligram dose is resolvable there and should be utilized. I guess the other question is, as you sort of plan for Phase III, how do you think about the dose range that should be explored as you kind of pursue the additional data? Do you need the 44 weeks to really decide on the top dose from your perspective? Or do you feel good that a 90, 120, 180 feels like the right profile. It looks like they're pretty tight in terms of their sort of dose response relationship.

And then just a final question. It's only 10 weeks' worth of data with the 2.5 milligram dose, but can you just provide maybe a simple order of magnitude reduction that you're seeing in the frequency of vomiting and nausea.

Thanks, Seamus. So we'll go one by one. So we completely agree with the 2.5. I think the data is very, very clear by starting at 2.5 and remaining at 2.5 for 4 weeks. It abates the majority of the adverse events that we saw by starting at 5 milligrams. So I think the data set is very, very clear and point in that direction for starting the newer studies, including the Phase III. In terms of the top dose, whether we go to 180 or 240 for Phase III, I think the important bottom line data here is that we have full characterization of efficacy and tolerability starting at 2.5 all the way to 240 milligrams. So that gives us the flexibility and the optionality to design what's the best dose for the Phase III. We'll have that option.

We just got the top line results. So we need to go through the full data and also continuing with the modeling work to define the doses for Phase III. But it's really, really positive and encouraging to see that full characterization from the 45 milligrams in the low end all the way to 240. And then the third piece of your question, you're mentioning the 10 weeks and how that translates into improvements in tolerability. We did not see any event of discontinuation, up to 10 weeks in the body composition. And there's no events of discontinuation of the study drug in the open-label extension either.

So those 2 are very clear indicators. And then when you compare the 5 milligrams with the 5 milligrams, so when you compare the 5 milligrams of the body composition or the OLE compared to the 5 milligrams ACCESS, ACCESS 2, we see more than half reduction in both nausea and vomiting, which is also very, very encouraging preliminary results. So in summary, we're very pleased with the starting dose at 2.5, and we're also very pleased to have full characterization all the way to 240.

Our next question comes from Terence Flynn with Morgan Stanley.

I guess the first one I had is there were some reports that the FDA could move to single Phase III trial for approval. So just wondering your perspective on that, Ray, as you think about the scope of the Phase III program. Obviously, you have some time here. And then the other question is just, can you remind us about the switch study that you're conducting and what you're hoping to show in that? It sounds like you're using GLP -- injectable GLP, not GLP/GIP, but just wanted to confirm some of the metrics there and what the goal of that study is.

Thank you, Terence, for the question. I'm going to hand this question over to Blai.

Yes. Thank you. So the single Phase III trial, this is an intriguing concept. Of course, usually the guidance that the FDA issued back in January, we're still talking about the 3,500 participants on exposed to dose at least for 52 weeks and 1,500 on placebo. That's the most recent update from the FDA. Now whether this can be executed as one single clinical trial or 2, that will depend as well on the future discussions that we're planning to have with the agency in the first quarter of next year. In terms of the Switch, we're very excited about the Switch study. It's an ongoing study. And what we want to interrogate that study is exactly on 2 questions.

One is what is the right dose to transition from an injectable into aleniglipron because that has never been explored before, and we need to generate that data. But then second, also very, very important is how well are maintaining our body weight reduction up to 12 weeks after the transition. So these are the 2 questions. The study, as I said, is ongoing, and we're very excited about the prospects of that strategy.

Terence, I would also add, I view it as a very positive sign. The action that's being taken by the current administration in regards to recognizing the importance of GLP-1s and Structure Therapeutics is very well positioned, given our oral small molecule cost of goods, our manufacturing capabilities and even the signaling that we're getting from the FDA with their recent guideline update with further clarity. So I think all of this bodes very well for developing aleniglipron into the market.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Congrats to the data and really thorough presentation. I guess, team, as we think about starting with 2.5 and then going to 120 and potentially even 240, what do you think could we achieve the same weight loss magnitude that you guys shared with us across ACCESS 1 and ACCESS 2? Just wanting to understand, could we end up at the same weight loss magnitude by just stretching and going slow over longer durability? And this is specific to the OLE study that's ongoing. So if you could share your thoughts around what we hope to see at week 28 when we get to the 90 mg dose group, that would be helpful.

And then the second one is a clarification. do you need to see the 2.5 milligram OLE data before you finalize your Phase III development? And how are you thinking about titration schedule?

Thank you, Yas. So it's Blai. I'll take that again. So starting at 2.5 and going to 120 or 240, I think there's a piece of information there that is very, very critical that we see preliminary signs of efficacy by starting already at 2.5. And I think this is very, very important because, of course, that can help control the discontinuations of some of the placebo participants in the beginning of the study. But most importantly, it provides the opportunity to have a healthy body weight reduction, especially in the beginning and during the titration phase. And so that's really, really relevant, and we're very pleased with the data that we have so far coming from the 2.5.

In regards to your second point, the need of CV OLE before starting the Phase III, that's not a necessary step. So we're good to go to start with the identification of the doses that we want to move forward into Phase III. And as I indicated, to have a meaningful interaction with the agency in the first half of next year to position the program Phase III ready.

And yes, one of the things that we did a number of years ago was when we were doing our research with physicians about what did they want to see in terms of GLP-1 medicines, every single time, the first word out of their mouth was dose flexibility. That because of the demand, they wanted to have as much flexibility as possible with their patients. And we think aleniglipron is really well positioned with this very broad dynamic range from 2.5 milligrams all the way up to whether they go to 90, 120 or 240 gives us -- gives physicians a really good opportunity with dose flexibility.

Our next question comes from Samantha Semenkow with Citi.

Congratulations on the data this morning. Just a bit of a clarification. So the body composition study, can you just share a bit about that patient population, how it compares to the patients enrolled in ACCESS and ACCESS 2? I'm wondering just how similar is it that we can really extrapolate the tolerability data that you shared to a potential Phase III study population. And then just a second question. When we think about a potential partnership or acquisition for aleniglipron, can you talk about how we should think about the oral amylin assets potentially fitting into this conversation?

Blai, you take the first part?

Yes. I'll take the first part. So the baseline characteristics are comparable, Sam. The eligibility criteria was also very, very similar between the studies and all of them have been done here in the U.S. And so average age is around 54, 48 in the body [indiscernible], predominantly female, 64% to 66% of female participation and baseline body mass index between 38 and 39. So pretty comparable and then normality in terms of HbA1c and the rest of the baseline characteristics.

And Sam, in regards to your second part of your question in terms of strategics and the way that we view this, we've been building a very strong and broad portfolio of our aleniglipron, our amylin franchise as well as the other molecules. And so it's really -- we have, I think, a very strong portfolio. With this data now in hand, we'll continue having that dialogue with strategics.

Our next question comes from Dave Risinger with Leerink Partners.

Let me add my congrats as well to you, Ray and the team. So just to follow up on that last question. Could you provide a little bit more color on the potential for partnering discussions, including the potential time line? Obviously, there's a lot of data to go through, but any additional color would be helpful. And then since others are asking an additional question, I'll ask one more, which is, Blai, could you talk a little bit more about the use of patient e-diaries and contrast that with how competitors have conducted their trials?

Blai, do you want to take the second part, and then I'll take the first part.

Sure. Thanks, Dave. So yes, the use of e-diaries is not very commonly instituted in this field. We wanted to do that because we wanted to prioritize the patient journey and making sure that we have the adequate support for those participants. The difference there is that we're proactively asking the participants about their symptomatology on a real-time basis. And that, of course, has the potential to overinflate the incidence of those events that you've seen in the table. There are other studies that have done that. And so if we compare, for instance, the reporting of nausea in the placebo arm when you don't use an e-diary, it's around 10%.

Compare -- contrasting that to those studies that use an e-diary, we're seeing around 20% of placebo event rates for that symptom specifically. And I'm just using that as an example. And we can use that as a proxy to indicate that we're seeing doubling the events by proactively asking instead of just not reporting [indiscernible]. So that's the decision that we made again because we wanted to have a full support to the participants in the study.

And Dave, in regards to your first question, these data are clearly very, very strong. We have a very safe drug in terms of off-target safety, best-in-class efficacy, a clear path for Phase III dosing for tolerability. A clear path for Phase III and to market, excellent manufacturing. I mean one point that we didn't stress on this call because there was so much data, but our ability to manufacture this, we can manufacture 6,000 metric tons enough for 100 million patients per year. We really have a solution at a very large scale. So with all of this in hand, we're looking forward to continuing discussions with strategics now that we have this data. We know everybody has been waiting.

Our next question comes from Roger Song with Jefferies.

Congratulations. Maybe at this point, a little bit kind of final question. First is, I think you mentioned most of the AEs in the first couple of cycles. Can you just give us a little bit of number on the percentage AE in the first 8 weeks and 12 weeks? Because you give us the 2.5 starting dose and then just try to estimate how much lower the AE for the 2.5 milligram starting dose. And then also in your ACCESS 2, the discontinuation due to AE go up quite a bit compared to ACCESS. Maybe that's due to the small end, maybe the open-label extension. Maybe just give us a little bit context there. How should we think about this 27.9% versus 11%?

Thanks, Roger. I'll take the first one. So the data on the 12-week in the body composition or the OLE, we're still -- those 2 studies are still ongoing. We have a median duration up to 10 weeks. But of course, that enrollment has been scattered. And so we're continually collecting the data. I think it's really encouraging, though, to see the differences between the first 4 weeks and the second 4 weeks while titrating to 5 milligrams. And as we've indicated, the fact that we don't have any discontinuations and that there's approximately half drop in the adverse events, I think it's really, really encouraging. Differences between ACCESS 2 and ACCESS.

Yes, there are differences. These are 2 different studies. We use different clinical sites. We use an open-label extension in ACCESS. We didn't do that in the exploratory ACCESS 2 that it goes to 44 weeks. And those things may play a role explaining that variability that we're seeing in -- between both the studies. The most important thing, though, when looking at the adverse events is that both the studies share a commonality that is an aggregation of both the tolerability events and the AEs leading to discontinuation in the beginning of the study, starting at 5, going to 15 and going to 30. And so that's the powerful insight there because then if you couple that with the data that we have starting at 2.5 the next step is very, very clear to start at 2.5, so we can mitigate that initial tolerability and the initial discontinuations. Thanks for the question. This is a very relevant topic.

Our next question comes from Prakhar Agrawal with Cantor.

Congratulations on this comprehensive update. So maybe just I had 2. Firstly, on the Manhattan plots on the time course of the nausea and vomiting that you provided. If you can just put it into context versus what aleniglipron showed on the prevalence chart and how persistent were these nausea vomiting events, especially towards the latter part of the trial? And just a quick clarification. The efficacy results are efficacy estimate. I know you will be presenting the IDT details sometime later on, but if you can qualitatively comment on how close the IDT data were tracking relative to the efficacy estimate and these readouts?

Blai, we're going to keep this answer short. And I'm going to remind everybody, we really need to have one short question because we're -- markets are open and we're over time.

Thanks, Prakhar. So talking about the Manhattan plots versus other compounds, the most important thing here is that the trend that we're seeing that we peaked in the first 4 weeks. And that's again, starting at 5 milligrams. And that's, again, coming back to the start of 2.5 that we're seeing a dramatic difference and a dramatic improvement. Compared to others, it's always very challenging to have cross-trial comparisons, as you well know, we don't have the same display from that molecule that you mentioned in the Phase 2b, where they composite the 4 events. But most importantly, I think what we're seeing here in terms of a peak in the beginning at 5 milligrams and then attenuating over time. That's very consistent.

In terms of efficacy, we've reported the primary efficacy estimate as indicated in the slides. We do not anticipate a lot of changes with the treatment estimate because the majority of the participants are still on treatment and in the study. But what we reported today, just to clarify is the primary efficacy estimate.

Our next question comes from Hardik Parikh with JPMorgan.

Just one high-level one for me. From a competitive positioning perspective, how do you look at this data when you take into context both aleniglipron ahead of you and then also some other oral small molecules in clinical development alongside you?

Thank you for the question. We're very pleased. We think we're in a great position. We believe that we are potentially best-in-class. The efficacy is very, very strong. The safety profile is very, very strong. We have a solution on the tolerability with the 2.5 milligram start. And so with all this in hand, we think that we're in a really good position to take a significant market share in the GLP-1 space.

Our next question comes from John Wolleben with Citizens.

Based on what we know from other programs, the PK you're seeing in your modeling, when do you expect weight loss to plateau with aleniglipron?

John, good question. This is why. So we -- the most important thing is that we have not seen plateauing all the way to week 44. And this is something that is truly differential here. And the curves are remaining as of the -- some of the injectable data. And as you know, when you looked at the Phase III of those programs, the weight loss plateau usually seen in the 60, 62 weeks. And so up to 44 weeks, we're seeing a similar pattern. So the prospects are to emulate here what we've seen in injectables in the past. And the initial indications are pointing in that direction.

Our last question comes from Patrick Dolezal with LifeSci Capital.

Are there any learnings on the magnitude of HbA1c changes as it relates to the potential of aleniglipron in type 2 diabetes? I know we're just digesting the top line obesity data here, but would love to sort of hear how your thoughts are progressing as it relates to the potential of aleniglipron in follow-on indications.

Thank you, Patrick. Yes, we also mentioned in the slide, we see meaningful reductions in HbA1c. We're talking about a 0.3% reduction at the end of week 36. And take into account that, that reduction happens in participants in the study that are not participants diagnosed with type 2 diabetes, which I think it's highly, highly relevant, also aligned with a significant reduction in systolic and diastolic blood pressure along with the clinically relevant body weight reduction. And so I think this data is also very, very encouraging to explore indications in the future for type 2 diabetes participants. And as we announced as well, the study with type 2 diabetes and high BMI is also ongoing.

We have a question from the line of Corinne Johnson with Goldman Sachs.

How many titration schemes do you think based on the data you would like to take forward into Phase III? And I'm curious how you're thinking about the study duration that will be needed to fully elucidate that efficacy profile given sort of the number of steps that might be required to get up to the final dose?

Thanks, Corinne. Yes, I'll take that. So I think it's very clear that the starting -- the optimal starting dose is at 2.5. Also very clear that the 4-week titration is the way to go. Now the questions that you're asking rightfully so, it very much depends on how much we want to go high in dose and what will be the top dose that we will declare for the Phase III. We think it's important in a chronic therapy to take the time to titrate, make sure that the tolerability is optimized while we continue augmenting in the body weight reduction. Good questions. But again, as I said, it depends on how high do we want to go in terms of the top dose in the Phase III.

This question comes from Annabel Samimy with Stifel.

I guess I'm curious what -- if you observed any kind of durability issues for the patients who did not move into the OLE study, what kind of weight loss persistence did you see there? And what were the reasons for not moving into the open-label study for these patients?

Yes. Thanks for the question. So the efficacy that we've seen after starting the OLE, we've described that, and we're very pleased to see the initial body weight reduction in the placebos that transition over to drug and then in the 3 doses. In regards to the rolling over into the OLE, the vast majority of the participants completing week 36 transition over to the open-label extension, which speaks very, very highly about the interest in continuing the study in additional 36 weeks. And when I say vast majority, we're talking about upwards of 90% of the eligible participants at week 36 that signed up for the open-label extension.

That concludes today's question-and-answer session. I'd like to turn the call back to Ray Stevens for closing remarks.

Thank you all for joining us today. We look forward to keeping you updated as we advance aleniglipron into Phase III, our amylin program and our multiple combination programs. Have a nice day.

This concludes today's conference call. Thank you for participating. You may now disconnect.