Structure Therapeutics Inc. (GPCR) Earnings Call Transcript & Summary

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 ACES 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 Structured 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 address 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 ACIS 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 signals 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. Blake 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 RAMs, 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. CTX1 is a marker of a steplast 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 CTX1 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 the 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 enrodents. 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 ATCG-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 pool 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 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. Lean 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 range 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 over-interpret the magnitude of weight changes observed. However, the timing, direction and the persistence of the change provide encouraging signs of early target engagement and provides 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, CTX1 and bone-specific alphas are markers used with previous backgrounds to assess bone health. Interestingly, by day 2 after a single dose, mean CTX1 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 [ paeti ] 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 alphas at day 2. At this stage, we view both CTX1 and alphas 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 ACIS open-label extension. As published in Nature Medicine in June of this year, the ACIS 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 ACIS 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 ACIS study continued dose escalation and ultimately transition to 180 milligrams starting at week 60 or later. The placebo cohort of ACIS shown in the bottom of the schematic, crossed over to olenglipron at week 36 and began at 2.5 milligrams instead of the 5-milligram starting dose of the ACIS 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 ACIS trial in the 45, 90 and 120 mg arms included 28, 42 and 43 participants, respectively, and the 2.5 of olenglipron crossover included 38, and this group enrolled the lowest number of female participants, 47%. Mean baseline BMI range 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 ACIS study, the participants starting at 2.5 with a slow titration reaching 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 explore 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 ACIS 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 weight 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 doses 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 range 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 lowest low 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 the 151 open-label extension participants, there were no cases of drug-induced liver injury, no cases of his 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, the 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 of 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, a secondary endpoint among many others. We are very excited about the accomplished 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 Structured 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 accomplished 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 Sera 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 accomplished clinical trials, the associated aleniglipron clinical trials and the ongoing ACCG-2671 multiple ascending dose clinical trial. Our next wave of catalyst 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 the 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.

Great. 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 2371. 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 app 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 SARA, 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, you want to.

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 testimal 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 Daphros, 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, Yas. 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, Yas, 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? -- congrats.

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, calcitonin, also showing in Phase I and also in patients with osteoarthritis a significant reduction CTX1 and an increase in alph1's 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 amyloid 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 r 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...

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] kind. 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 DBI plans for 2671 are also ongoing, and we'll provide further details as the program...

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 this body weight reduction and then the dynamic changes in the 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 2627, 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. 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 ACCOMPLISH...

Our next question comes from Jon Wolleben with Citizens.