Good morning, and welcome to the Structure Therapeutics Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. In order to ask a question, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised today's conference is being recorded. I would 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 risk 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 8th, 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're making across our oral small molecule portfolio for chronic weight management and to make medicines more accessible to all. We have two 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. 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-naïve patients. This suggests oral medicines are not simply shifting patients from one treatment to another. They are 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, as we stated we would deliver in Q3, today we will focus on two 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 six-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. In 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 two 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 mg dose as designed into the phase III program. Importantly, this potential best-in-class efficacy was accompanied by improved tolerability with a 2.5 mg 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're 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 three 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 mg, 2 mg, 5 mg, and 10 mg cohorts with a 3 : 1 allocation to active treatment and placebo. The primary objectives in this first 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 mg through 5 mg cohorts and day 24 for the 10 mg cohort. We were pleased to not need to evaluate the 20 mg 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 ACCG-2671 completed treatment and the study. Mean age ranged from approximately 34 to 44 years.
Mean BMI was between 26 and 27 kg per square meter, indicating healthy participants not living with obesity, and women represented 50%-80% of the active dose cohort. Seven out of eight pooled placebo participants completed the study. Let's now review the pharmacokinetic properties of ACCG-2671. The pharmacokinetic profile of the molecule is well-suited for further development. We are sharing two PK curves here. On the left is the linear ACCG-2671 concentration time profile following single oral dose administration across the dose range of 1 - 10 mg for the first 24 hours, and illustrates the rapid absorption of ACCG-2671, with maximum concentration reaching approximately one to 1.5 hours.
On the right-hand side of the slide is the log ACCG-2671 concentration time profile over the whole sampling time to 504 hours for the 10 mg cohort and shows the similar elimination profile of ACCG-2671 across this dose range. Additionally, exposures were consistent with dose proportionality, and remarkably, ACCG-2671 shows a terminal half-life of approximately six 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. 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 mg, nausea and vomiting were reported in 80% and 60% of participants, respectively, and at 10 mg, all six 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 agonists, 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 inform our ongoing phase II study.
It is important to highlight the value of the data at 1 mg and 2 mg, 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 ACCG-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 ACCG-2671. At doses from 1- 5 mg, mean body weight change ranged from 0.1% to -1.2% and could be attributed to physiological variability. Interestingly, in the 10-mg 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 to 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 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 DACRAs to assess bone health. Interestingly, by day two after a single dose, mean CTX-1 had decreased by approximately 60% in every dose cohort of ACCG-2671, while the placebo group showed a slight increase.
As you can see in the spaghetti plot on the right, the response was rapid and broadly consistent across all dose levels of ACCG-2671, with values moving back toward baseline at later visits after a single administration. Additionally, the participants dosed with ACCG-2671 also experienced a 10.7% increase in bone-specific alk phos at day two. At this stage, we view both CTX-1 and alk phos as evidence of biological activity across all dose ranges, and together with the observations 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 three 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. Third, to explore bone biomarkers and explore the profile of ACCG-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 are 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 mg 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 dosage 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 three aleniglipron cohorts of the ACCESS study continued dose escalation and ultimately transitioned to 180 mg 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 mg instead of the 5 mg starting dose of the ACCESS study, followed by titrations every four 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 kg 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-mg arm, 14.4% in the 90-mg arm, and 16.2%, or 40.5 lbs, in the 120-mg arm that later transitioned to 180 mg. The two 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 are also pleased to see the substantial body weight reduction observed in the placebo crossover cohort, achieving 9%, or 22.7 lbs, 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 mg 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 two 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 mg all the way to 180 mg that informed the design of the phase III. Number two, achieving 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 summarize 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. 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 eight 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 is 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 mg 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 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 6-12 mm of mercury, and diastolic ranging from two to six. Additionally, participants on aleniglipron also experience a clinically meaningful reduction in waist circumference and up to 64% reduction in hsCRP. 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 four weeks to reach 120 mg, and the dashed green line indicates the OLE 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. Lastly, I want to bring your attention now to the far right end of the slide, where the dark cells indicate 180-mg 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 OLE study at target dose. 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 five. The gray section on the left represents the first 36 weeks on placebo, followed by the OLE 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 the 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. When on drug, indicated on the right of the slide, there was no accumulation of vomiting events.
Lastly, as designed, we had a limited time of exposure at 180, described in the efficacy slide. But importantly, a key message from the slide, continuous efficacy from 180 came without an increase in the incidence of vomiting events. Taking these two 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 mg 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 mg 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 zero through 36, shown by the light blue bars, participants started at 5 mg 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 mg 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 three 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 10 x the upper limit of normal. Six participants had ALT elevations of at least 3 x the upper limit of normal, and two of them reached at least 5 x. One participant had AST of at least 3 x 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 began 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 mg maintenance doses beginning at 2.5 with four-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 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 two 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 two 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 mg dose for 52 weeks of maintenance, compared with only eight weeks at the dose in ACCESS 2. 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 two 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. This roadmap 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 30th, 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 three 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 mg and going up to 180 mg. 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 are 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.
Thank you. Thank you, ladies and gentlemen. If you have a question or a comment at this time, please press star one one on your telephone. If your question has been answered or you wish to remove yourself from the queue, please press star one one again. We'll pause for a moment while we compile our Q&A roster. First question comes from David Risinger with Leerink Partners. Your line is open.
Great. Thanks very much, and congrats, Ray and team, and thank you for all of the detailed commentary this morning. Regarding the multiple ascending dose trial that we'll 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? Also comment on the planned additional assessments of calcitonin agonism. 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. Thanks very much.
I'll let Blai take the first half of that question, Dave, and then I will try to tackle the second part of your question.
Yeah. Thanks, Dave. Very excited about the ongoing Multiple Ascending Dose phase IIa for ACCG-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. I think that 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 the 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 ACCG-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.
Dave, in regard to your question about Lp(a), the recent data, I think that this is still ongoing study, 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. We think that that's a good combination of having both of those mechanisms together. That's why we believe GLP-1 and amylin as well, is a really good mechanism for improving cardiovascular health.
Thank you.
One moment for our next question. Our next question comes from Evan Seigerman with BMO Capital Markets. Your line is open.
Hi, guys. Thank you so much for taking my question, and congrats on both of 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 two 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? Thank you.
Thanks, Evan. I will take the question. We are very excited about this potential combination. We are on track to start a combination of the GLP-1 plus the amylin receptor agonist towards the end of the year. Thanks for raising that question on the combination based on the data that you have seen today. One common question is how are we combining a molecule with PK properties that are substantially different? It is 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 a cheapest steady state later than the GLP-1 receptor agonists, 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.
We are really, really excited about the prospect of that program.
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 add-on effects, so 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 two, and we can learn a lot from the injectables by combining our oral amylin while we pursue our fixed-dose combination studies.
Great. Thank you.
One moment for our next question. Our next question comes from Seamus Fernandez with Guggenheim Securities. Your line is open.
Oh, great. Thanks for the question. 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 mg dose is key. I think one question we are 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 mg. The second question really is, if I have one takeaway from your amylin data, it is 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. Also looking at the SAD, those look extremely comparable.
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 benefits, but perhaps may have a better tolerability profile, as we've seen with other programs? Then maybe just the 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. Thanks.
Hello.
Seamus, I'll start with your first question, and thanks for raising these. Yes, we're 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. We feel that maintaining those four-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 is the right sweet spot for the phase III. That's the answer to your question. We're 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. That on, aleniglipron, you want to-
Yeah. 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 in the execution. I think it's destined old execution by the clinical team. In regards to SARA, we're excited about the mechanisms. At the recent American Diabetes Association meeting, there was a session on amylin, and there was a highlight about the potential importance of DACRAs, 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. This is purely exploratory at this stage, but we think that that's an interesting opportunity.
We do continue to work on a small molecule, selective SARA amylin molecule, and we'll be updating on that further. Then in terms of IP, sorry. The IP question, yeah, 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. We have, I think, an even more, a stronger IP position around the amylin case.
Thank you. One moment for our next question. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.
Good morning, team. 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, how this product profile already looks versus other amylin programs in development. What differentiation do you see at this point? My 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 ACCG-2671 as you're embarking into your 12-week study?
I'll start with the answer to that question, Yas. Thank you for it. Blai, please fill in any other details. I think, the biggest differentiator, we're talking about an oral small molecule. The biggest advantages there is that what we hear, we've seen this tremendous growth in the uptake of oral medicines in this space. I think an oral pill is a key differentiator in the amylin space. Second, small molecules, 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?
Yeah. 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. Then seeing those three parameters of target engagement already on a phase I is highly encouraging, and that's part of the reason of the excitement at Structure on the ongoing phase II. 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 biology, in terms of the tolerability, the build-up, and the receptor desensitization, it's pretty comparable and pretty similar. We're planning to do the same steps that we've done in the GLP-1.
Starting at a low dose that we have already identified with 1 mg or 2 mg of ACCG-2671, and start the titration from there.
But one additional point, Yas, and somebody else asked a previous question on this. We think that the shape of the curve, of the weight loss curve, is really important. We have always believed that a linear, what we hear from physicians is what they care the most about is more of a linear. They do not care about the sort of really rapid weight loss. So they are sustainable, that they see something in the early days, and that they continue seeing weight loss over time. That is what the physicians and the patients are really looking for. And all of our learnings, the shape of the aleniglipron curves and how we will apply that to the amylin program, I think gives us further confidence in how the amylin program will progress.
Thank you so much.
One moment for our next question. Our next question comes from Prakhar Agrawal with Cantor Fitzgerald. Your line is open.
Hi, thank you for taking my questions, and congrats from my side as well on these very strong data sets. 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 ACCG-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 orforglipron that also have 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? 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 trials throughout? Thank you, and congrats again.
Prakhar, thanks for your questions. We will start with the amylin and the bone biomarkers. These have been already reported in some programs of dual amylin calcitonin receptor agonist, pramlintide, salmon calcitonin. Also showing in phase I and also in patients with osteoarthritis, a significant reduction in CTX-1 and an increase in alk phos. That is always the 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. Because as we all know, especially for certain pockets of participants and patient populations, this is a large unmet medical need for these patient populations. In terms of the MAD trial and how to titrate, it is still very early. We are in early days of the small molecule amylin receptor agonists.
We need to understand very well the biology. We are following the same steps as we were alluding to in the previous question in terms of 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 will identify that in the multiple ascending dose that can be incorporated in the later development. Then the last question on aleniglipron, and thanks for raising these retention strategies for aleniglipron phase III, because we spend a lot of time internally and with our external collaborators in defining what the best strategy for ACCOMPLISH-1 and ACCOMPLISH-2, and we feel very confident about the strategies that we put in place.
Of course, we cannot get into the details that we have learned a lot about 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 number one priority, and that is how we structured the program.
Thank you.
Thanks for your question.
One moment for our next question. Our next question comes from Terence Flynn with Morgan Stanley. Your line is open.
Thanks. Congrats on the data. I guess two for me on ACCG-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. 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 a later amendment. Then the second question is, looks like you've completed some of the food effects studies already. So just anything notable there, then maybe provide an update on where you are in terms of drug-drug interaction studies and anything to note or think about for ACCG-2671. Thank you.
Thanks, Terence. I'll take one by one. So on the add-on cohort, let me clarify. This is one of the cohorts 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 ACCG-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 kind of QC'd, but what we can share today is that we're not requiring any kind of food restriction for the ongoing phase IIa study. Then the DDI plans for ACCG-2671 are also ongoing and we'll provide further details as the program moves along.
Thank you. One moment for our next question. Our next question comes from Roger Song with Jefferies. Your line is open.
Great. Congrats for the data, and thank you for taking our question. 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. 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? How consistent this weight loss across patients, particularly for the 10 mg cohort? How should we think about the kinetics from 17 to 24 days? That's on the amylin. On the aleni, thanks for sharing the patient journey chart again, which give us a lot of the context for the tolerability.
For the placebo crossover, just thinking about the reshoot 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 titration up to 24 weeks. On the weight loss part, how confident you will get to 15%+ just like the OLE 72 weeks is 16%? Thank you.
Thanks, Roger, for your questions. We'll start with ACCG-2671 and the context of that observation on body weight loss for the 10 mg. As you well pointed out, that was observed, that 3.3% observed at day 24. The relationship with the gastrointestinal events, it's the right question to ask, so 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 one, and one participant had another event on day two. But we didn't see in that cohort any other event of vomiting beyond that point.
Again, we don't want to over-interpret that 3.3%, but it's another sign of target engagement when you put together the three pieces, the gastrointestinal induction study at 5 mg, this body weight reduction, and then the dynamic changes in the bone biomarkers are all pointing out in the direction of finding efficacious doses of ACCG-2671 very early on. So that's on ACCG-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 was 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. So we looked 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 four 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. 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. That's what is most important, and we're planning to execute the phase III program the same way. 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 result of the open-label extension achieving a 16%, just with a median time at 180 of seven to eight weeks, the results are highly encouraging to be continuing the lead in that small molecule field. We're very confident about the prospect of the ACCG-2671. Thanks for your question, Roger.
Thank you.
One moment for our next question. Our next question comes from Jon Wolleben with Citizens. Your line is open.
Hey, thanks for the update and taking the questions. For aleniglipron, wondering for phase III expectations, do you think there's a rate of nausea, diarrhea, vomiting that represents 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 their tolerable dose? On the amylin programs, can you remind us of the differences between ACCG-2671 and ACCG-3535? Would you move both forward with differentiated profiles, or is the goal to pick out the best of the class there after the MAD data? Thanks.
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 paramount because at the end of the day, we need to continue improving the participant experience, make sure that the level of compliance is the highest possible so they can benefit off the efficacy of the drug. After all this time, the learnings are 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. With that titration step, higher rates of continuation on drugs and ensuring that we will have enough time to add the management dose, that positions the program in a very good place. Back on aleniglipron, do you want to-
Yeah. I'll take the, Jon, I'll take the question on amylin. First, we're really excited about ACCG-2671. It's quite a unique molecule, so we'll continue pushing that full steam ahead. In terms of ACCG-3535, first, it's good practice to have additional molecules in the pipeline. We're in this to win, so we're going to put multiple molecules in the clinic. If you think about with the GLP-1s, you have the danuglipron versus the orforglipron scaffolds that have been used. That's our philosophy. We continue to work on additional generations, in part, as we continue exploring and building our intellectual property case. 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.
There's nothing in particular, other than different chemical scaffolds between those two and the need to continue exploring this space aggressively.
Got it. Thanks again, guys.
Yeah. Thank you, Jon.
One moment for our next question. Our next question comes from Patrick Dolezal with LifeSci Capital. Your line is open.
Hi. Thanks for taking the questions. For ACCG-2671, could you give us some color on how the PK exposures achieved in the SAD portion map to some of the preclinical obese non-human primate data in which you saw these sort of nice deep reductions in weight over time? Obviously, I know it is just the SAD data, but is there an indication that you are getting the exposures that you were targeting based on the preclinical experience? The second question is, are there any internal benchmarks for success that you would be able to share for amylin on the MAD portion? Just curious how you are 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 are pioneering, and you already have aleniglipron in the pipeline. Thank you.
Thanks, Patrick. I will take the first question on ACCG-2671 and the PK that we were expecting. We were not surprised to see the level of exposures that we have seen. Also not surprised to see the dose proportionality. We were not expecting such 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 back today in non-human primates and what we have reported today. Bottom line as well, I think it is important to reflect on what we are seeing at 5 mg and 10 mg is clear signs of target engagement. That gives us all the information that we needed to design the multiple ascending dose. I will start with the TPP and the expectations for the multiple ascending dose and in that way continue elaborating. We are 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 titration strategies.
Nothing to add. I think you did a great job answering that question, Blai.
Thank you. One moment for our next question. Our next question comes from Andy Hsieh with William Blair. Your line is open.
Thanks for taking our question. I am just curious if you could contextualize the CTX-1 bone health data for us. Just looking at REDEFINE 2, it seems like TAGRISSO treated patients experience increases from week eight all the way through week 20. Here you see a pretty dramatic drop in day two, but largely normalized by day eight. How would you interpret these results? Thank you.
Thanks, Andy. We are very pleased with the results on the bone biomarkers. One thing, think about these as a single-dose administration. In order to interpret the rebound back to baseline, you also need to take into account the half-life of the biomarker itself. It is not always easy to compare those two dynamics at the same time, but directionally are moving in the right direction because we are seeing a dramatic decrease in the CTX-1 and the expected increase in the bone-specific outputs, which is something that is biologically logical based on the previous results. In terms of the magnitude of the effects, we are seeing similar reductions with pramlintide that have reported results and also, as we mentioned before, in salmon calcitonin in healthy individuals. That is also consistent with previously published data.
Andy, please keep in mind, this is purely exploratory. We think this is a very important area. It is a very big unmet need. At this stage, it is exploratory and what we believe worth pursuing as we enter into the multiple ascending dose phase.
That is helpful. Thank you.
Yeah, thanks.
One moment for our next question. Next question comes from Samantha Semenkow with Citi. Your line is open.
Hi, good morning. This is Ben on for Sam. Thanks so much for taking our question. If I may, what does the 3.3% mean weight reduction after a single dose of ACCG-2671 imply about the weight loss potential you're hoping to demonstrate in the 12-week MAD study? Thank you.
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 two data points that we've provided during the call, the gastrointestinal induction starting at 5 mg and the impact on the bone biomarkers. We wouldn't take that as an 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 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.
Thank you. One moment for our next question. Our next question comes from Annabel Samimy with Stifel. Your line is open.
Hi, thanks for taking my question. I have a couple on aleniglipron. I am just hoping you might be able to comment on how you arrived at the maintenance dose levels for the phase III trial. ACCESS OLE cohorts kept on titrating up to 180 to keep weight loss going. I guess they were on it for only eight weeks, and in the phase III, you have two cohorts that do not go beyond 45 and 90 mg. What was the thought there, and what is the longest time patients have been on 180? The last point in ACCOMPLISH, notice that the titration through 120 to 180 arm was skipped. A little bit more color around that would be great. Thanks.
Thanks, Annabel. The thought behind the ACCOMPLISH-1 and -2 is to have a range of doses that go from the low 45 mg, that is low efficacious dose to 90 mg and 180 to maximize that level of efficacy. The open-label extension, as you have seen, we had a median of seven to eight weeks in the top two arms in the study. The maximum that you could get exposure in the open-label extension was 12 weeks because the protocol was amendment starting at week 60. That was the maximum exposure that it is relatively limited. Despite that, you can see also the shape of the scene starting at that week 60 and not indicating any fluctuating after that. Thanks for raising the question about the 120/180.
We had, 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. That is the reason why we are providing the design of the study in ACCOMPLISH-1 and -2 on that move from 90 to 180.
Annabel, one of the things that we have been hearing from the KOLs for many years is what is most important is, at the beginning, you want to start low and go slow, then in the later stages, you can have different jumps. So Blai and his team carefully evaluated the jump 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.
Thank you.
One moment for our next question. Our next question comes from Alexandria Hammond with Wolfe Research. Your line is open.
Hi, Cameron DeGuzman on for Alex Hammond from Wolfe Research. Thanks for taking the question. Perhaps another one on bone markers. The 60% CTX-1 suppression from a single dose was quite striking. It is being framed positively as target engagement, but with a six-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? Is there a point, I guess, in which chronic suppression of bone resorption at a steady state could become a concern? Thanks.
Yeah. Thanks for the question. 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 deleterious 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 on bone imaging, and that's the intent of the program.
Thank you. One moment for our next question. Our next question comes from Ananda Ghosh with H.C. Wainwright. Your line is open.
Hi. Thanks for the question and 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 DEXA to kind of answer the questions on the bone health? The second question is, looking at that tolerability profile at 10 mg or 5 mg, how do you interpret the therapeutic index or the therapeutic window for the amylin drug? Thank you.
Yeah, 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. 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 these, and so probably we'll need to wait for longer studies to assess the impact on DEXA. 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 seen repeating with the GLP-1 should apply here on the amylin receptor agonist.
And so tolerability index, we know at what first dose we have been inducing the gastrointestinal event, and that has been evidenced at 5 mg. But what we need to explore now is that starting at 1 mg or 2 mg, how much improvement in tolerability we can make, yet still achieving an efficacious dose. And so that is one of the questions that we have in the design for the multiple ascending dose.
Thanks.
Thank you.
One moment for our next question. Our next question comes from Hardik Parikh with JPMorgan. Your line is open.
Hey, good morning. I was just wondering for ACCESS OLE in the PBO crossover arm with moderated titration, we saw improvement in vomiting, discontinuation rates. There is also 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 consider diarrhea and constipation? And then one on the oral amylin. You mentioned you would test both the daily and weekly dosing in phase II. And I am just wondering if you could just give us some high-level comments on how you see the trade-off of efficacy versus safety or tolerability when you consider those two dosing options. Thank you.
Let me start. I'll sort of hand it over to Blai in a little bit of a break. Hardik, I think one thing to sort of consider, we've been very intentional about collecting as much data as possible. For example, in all of our studies today, particularly all the phase II's, we use e-diaries. We collected a lot of information. We think this leads to an over-reporting, particularly in nausea. In the phase III, we will not be using e-diaries. It's just too long of a study, and it's not the right sort of setting. In phase II, all that data we collected, we think we'll see even more improved numbers as we go into the phase III. Slide.
Yeah, 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 confident. Again, as we mentioned in the presentation, focusing all the priorities around the retention, it's something that we've been very thoughtful and very careful about it. 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 impacts 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 those important and relevant questions.
That applies to the excitement around the combinations as well. We think there's some very important combination opportunities as well as we look forward to the future.
Thank you. I'm not showing any further questions at the time. I'd like to turn the call back over to Ray for any further remarks.
First of all, thank you all for joining us today for the very positive updates on our amylin and GLP-1 programs. The world needs more accessible options for chronic weight management. At Structure Therapeutics, 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 concludes today's presentation. You may now disconnect and have a wonderful day.