Good day, and thank you for standing by. Welcome to the Structure Therapeutics Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question- and answer session. To ask a question during the session, you'll 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 that this conference is being recorded. I would now like to hand the conference over to your speaker today, Danielle Keatley, Head of Investor Relations for Structure. Please go ahead. Thank you and good morning. Earlier today, we issued a press release providing a comprehensive program update for our oral GLP-1 receptor agonist, GSBR-1290, including initial data from the phase IIa study in diabetes and obesity. A copy of this release and the presentation to accompany this call are available on the Investor Relations section of our website. Joining me on the call today to present the data are Dr. Raymond Stevens, Founder and CEO; Dr. Blai Coll, Vice President of Clinical Development; Dr. Mark Bach, Chief Medical Officer; and Jun Yoon, our Chief Financial Officer, will join the call for Q&A. Before we get started, I would like to remind everyone that some of the statements that we make on this call and information presented in the slide deck include forward-looking statements as outlined on slide 3. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in our most recent Form 10-K and Form 10-Q filed with the SEC, and any other future filings that we make with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements, and Structure Therapeutics disclaims any obligation to update such statements. A brief agenda for the call this morning can be found on slide 4. With that, I will turn the call over to Dr. Raymond Stevens, CEO of Structure. Thank you, Danielle. Good morning, everyone, and thank you for joining us today. I'd like to start off by reminding everyone of what we set out to do at Structure Therapeutics: to create a best-in-class oral GLP-1 agonist. The potential that this class of drugs has to address obesity, diabetes, and related diseases is truly significant. Today's comprehensive program update is an important step forward in our journey, and on slide 5, I'll provide a summary of the data that we'll be presenting today. As expected, we are sharing top-line results from the 12-week phase IIa study of GSBR-1290 in patients with diabetes. We're also very aware that this space is evolving extremely rapidly, and we recognize the urgency in moving this program forward as fast as possible. In order to do this, we made the decision to unblind the obesity interim data now to look at the entire program comprehensively, rather than wait until we have the full 12-week data in the second quarter of 2024. So we'll go through the diabetes and the interim obesity data from our phase IIa study, and we'll also share results of the Japanese bridging study and our 6 and 9-month toxicology studies, both of which support progress in the phase IIb development. First and foremost, GSBR-1290 consistently demonstrates very encouraging safety and tolerability results. In the phase IIa data that we are presenting today, the majority of adverse events were mild and moderate, with a very low single-digit discontinuation rate of 2.8% due to drug-related AEs in the diabetes arm and no discontinuations due to AEs in the obesity arm. Turning to efficacy, today we are sharing our first data in people living with diabetes. In our phase IIa study, the patients with diabetes demonstrated a statistically significant reduction in both weight and hemoglobin A1c at 12 weeks. These first results of GSBR-1290 in people with type 2 diabetes support our hypothesis that the drug could have significant potential in diabetes. In individuals with obesity, GSBR-1290 continues to demonstrate clinically meaningful activity in the phase IIa study, with significant weight reduction at 8 weeks. We are excited to see the magnitude of reduction in both body weight at this eight-week time point, highlighting its competitive position, as you will see. We are encouraged about its potential at 12 weeks, given the downward trends with no sign of plateau at 8 weeks. Today, we will also discuss results from two phase IIb enabling studies. First, our Japanese bridging study showed substantial weight reduction in healthy, lean individuals, and the results from our 6-month and 9-month toxicology studies showed no major safety findings and enable longer-term evaluation in future studies. With that, let's dive into the safety and efficacy data so that you can clearly see why we are encouraged by our progress and why we believe GSBR-1290 has the potential to be a best-in-class oral GLP-1 agonist. One that we believe could become a foundational therapy and also a backbone for future combinations to address large cardiometabolic indications. I would now like to turn the call over to Dr. Blai Coll, Vice President of Clinical Development, who'll be presenting the data. Thank you, Ray. I'm pleased to summarize the data for GSBR-1290 and get into the details of what will be presented today. First, we thought it would be informative to provide a high-level overview of what will be shared, the data already presented, where we are now, and where we're going with GSBR-1290. As you can see in slide number 7, you recall that we presented phase 1b 4-week data in September, showing for the first time that treatment with GSBR-1290 reduced body weight. Today, we will analyze with you the first data set in participants with type 2 diabetes. The study achieved the goal of demonstrating favorable safety and tolerability results, while achieving positive efficacy results at both 45- and 90-mg doses of GSBR-1290. As next steps in type 2 diabetes, we have identified opportunities to optimize GSBR-1290 in phase II. Specifically, we look forward to studying different dosing and titration schemes and a potentially optimized formulation in 2024. In addition, today we will also show you the interim results of our second study in participants with overweight or obesity, also demonstrating encouraging safety and tolerability and positive efficacy results at 120 mg. As next steps in obesity, our company's efforts will be focused on initiating the phase IIb 36-week study in the second half of 2024. We believe the data reinforces our conviction that GSBR-1290 has the potential of being a best-in-class oral GLP-1 receptor agonist. Let's transition now into the design of the phase IIa study, which you will see on slide 8. The study enrolled 54 participants with stable type 2 diabetes with overweight or obesity, defined by a body mass index of at least 27. Individuals were required to be on metformin therapy and an HbA1c between 7 and 10.5%. We used two different target doses of GSBR-1290, 45 or 90 mg versus placebo, and enrolled participants were titrated on a weekly basis, starting at 5 mg and remaining on target dose for the last 8 weeks in the study. The primary endpoint was safety and tolerability, and as secondary endpoints, we measured efficacy, defined as HbA1c, weight changes, and metabolic measurements after a mixed meal tolerance test. As a reminder, the study was powered to detect differences in HbA1c at 1% and weight 5% between the group of 90 mg and placebo. In the bottom part of the slide, you can see the design of the cohort of participants with overweight or obesity and no type 2 diabetes, defined by a body mass index between 27 and 40 and HbA1c lower than 6.5%. In this cohort, we enrolled 40 participants, targeting 120 mg of GSBR-1290 versus placebo on a weekly titration scheme and 8 weeks of maintenance dose at target. As indicated in September, the study is currently enrolling the 24 replacement participants, who will also be randomized 3:2 to GSBR-1290 or placebo. With that, let's turn to slide 9 to review the demographic and baseline characteristics in both cohorts. On the left-hand side of the slide, for the type two diabetes cohort, we enrolled approximately 40% of females, predominantly of Hispanic, Latino ethnicity, aged between 55 and 60 years old, with a mean BMI ranging from 32-34 and 11-12 years of diabetes duration. All enrolled participants were on metformin, and their HbA1c at baseline was around 8%. Heart rate and systolic and diastolic blood pressure were within normal values. For the overweight and obesity cohort on the right-hand side of the slide, participants were younger, around 46 years old, predominantly non-Hispanic or Latino, with a mean BMI at baseline of 31, HbA1c around 5.5%, and similarly to the type 2 diabetes cohort, heart rate and blood pressure within normal values. Let's now review the participant disposition of each cohort. As you can see on slide 10, on the left side of the slide, summarizing the type 2 diabetes cohort, 2 participants discontinued the study due to an adverse event, and both participants were allocated to the 45 mg group. The cause for one of the discontinuations was COVID-19 infection, which was unrelated to GSBR-1290. The other discontinuation was due to intermittent nausea and vomiting, and this was the only adverse event leading to discontinuation related to study drug. This represents an overall discontinuation rate due to study drug in type 2 diabetes cohort of 1 out of 36 participants, or 2.8%. We did not see any participant discontinued due to adverse events in either the 90 milligram group, in the type 2 diabetes cohort, or in the group of participants with overweight or obesity, targeting 120 mg, as indicated in the table. As previously communicated, the protocol allowed participants to remain in the study at a lower dose if necessary. 37%-42% of participants had their dose reduced, discontinued, or put the dose on temporary hold, and the majority of those individuals were able to continue dosing with GSBR-1290 at a lower than the target dose and complete the 12 weeks of therapy. As you know, this has been implemented by other sponsors in the field, and future analysis of those participants can shed light into design elements for future studies, such as starting dose or titration length. In slide number 12, we summarize the safety data, showing a higher number of adverse events in the treated group versus placebo in both cohorts. The majority of events were mild to moderate in severity, with no serious adverse events related to study drug. In the group of participants with type 2 diabetes, there were two serious adverse events not related to study drug, one subject with a pulmonary embolism and another subject with tenosynovitis that required surgical intervention. Again, both of these events were deemed not related to study drug by the principal investigator.... To better characterize the tolerability, we summarize in slide number 13, the most commonly observed adverse events. As expected by the class of GLP-1 receptor agonist, nausea was the most common, with 70%-87% of participants experiencing at least one event, followed by vomiting, with incidences ranging from 40%-62% per cohort, varying degrees of diarrhea, and with approximately 20%-34% of participants with decreased appetite. Outside the gastrointestinal area, we observed lower incidences of headache compared to the phase Ib four-week data. We did not see any events of drug-induced liver injury in either cohort of the phase IIa study. One subject in the type 2 diabetes group experienced an event of elevated liver enzymes. This was a female participant with previous history of hypercholesterolemia, treated with 40 mg of atorvastatin and obesity, who had an elevation of liver transaminases at day 8 while receiving 5 mg. Consequently, the principal investigator decided to discontinue study drug on day 21. The participant was diagnosed with fatty liver disease while in the study, and importantly, the bilirubin concentration remained normal throughout the 12 weeks. Looking across our 4-week phase I study and the 2 cohorts of our 12-week phase IIa study, changes in liver enzymes from baseline were not clinically meaningful. One important way to characterize the tolerability profile is to analyze the data over time, and in slide number 14, we can see the incidences of the 2 most common adverse events over the 12 weeks of the study. In the left panel, we show the results for the type 2 diabetes cohort, showing higher incidences in the first 4-6 weeks, coinciding with the titration phase of the study. It is important to highlight the absence of events of nausea or vomiting in some of the weeks while participants are at target dose of either 45 or 90. We can also appreciate a similar pattern in the group of participants with overweight or obesity, with incidences of nausea trending down from week 5 and several weeks in the maintenance phase of the study without events. This data is encouraging and represents an indicator of improved tolerability with longer titration steps for future studies. As you know, one of the known effects of GLP-1 receptor agonist is an increase in heart rate, and in slide number 15, we can find a summary of the findings in the phase IIa study. As expected, we see increases in heart rate taken at 6 hours post-dose in the three groups of participants exposed to GSBR-1290, ranging from 5-8 beats per minute and consistent with other programs in the field. The increase in heart rate was seen in the first 4-5 weeks of the study, coinciding with the titration phase, and remained stable during the maintenance phase in the two groups with type 2 diabetes and a trend towards returning to baseline in the 120 milligram group in the cohort with overweight or obesity. And now let's turn to the efficacy analysis in the two cohorts of our phase IIa study. In slide 17, we present the results of the HbA1c changes, which showed a significant reduction at day 84. In the left panel of the slide, we can observe the significant reduction in HbA1c for both groups of GSBR-1290, and the difference persists throughout the duration of the study, representing a reduction in HbA1c of 0.79%-0.84% at 12 weeks. In the table below, you can see the placebo-adjusted change with a 1.01%-1.02% reduction, with a statistically significant difference versus placebo for both 45 mg and 90 mg. In terms of weight reduction, we summarize the findings in slide 18. The study achieved its efficacy endpoint with a significant reduction in weight at day 84. Similarly to what I just presented for HbA1c, the curves started separating from placebo within the first month and trend towards a continuing reduction in weight throughout the 12 weeks of therapy. Despite not capturing a dose response, it is important to highlight that there was no plateau effect, and it's possible we could continue seeing additional weight reduction in longer studies. The absolute percent weight change at day 84 is presented in the bar graph, and the table below describes the placebo-adjusted weight reduction, ranging from 3.26%-3.51%, statistically significant differences for both doses compared to placebo. Continuing on efficacy endpoints, we collected fasting plasma glucose results shown in slide 19, highlighting a significant reduction in glucose observed for both doses compared to placebo. Similarly to what I just presented, plasma glucose was significantly reduced at day 35, achieving a reduction ranging from 2.5-2.7 millimoles per liter, placebo-adjusted at day 84. Again, statistically significant differences for both doses versus placebo. Lastly, we want to show you the results of the mixed-meal tolerance test in slide 20. The results presented in the slide summarize the end of treatment compared to baseline and are placebo-adjusted, highlighting significant reductions in postprandial glucose, significant improvement in HOMA-IR as a marker of insulin resistance, and a significant reduction in insulin. Let me now turn it over to overweight or obesity. It is really exciting to see transformative therapeutic options for people living with obesity, and at Structure, we're very enthusiastic in working in this field. On that note, we're really excited about the interim analysis results for the group of participants with overweight or obesity and no type two diabetes, shown in slide 21. The study observed a significant reduction in weight, with curves separating early on in the trial, and importantly, showed no signs of plateauing, achieving a 5.55% reduction at day 56. In the table below, we can see the efficacy placebo-adjusted, reaching a statistically significant reduction of 4.74% weight loss. As you know, this cohort of the study is ongoing with the participant replacements, and we are on track to complete the study in the second quarter of 2024. We're encouraged to see these interim analysis at eight weeks, and we believe the increased efficacy trend that we observe to eight weeks could continue into 12 weeks. On that end, we want to summarize for you the totality of efficacy data, specifically body weight reduction, generated to date with GSBR-1290 on slide number 22. In the Y-axis, we describe weight changes in percentage compared to baseline, and in the horizontal axis, time up to 12 weeks. As you can see, the placebo arms in the studies are indicated in gray, and we can clearly differentiate the group of participants with type 2 diabetes up to 12 weeks, shaded in the darker blue, and also the group of participants with overweight or obesity up to 8 weeks in lighter blue. It is very encouraging to see the different degrees of weight loss in the groups enrolled, especially for the group of participants with overweight or obesity without diabetes, that, as we know from other programs, generally demonstrate higher reductions in body weight compared to type 2 diabetes. We want to summarize the interpretation of the data in 2 key takeaways. 1, consistent weight reduction throughout the program without signs of plateauing up to week 12 in different patient populations. And 2, the efficacy is significant at a dose of 45 mg in participants with type 2 diabetes. This is a substantial result considering the small sample size and that the study was not designed to see differences in this group. As expected, we gained valuable insights from our first exposure of GSBR-1290 to patients with type 2 diabetes, and we have identified additional opportunities to potentially optimize GSBR-1290 in this patient group, and that will gravitate around dosing and titration optimization, along with potential formulation improvements. For the phase IIa cohort of participants with overweight or obesity, the interim 8-week analysis is encouraging, and we're looking forward to completing the 12 weeks of dosing in the replacement cohort, and we're on track to launch the phase IIb in the second half of 2024. To put the data in context and analyzing the obesity landscape for oral small molecules targeting the GLP-1 receptor, this data presented today makes us confident about GSBR-1290. In slide 23, you can see weight changes in the Y-axis over time up to 36 weeks, the usual duration for obesity phase IIb studies. We described a trajectory of weight reduction in the red lines for orforglipron based on their phase IIb studies, and also showing the results of our interim analysis at 8 weeks, suggesting a comparable level of efficacy at 8 weeks. This data gives us confidence in the potential of GSBR-1290, and we will continue advancing the compound for a chronic weight management indication as rapidly as possible. To finalize this part of the GSBR-1290 update, we want to provide an progress on the phase IIb enabling activities the team has been advancing. Let us start with the top-line results of the Japanese study, conducted as a first step in our plans to develop GSBR-GSBR-1290 globally. As you see on slide 25, this was a four-week study aimed at safety, tolerability, and PK in Japanese and non-Japanese individuals. We enrolled 18 healthy participants, as described in the top left corner of the slide, in two different cohorts: 12 Japanese participants, 9 randomized to GSBR-1290 and 3 to placebo, and 6 non-Japanese who received GSBR-1290. Protocol started at 5 mg per day and followed a weekly titration to a target dose of 60 mg. Participants were predominantly female, aged between 34 and 46 years old, and normal BMI between 21 and 22. All participants completed the study as per protocol with no discontinuation or down titrations, and the study did not report any serious adverse events. As you can see in the table at bottom left, and as expected, the majority of adverse events were gastrointestinal, with nausea being the most common in both cohorts, followed by decreased appetite and early satiety. The study did not see any cases of elevated liver enzymes. As these participants were lean, it's interesting to highlight the meaningful body weight loss observed in this study, as displayed in the right-hand side of the slide, with marked reductions in weight for the two groups receiving GSBR-1290. 2.3 kg weight loss in Japanese participants and 3.1 kg in non-Japanese. That translated into weight loss from 3.91%- 5.13% versus 1.67% in participants receiving placebo. The study met its objectives, and the data will be used for future regulatory interactions in Japan, and as previously mentioned, we have also completed the 6- and 9-month tox studies. On slide 26, you can see the summary of the results. In rodents, at 6 months, with a max dose of 1,000 mg/kg/day, including 15 animals per group, the study did not reveal any tox findings, and therefore, the NOAEL remains, as previously communicated, at 1,000 mg/kg/day, representing over 100-fold safety margin at a dose of 120 mg. We also completed the 9-month study in non-human primates at 3, 10, and 30 mg per kg per day, including a total of 60 animals. Pending the final report, we want to highlight a dose-dependent body weight reduction, ranging from 3%-17% from baseline. Importantly, there were no increases in liver enzymes or microscopic liver findings. It is exciting to see these encouraging preclinical data as they enable the program to progress to longer durations of exposure in clinical trials, specifically our planned 36-week phase IIb program. With that, let me turn it over to Mark. Mark? Thank you, Blai. We've seen a lot of data, and let's put this all in perspective. Turning to slide 28, phase IIa is an opportunity to demonstrate proof of concept of a new drug candidate in the intended diseases, and we believe we've clearly done this with GSBR-1290. We see GSBR-1290 as potentially best-in-class as a once-daily oral therapy for individuals with overweight or obesity. We saw efficacy characterized by a statistically significant 4.7% decrease in weight at 8 weeks and are looking forward to the 12-week data, which will be available in 2Q-2024. In the cohort with overweight or obesity, we saw no SAEs, no discontinuations up to week 12. For tolerability, most, about 96% of AEs, were mild or moderate, with nausea or vomiting most frequently reported. There was a tendency to have more of these AEs reported during the titration period than during the ongoing treatment at the target dose. Our results continue to support once-daily dosing, taken with food. In participants with type two diabetes, we observed a decrease in hemoglobin A1c of 1.02% at week 12, along with up to a 3.5% decrease in weight. In the cohort with type two diabetes, we observed no SAEs and one discontinuation related to study drug. Distribution of severity and the most common types of AEs were similar to those in the obesity cohort. The observation of no significant, no significant findings in our 6- and 9-month GLP toxicology studies enables longer treatment in clinical studies, as well as potential use of higher doses. We're actively evaluating opportunities to optimize weight loss using several approaches, which Ray will describe in a moment. On slide 29, one of our key next steps, as we have previously mentioned, is an ongoing study evaluating capsule-to-tablet formulation bridging in participants who are overweight or obese. At the top of the slide, we see that Part One is a standard capsule-to-tablet, 10-milligram, single-dose pharmacokinetics crossover study. Recall that in our phase IIa study, we intentionally used a weekly titration schedule to maximize treatment duration at the target dose. So a second objective for this study is to take the opportunity to further optimize GSBR-1290 by exploring alternative titration regimens. At the bottom of the slide, Part Two is a 12-week parallel cohort study looking at starting doses of 5, 10, or 15 mg, as well as different titration steps of between 1 and 4 weeks. In cohorts 1 and 2, the target dose is 120 mg. In cohort 3, we look at an additional titration scheme, with the final 4 weeks constituting a multiple- dose PK crossover study at 60 mg. This study should help support use of a tablet formulation in phase IIb, as well as helping us determine a titration regimen or regimens with the potential to optimize tolerability. With that, I'll turn it over to Ray to summarize our progress and path forward with GSBR-1290, as well as our entire oral metabolic franchise. Ray? Thank you, Mark. Thank you, Blai. As you've heard from our presentation today, we've made significant progress with GSBR-1290 this year, shown on slide 31. Given the consistently encouraging safety and tolerability data, the efficacy data and trends that we are seeing, particularly with the unblinding of the obesity interim weight loss data, we are confidently moving forward into the next phase II studies, with the belief that GSBR-1290 has the potential to become a backbone of treatment in the future, both as a mo-- both as a monotherapy and in potential combinations. With this in mind, we are accelerating GSBR-1290 development as much as possible in 2024. We are enrolling the phase IIa overweight, obese replacement participants and expect 12-week data in the second quarter of 2024. Similarly, we expect results from the fully enrolled capsule-to-tablet PK bridging and titration study in the second quarter. Following completion of these two studies and our planned IND submission in the second quarter, we expect to initiate our phase IIb study in obesity in the second half of 2024. In follow-up to the phase IIa data in type 2 diabetes, we also plan to initiate an additional phase II study in this population to optimize efficacy and tolerability. In summary, on slide 32, our comprehensive program update today provides the proof of concept data that we needed in order to accelerate development in this rapidly advancing space.... and we are moving full speed ahead with a plan in place to initiate our next phase II studies in the second half of 2024. I would now like to also highlight the rest of our oral metabolic franchise on slide 33. The proof of concept data that we have presented today support GSBR-1290's potential as a promising medicine, both by itself and as a backbone for combination therapies. We are actively advancing our dual GIP/GLP-1 and amylin plus GLP-1 receptor agonist programs. Both of these programs are actively in lead optimization, and we continue to be on schedule to nominate development candidates in the second half of 2024. We are also excited in fast-tracking our apelin receptor agonist together with GLP-1, given our discovery efforts and its potential for selective weight loss and muscle maintenance, and we expect to share data from this program also in 2024. As you recall, our apelin receptor agonist, ANPA-0073, has already completed a phase 1 safety study. Obesity and diabetes are two extremely important therapeutic areas where oral GLP-1 receptor agonists are positioned to potentially transform treatment, and these areas have been our focus. As we continue to advance GSBR-1290, we will look at its potential application in other large cardiometabolic indications, where we believe it could also provide a meaningful opportunity. On slide 34, I'll spend a minute on why we believe that GSBR-1290 continues to be potentially best-in-class and why we're accelerating our program as much as possible. The opportunity in this space is tremendous, and the field has advanced significantly in 2023. Oral GLP-1 agonists are poised to become one of the biggest class of medicines to help modern-day society for the treatment of many cardiometabolic diseases, including obesity, diabetes, also chronic kidney disease, MASH, and many others. Oral GLP-1 agonists can become foundational medicines and potentially a backbone for combination therapies of the future. With any combination therapy, safety and tolerability become paramount and are necessities for combining with different mechanisms of action and allowing optimization of therapy. There are many promising mechanisms, including other incretins, such as GIP and glucagon, as well as amylin and muscle maintenance targets, such as the apelin receptor agonist. Based on today's comprehensive update, we believe that GSBR-1290 has the potential to be an ideal oral GLP-1 in this space. Its encouraging safety and tolerability results are potentially differentiating. It has been generally well-tolerated in clinical trials, with very low discontinuations due to adverse events related to study drug: 2.8% in phase IIa diabetes cohort and 0% in the obesity cohort. These safety results are supported by the 6-month and 9-month toxicology studies presented today. We have also shown clinically meaningful and statistically significant efficacy in both obesity and type 2 diabetes. With today's data, we now have the information we need to optimize this promising safety, tolerability, and efficacy profile as we move this program forward. In summary, these data show that, 1, we have an active molecule. 2, the safety and tolerability results are very encouraging and differentiating. And 3, we have a clear path forward to longer-term data, particularly on weight loss, where we're observing downward trends with no signs of plateauing. Thank you all for listening. I would now like to turn the call back to the operator, so we can start the Q&A. 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 and 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. Our first question comes from Seamus Fernandez with Guggenheim Securities. Your line is open. Oh, thanks for the question. So just hoping to tackle a couple of things. First, you know, Ray, as we think about the next data set, so the phase IIa in obesity, at 12 weeks, can you just help us, you know, think about, you know, what you believe sort of the, the target threshold or, or the achievable sort of weight loss at 12 weeks in an obese patient population, is to be competitive? And then, you know, on the other side, you know, and I think Ray and the team can, kind of, comment on this, but, you know, oral GLP-1s have been extraordinarily difficult for the industry to, to get at. Obviously, there are more in market today, but especially really safe ones, I think, are, are, you know, truly unique. And I think the safety profile here, as you highlight, is definitely exciting from a combination perspective. Just hoping that you could maybe talk a little bit about the opportunity to accelerate and advance your apelin agonist alongside GSBR-1290 in terms of the opportunity there. And then just in terms of the diabetes patient cohort, one thing that struck me in this patient population to some degree was. Basically, the duration of diabetes in these patients of 12 years. Can you just talk a little bit about how that compares to other data sets? And how that might impact or other baseline characteristics that might impact weight loss in a diabetic patient population, apart from just the patients being diabetic themselves. And then I'll jump back into queue. Thanks. Absolutely, Seamus. So thank you, and I, I counted three questions there. I'm going to let Blai answer number one and number three, and then I will take, uh, question number two. So in regards to safety, we use our structure-based drug discovery technology platform to discover and develop this drug. And so because this GLP-1 is such a validated target by the pioneers in the field, we were able to spend extra time really focusing on the safety profile, and we're very, very proud of that. As was noted, you know, in the six-month rodent studies, you know, that 1,000 mg per kg is the maximum, that one will go up to in these studies. So we're really pleased to see. We saw that at three months and be able to see that at six months, very excited about that. And then in the non-human primates, we also saw a very clean profile. So I think on the safety, you know, using our technology platform, we're very pleased, with the safety that we're seeing. I will turn it over to Blai for questions one and three. Yes, Seamus, thanks for the question. Question one, in terms of the 12-week data in the obesity cohort, we're very excited about the results and interim analysis at 8 weeks. It overlaps very, very well and very competitively with what has been presented from other programs in a similar timeframe, and so we're very, we're very encouraged to see that data. And at the end of the day, I, I think, you know, the data that we're generating right now, up to 12 weeks, and that's just the first step into demonstrating a robust efficacy in a phase IIb with the adequate dose ranging study that we are very confident with the data that we got today, that will have a lot of valuable information. And so we're looking at the data very, very positively, and we're very excited to accelerate that phase IIb program for overweight or obesity as much as possible. So that's for the 12 weeks study in obesity. The third question in regards to the baseline characteristics in the type 2 diabetes and how potentially that could impact the results that we've seen. There are a couple of or three variables there, and you pointed out one and the duration of diabetes. There's, as you have seen, overrepresentation in terms of Hispanic Latinos ethnicity in the diabetes study. And these are solid hypotheses. We're aware of other programs demonstrating in some analysis different degrees of efficacy based on those baseline characteristics, and we will analyze those very, very carefully. The results that we present today are top line, and so we'll take those hypotheses in terms of duration of diabetes, that in our study, slightly higher, the ethnicity issue, very, very carefully in future analysis. Hope that answers your questions, Seamus. Yeah, thanks so much. 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. One follow-up from what Seamus had, just on the kind of ethnic background of the population in the diabetes trial, can you walk me through why there was such a high rate of Hispanic or Latinos? And do you think that impacts the data whatsoever? And then just taking a step back, you know, given the issues with the initial weight loss trial, where the patients were not weighed properly, do you have confirmation that patients were actually taking the drug as prescribed, either by kind of blood plasma testing or kind of PK testing? And my final question is, just maybe expand us to a little bit as to why we saw, you know, weight loss that looked better at week 4 versus week 8 in the obesity program. Thank you, guys. Blai, those are all yours. Thank you, Evan. So in regards to the ethnicity, as, as you're aware, there are some positive analyses from, specifically from the semaglutide, injectable program, that, that shows some degree of, heterogeneity in terms of efficacy when compared to different ethnicity. And so that's, that's the, the hypothesis that it's out there, and, and again, as I said, we'll analyze these very, very carefully. The reason why we have the, these percentages is because of the distribution of sites across the U.S., and some of the sites in populations where, where that ethnicity is overrepresented. So that's the, the explanation there. In terms of the second question for the overweight or obesity group and the level of compliance and exposure, as you may recall, we, we implemented an eDiary, so subjects were entering information on a daily basis about symptomatology, but also about compliance of, of the medicine. Based on that, the compliance has been adequate, and we're in the process of looking in detail into exposure and PKs, but that's in progress, and we cannot report any results as of today. Then the last piece of your questions were the potential differences between week 4 and week 8, and the reason behind that apparent gap is related most likely to the sample size and also to the different titrations. We've explored different titrations, all weekly, but at different doses, and at week 8, having a more robust sample size and a longer period of time, we feel more confident about the results than what we presented in the past. Hopefully, these answers your questions. Thank you. Thank you. One moment for our next question. Our next question comes from Roger Song with Jefferies. Your line is open. Great. Thanks for the update and taking our questions. A couple questions from us. The first one, I agree, the safety probably looks pretty outstanding. Maybe in the case of this one, ALT/ AST elevation, can you give us a little detail around the nature of the event, like level of the elevation and if it's drug-related? And also, we all know, also in released also in phase II, they also see some elevation case. So how would you contextualize this case versus other oral GLP-1? And I have a couple follow-ups. Thank you. Thank you, Roger. So the subject that we described in the presentation was a female participant with a previous history of hypercholesterolemia treatment with atorvastatin and aspirin, and presented with an elevation in ALPs and GGT within the first week of starting at 5 mg and followed with an increase in ALT/AST, as we described. And the ALT and AST progressively increased, and that was the motivation for the principal investigator to discontinue study drug in that subject. It is important to highlight, though, that the bilirubin concentration remained normal and flat throughout the duration of the study, so not a definition of drug-induced liver injury. And then the clinical presentation showing first an increase in cholestasis enzymes, such as ALPs and GGT, is not a classical presentation of drug-induced liver injury either. So that's the detail that we can provide. In terms of context, as you well pointed out, other programs in the field, specifically orforglipron, has reported similar numbers of increases in ALT, AST in their phase IIb. If I remember correctly, there were three subjects with different degrees of increases in ALT and AST that subsequently trend back to normal. That's something that we'll continue the regular surveillance in future studies. We're not changing or modifying the plans there, and that's what we can share in terms of that individual subject. Is that providing enough information, Roger? This is great. Thank you. Thank you. Thank you. Then, in terms of you have around 40% patients with those down titration or hold or discontinuation for the dose, how were those patients included in your efficacy estimate analysis in terms of weight loss and HbA1c? Is that all kind of excluded, or that's your patients can also included in the efficacy? Thank you. Thank you for the question, Roger. Yeah, that's, that's important to clarify. So the efficacy data that we've shown is based on the primary efficacy estimate, and that just includes those participants who were able to follow the protocol as required and be up titrated as the protocol indicated, and remain on the target dose for the maintenance dose all the way up to week 12. So that's the results that you've seen is based on the completers as per protocol. Excellent. That's good clarification. Last question from us. I believe you mentioned in the type 2 diabetes phase II, you will explore higher dose. Just curious, would you explore higher dose for obesity as well? And, given your tox study, do you need to do anything else before you can start higher dose 90 for diabetes and 120 for obesity studies? Thank you, Roger. I can take that as well, and Mark and Ray can elaborate if needed. So for both indications, the data is really encouraging to continue exploring higher doses, and that would be the plan. Now, we'll need to collect more data, as Mark displayed in his presentation. We're conducting the formulation bridging study with the tablet up to 120, and these piece of data, along with the 24 new replacements and the PK/PD modeling and simulations that the team already started, will further inform on the dosing for the next studies. But we agree with you that the ample safety margins that are reinforced by the 6- and 9-month tox data allow us enough room to increase the doses even higher for both indications, type two diabetes and the chronic weight management. And, Roger, I'll add on to that. You know, the purpose of a phase IIa study is really to learn, and we're really pleased. We learned a tremendous amount that we're now evaluating and will take into consideration as we design the future studies. Got it. Thank you. Thanks for all the comments. Thank you, Roger. One moment for our next question. Our next question comes from Jon Wolleben with JMP. Your line is open. Hey, thanks for taking the questions. I was hoping you could give us a little bit more detail on the 2Q data we're going to get. I know you're enrolling 24 more patients. Are we going to get body weight from them as well, or just, you know, continued 12-week data from the 8-week results we've seen today? Yeah, so in Q2, we have two sets of data coming up. One will be the full 12-week data for the phase IIa obesity/overweight cohort, and that will include 64 subjects up to 12 weeks with safety and tolerability data, and 40 subjects, approximately 40 subjects, including the 24 replacements with efficacy data. So that's one data set that is on target for Q2. And then the other piece of information for Q2 will be the results of the formulation, the capsule to tablet, that both part one and part two will be completed. And in part two, this is, as Mark presented, a 12-week data study with two arms targeting 120 with a tablet, and then we'll have also the cross comparison at 60 mg between capsules and tablets. So that will be the second data set, more focused on the tolerability and the safety than in efficacy, but of course, we'll look at everything comprehensively. Got it. And I was hoping you could comment a little bit on the lack of dose response here. And have you looked at the PK data? Did it behave as you expected? And, will you plan on releasing PK data from the study or the 12-week update to 2Q? Yes, I'll, I'll take that as well. So the lack of dose response is a good observation. We were not expecting to see differentiation in doses in a 12-week study between 45 and 90, and that's how the study was designed. That's why you see that in the 45 arm, we included 10 subjects versus 26 in the 90 mg. So the design of the study was not to detect differences between 45 and 90, but your point is well taken. And within 12 weeks, it's extremely difficult to see differences in weight reduction. When you looked at other programs, the curves are overlapping when it comes to different effects of the different doses. So we're not surprised to see that. I think what it's really encouraging is to see, significant levels of efficacy in type two diabetes as low as 45 mg. So that's, that's one, and then can you remind me of the second part of your question? My apologies there. PK data. PK. Did it behave as you expected, and when you might release that? Yeah, good point. Thanks. So the PK will be released once we have the completion of the phase IIa obesity cohort, with the completion of the 24 replacements, in addition to the full PK of the tablet, the new formulation that we're planning to conduct the studies for phase IIb. So that will be 2Q 2024. Got it. Okay. Thanks again for taking the questions. Thank you. One moment for our next question. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open. Yep. Good morning, team. Thank you so much for taking the question. I have a few for you. I would like to just go one by one, if that's okay. Maybe the first question is, today's data in regards to discontinuations look really strong. I mean, I think you guys guided in the teens, and you ended up at 2.8%. Could you maybe comment on what you hope to see in cohort four, that you're going to report out in 2Q? What's, you know, like, now, what is the expectation, right? Do you want to be in that ballpark below 5%? What are you seeing so far? Maybe we can start there first and then a few more follow-ups. Yes, thanks for the question. So in cohort 4, up until 12 weeks for the 40 initial subjects enrolled, we have not seen any discontinuation of the study due to adverse events. And so this is really encouraging. Of course, the 24 enrollment subjects is ongoing, and we don't have any data in there, but what we can report very clearly is that in the 12 weeks for the initial 40 subjects, we didn't see any discontinuation due to adverse events. Got it. Thank you. And then I know, earlier in the call, I think when you followed that slide 23, you plotted nicely the weight loss curves, versus other products. And if you follow that line, you would expect that in cohort four, you would get, you know, that 8% weight loss, and maybe placebo would be 1% or 2%. Like, I guess, as like—what are the assumptions that could tell us that that curve or that extrapolation or prediction is right? What could be some caveats that could maybe deviate from it? Could you maybe, you know, I think a lot of investors are going to look at that and expect that sort of as the bogey into the next read out, and I just want to be mindful of, like, how accurate that really is going to be and what that standard deviation of that number would likely be? Yes, thanks for the question. The data that it shows right now, both in diabetes, but specifically in the cohort four in the interim analysis, and that trend downwards within the first 8 weeks is really encouraging to see that the profile is competitive with what has been presented. And we're on track to present the results at 12 weeks, and we're encouraged to see these data at 8 weeks. I think, you know, you're bringing up a good point. It's not just the point estimate that it's important, but it's also the shapes of the curves, and the shapes of the curves being trend downwards and without a plateauing effect, we see this as a very positive sign. And it gives us, you know, a lot of excitement to look into the 12-week data in Q2 2024. Okay. And then the other item that I think a lot of investors have noticed is that the nausea rates are, you know, high. I guess even though discontinuations are low, like, could you maybe talk about the severity of the, you know, nausea, vomiting, and diarrhea? Like, are these grade one or grade two? Like, and then also when you broke down the bar graph week for week, there would be one week where nothing is recorded, and then the week after you see, like, a increase. So like, is it like, why is there, like, a little bit of fluctuation as the weeks continue? If you could just maybe talk about that, and then I have one last question. Yes, thank you. So the majority of adverse events, including nausea, vomiting, and diarrhea, were grade 1 or grade 2, especially in the nausea and the vomiting, but also applicable to the diarrhea event. As we all know, the nausea is somehow subjective, and that has been reported in different programs, but the severity was between 1 and 2. The fluctuation in the slide over time, I think it's something expected. Because again, sample sizes for the group of 45, for instance, we had 10 subjects, and so having 2 episodes of nausea in a determined week kind of skewed the percentages. But I think it's important to look at the trends, and there were weeks with no events of nausea or vomiting towards the end of the study, despite subjects having at 45 or 90 mg. So that's the interpretation of the data in terms of the adverse events. Great. And then the last question is, I think just, you know, a lot of investors have seen quite an uptake in M&A in obesity. Obviously, you will continue to generate, you know, strong data sets, a differentiated product, especially on the safety side and competitive weight loss. Could you maybe capture, you know, now with the utility of this data on hand, how you plan on... What are your thoughts on partnering this program? Hey, yeah, this is Jun. I'll take that question right now. So basically, you know, we recognize that the obesity and metabolic disease market is very large and, you know, as you stated, you know, we'll require our strategic partner to help us with late-stage development and commercialization. So with this comprehensive program update, the early round of data that we have in obesity, we want to enable the ability to accelerate, you know, phase IIb and be also in the best position for a strategic partnership at the right time as we engage with potential partners. We've had a number of inbounds over the past few months, given both the activity in the space as well as our GSBR-1290 program and the broader franchise, and we expect this interest to grow and continue to move in that process. Thank you so much, and I'll jump back into the queue. So ladies and gentlemen, this concludes the Q&A portion of today's conference. I'd like to turn the call back over to Jun for closing remarks. Great. So, thank you again for listening. In summary, the data that we've shared today shows that we've got an active molecule. The safety and tolerability results are very encouraging and differentiating, and we have a clear path forward to longer-term data, particularly on weight loss, where we are observing downward trends with no signs of plateauing. Thank you all for listening and joining the call today, and we look forward to continuing our programs and making medicines more accessible to all, and we'll follow up with any questions separately. Thank you, ladies and gentlemen. This concludes today's presentation. You may now disconnect and have a wonderful day.