Good day, and thank you for standing by. Welcome to the Structure Therapeutics GSBR-1290 phase Ib data conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Danielle Keatley of Structure Therapeutics. Please go ahead. Thank you, and good morning, everyone. Earlier this morning, we issued a press release providing an overview of positive results from our phase Ib clinical study of our oral GLP-1 receptor agonist, GSBR-1290, as well as a program update. 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 are Dr. Raymond Stevens, founder and CEO, Dr. Mark Bach, Chief Medical Officer, Dr. Blai Coll, Vice President of Clinical Development, and Jun Yoon, our Chief Financial Officer. 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 two. 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 10-Q, filed with the SEC and any other future filings we may make with the SEC. You are cautioned not to place an undue reliance on these forward-looking statements, and Structure Therapeutics disclaims any obligation to update such statements. I will now turn the call over to Dr. Raymond Stevens, CEO of Structure Therapeutics. Thank you, Danielle. Good morning, everyone, and thank you for joining us today. For those of you following along, I will begin on slide five. I'm very pleased to be here today with our team to present our positive phase Ib MAD data for our GLP-1 oral small molecule, GSBR-1290. First, I want to briefly level set so we're all on the same page on the overall goals of Structure Therapeutics. We believe the GLP-1 class of drugs has the potential to become one of the biggest class of medicines to help modern-day society for the treatment of type 2 diabetes, obesity, and potentially other related diseases, including NASH. There's been a very exciting development in the field over the past 20 years, with the initial discovery of injectable GLP-1 peptides, as shown in the top of the slide. Our solution is to make this class of medicines more accessible by making it orally available with true small molecules that will be more accepted by patients. With our expertise and strong investment in structural biology, we have early mover advantage with our selective GLP-1 agonist, GSBR-1290. I'll also highlight the breadth of our pipeline, as you can see on the bottom half of the slide, with our dual GLP-1/GIP small molecule agonist, as well as our amylin small molecule, now in lead optimization, with DC set for both of these molecules for next year. We're excited to share with you the positive results from our phase Ib multiple ascending dose clinical study of GSBR-1290, as highlighted on slide six, which Dr. Blai Coll and Dr. Mark Bach will discuss in greater detail. As a high-level summary, the study achieved its objectives of evaluating the safety and tolerability of GSBR-1290 in 24 healthy, overweight, or obese individuals. In the 28-day study, GSBR-1290 demonstrated significant weight loss, supporting once daily dosing in an encouraging safety and tolerability profile. Importantly, no participants discontinued study drug due to adverse events. We believe these positive 1b results strongly support the ongoing and future development of GSBR-1290 as a potential best-in-class oral GLP-1 receptor agonist with a differentiated profile. In review of our overall development program for GSBR-1290, as a reminder, in August, we announced that our placebo-controlled phase IIa study to evaluate GSBR-1290 over 12 weeks of treatment was fully enrolled with two cohorts in type 2 diabetes and obesity. Top line data from the phase IIa type 2 diabetes cohort remain on track for the latter half of the fourth quarter of 2023. Regarding the obesity part of the phase IIa study, this part of the study explores a once-daily target dose of 120 mg up to 12 weeks. As a reminder, our target weight loss at 12 weeks is 5% or better. The protocol was executed as planned, with the exception of weight measurement at week 12, which was not collected for 24 of the 40 participants. This was due to a data collection omission at a clinical trial site. Other safety and laboratory assessments were measured at all visits, including week 12 visit, as per protocol. We want to note our frustration, but importantly, this was an isolated incident. We have discussed the issue with our CRO and are putting measures in place, such as additional on-site monitoring, to ensure that this does not happen again. To be clear, we do not see any read-through to other parts of the GSBR-1290 development program, and we plan to replace those 24 participants for whom 12-week weight data was not collected. The replacement participants will follow the same study protocol without changes in the titration schema or target dose of 120 mg once a day. This will result in data being available in the first half of 2024.... While we remain blinded to the data from the phase IIa study, there's one very important piece of information from the phase IIa obesity cohort that I would like to highlight for you. There were no study drug discontinuations due to adverse events through the end of the study at 12 weeks for any of the participants in the phase IIa obesity cohort, including participants whose weight was not collected at week 12. This is quite important information to us. To reiterate, there were no discontinuations due to adverse events all the way up to and including the 120 mg dose in the obesity cohort of the phase IIa. Importantly, this delay in reporting of the obesity results from the phase IIa study will not impact our overall development timelines for GSBR-1290, as Dr. Mark Bach will describe later during the call. We plan to initiate the two phase IIb studies in type 2 diabetes and obesity as planned in 2024. I would now like to turn the call over to Dr. Blai Coll, Vice President of Clinical Development at Structure Therapeutics, who will be presenting the top-line data of the phase Ib MAD study. Thank you, Ray. Let me start by saying we are encouraged by the data we're going to share with you for three main reasons. First, we see early signs of clinical efficacy as early as 4 weeks for the two top doses, 60 mg and 90 mg. Second, GSBR-1290 demonstrated an encouraging safety and tolerability profile. And third, the efficacy results support once a day administration. But before diving into the details of the data, let's project slide eight. I would like to level set everyone and briefly review the design of the study. This was the phase Ib, four-week multiple ascending dose study. Key eligibility criteria were defined by the presence of overweight or obesity, defined as a body mass index of at least 27 and less than 40, but otherwise healthy individuals and aged 18 to 75 years old. These criteria are consistent with similar studies performed in the incretin space. We designed this study in three different cohorts to assess different target doses and titration schemes. Cohort one had a target dose of 60 mg a day, started at 5 mg, and followed a weekly titration of two or threefold increase in dose to the 60 mg target. Cohort two target dose was 90 mg. Subjects started at 10 mg and followed a weekly titration that ranged from 1.5- to threefold increase to the target dose of 90. Cohort three had a target dose of 30 mg, started at 10, but unlike the first two cohorts, remained at each titration step for two weeks to the target dose of 30 mg. All participants in all the cohorts were dosed once a day, and the administration was given with fold. For the rest of the presentation, I will refer to the different cohorts as the target dose of 30, 60, or 90. The primary objectives of the phase Ib study were safety, including adverse events and tolerability parameters, along with laboratory variables and vital signs. Secondary objective included, as part of the exploratory analysis, the effects on body weight after four weeks of dosing. So with that in mind, let's move to slide nine. The study randomized 24 participants, six allocated to each group of GSBR-1290 and six subjects to placebo. Importantly, no participant discontinued study drug due to an adverse event. I also want to highlight that there were no subjects who had their dose down-titrated or paused, and all but two subjects completed the study. The two participants discontinued due to personal travel reasons, one in the 90 mg group and one in placebo. In the next slide, you can find a description of the baseline characteristics. In summary, participants were predominantly female, average age between 41 and 49, and the rest of baseline characteristics, including body mass index, consistent across groups. These baseline characteristics are generally in line with those of similar phase Ib, multiple ascending dose studies conducted in this space. The first data set that I want to share with you is regarding efficacy, shown on slide 11. We acknowledge the small sample size of the study and the short period of time of exposure, and those two variables should be taken into account in interpreting the results. With that said, the study demonstrated a significant reduction in weight at four weeks for the 60 mg and 90 mg doses of GSBR-1290. In the left panel, we describe the weight changes in kilos over time. The gray line indicates participants on placebo, the light blue subjects on 30 mg, and the darker blue lines represent subjects at 60 mg and 90 mg respectively. As you can appreciate, for the two top doses of 60 mg and 90 mg, the curves started separating from placebo in the first week and continue separating through day 28 to achieve an approximately 5 kg reduction in weight. Both the 60 mg and 90 mg groups achieved a statistically significant difference in weight loss when compared to placebo. On the right panel, we describe the percentage weight change from baseline to day 28. Participants at 30 mg achieved a 1.6% weight reduction, the 60 mg group reached a 5.2% weight reduction, and the 90 mg group experienced a 5.4% body weight reduction after 4 weeks of dosing.... In the table below, we show the results adjusted by placebo, with up to 4.9% reduction in weight at day 28 in the 90-mg cohort. For both 60 mg and 90 mg groups, the differences in percent body weight change were statistically significant compared to placebo after four weeks of treatment. In summary, I want to reiterate that although preliminary, due to the length of the study, four weeks of dosing and the sample size, six subjects per arm, we interpret these results as encouraging early signs of efficacy. These weight loss results for GSBR-1290 were consistent with another metric of efficacy, a reduction in fasting plasma glucose, which is described in slide 12. Compared to baseline, subjects receiving increasing doses of GSBR-1290 experienced reductions in plasma glucose, ranging from 7 mg-8 mg per deciliter, placebo-adjusted. As you know, the subjects enrolled in the study were not diagnosed with diabetes, so we need to be cautious about the interpretation of the glucose reduction. That said, these results are consistent with other GLP-1 receptor agonist molecules, so we see this as encouraging and supporting evidence of clinical activity. Lastly, to complete the clinical activity section of the presentation, I want to move to slide 13 and show the data on heart rate. Increased heart rate has been consistently described in studies of the majority of the GLP-1 receptor agonist drugs, and we also observed that effect with GSBR-1290. The heart rate increases range from four-10 beats per minute, placebo-adjusted, without dose response, which is also in range observed for other GLP-1s. Moving to safety and tolerability, slide 14 shows that no participants experienced a severe or serious adverse event. The majority of AEs, 50%-66%, were mild based on the principal investigator's categorization, and as indicated on slide 15, the majority of adverse events, as expected, were gastrointestinal and dose-related, with higher incidences of nausea and vomiting in the higher doses of GSBR-1290 compared to 30 mg and placebo. Specifically, 83% of subjects at both 60 and 90 experienced at least one event of nausea, compared to 16% in the 30 mg group. The second most common GI-related adverse event was vomiting, and half of the subjects at 60 mg and 90 mg had at least one event. We saw similar incidences of diarrhea, and the rest of gastrointestinal events listed in the table were less commonly observed. We know this tolerability profile can be optimized in future studies with refined titration schemes, but we wanted to highlight that those adverse events did not trigger any discontinuation of study drug. Beyond gastrointestinal adverse events, headache was the most common AE without a clear dose response. In terms of events of special interest, no subjects in the phase Ib study experienced clinically meaningful changes in liver function tests, and there were no events of hypoglycemia. To better characterize the gastrointestinal tolerability profile of GSBR-1290, I want to share with you the temporal course of the two most common adverse events in the study. On slide 16, we plotted the incidence of nausea in the Y-axis over time in the X-axis for the three cohorts. Blue bars indicate mild events, and orange indicate moderate events in severity. Starting from the left of the slide, the group with a target dose of 30 mg in every 2-week titration steps saw a stable incidence of nausea at 16% without any temporal trend, despite the up titration from 10 mg- 30 mg. For the participants with a target dose of 60 mg, they experienced varying degrees of nausea, peaking in the first week, 50%, and importantly, decreased over the course of the study while subjects were being up titrated to reach the target dose of 60 mg. For the group with a target dose of 90, we saw higher incidence of at least one event of nausea in the first week, peaking at 80%, with 30% of those events moderate in severity. Importantly, as seen for subjects in the 60 mg group, the incidence of nausea decreased while subjects titrated to the 90 mg dose. We similarly described the incidence of vomiting in the slide 17. We did not see any events with the lowest 30 mg target dose group. For the cohort with a target dose of 60 mg, all the events accumulated in the first week. For the cohort with a target dose of 90 mg, we observed a different pattern, with the highest incidence of vomiting coinciding with the week in which subjects were first titrated to the target dose of 90, with roughly half of the participants receiving GSBR-1290 experiencing at least one event of vomiting. As I stated before, and consistent with previous GLP-1 receptor agonist programs, we're confident that fine-tuning the titration schemes in subsequent studies will help achieve improved tolerability results. And that brings us to slide 18, which summarizes the findings of the phase Ib data presented. We continue to see GSBR-1290 to potentially be best in class in this space, and I want to highlight three key takeaways that support this. One, significant weight reduction at four weeks. Although preliminary, due to the sample size and the study duration, a weight reduction up to 4.9% placebo-adjusted, gives us confidence about the prospects of the molecule in moving forward. Two, an encouraging safety and tolerability profile without any participants discontinuing the study drug due to adverse events up to 90 mg in four weeks. And third, the clinical efficacy signs observed support once daily dosing. With that, let me turn the call over to Dr. Mark Bach, Structure's Chief Medical Officer. Mark? Thank you, Blai. So turning to slide 20, I'd like to review the current plan for the GSBR-1290 phase IIa study. At the top of the slide, you see the design of the type 2 diabetes cohort, with 54 participants randomized to receive GSBR-1290, 90 mg, 45 mg or placebo for 12 weeks, including a 4-week dose titration. Key endpoints include change in hemoglobin A1c and in weight. This group is ongoing, and the data will be shared in the latter part of the fourth quarter as planned. On the bottom of the slide is the outline of the phase IIa cohort with overweight or obesity. 40 participants were originally randomized to GSBR-1290, 120 mg or placebo. As Ray described, there were no AE-related discontinuations up to week 12. However, due to a data collection omission, the 12-week weight measurement was not collected for 24 of these participants. These participants will be replaced so that the dataset will include week 12 weight measurements for the full 40 participants, and for all other assessments and time points, we'll have data from the original 40 plus 24 replacement participants. These data will be available in the first half of 2024. Turning to slide 21. As you can see, GSBR-1290 is currently being evaluated in a comprehensive clinical development program, and we're making good progress. We're excited about the results of the phase Ib MAD study, which Blai described. On the left side of the slide, within this year, in addition to the ongoing 12-week phase IIa type 2 diabetes results, in the latter half of the fourth quarter, we plan to share key phase Ib and 2a data PK, as well as the results from our completed 4-week Japanese PK ethno-bridging study in 18 healthy Japanese and non-Japanese participants with doses up to 60 mg. On the right side of the slide in 2024, in addition to the results of the 12-week phase IIa cohort of participants with overweight or obesity, we're looking forward to sharing the results from a separate capsule-to-tablet formulation bridging study, which is expected to initiate in the fourth quarter of 2023 and complete in the second quarter of next year. Pending supportive data from this bridging study, the tablet formulation would be used for future GSBR-1290 studies, starting with the planned phase IIb study, which I'll describe next. In the second half of 2024, we're on track to initiate two phase IIb studies of GSBR-1290, including an approximately 26-week type 2 diabetes study, which is expected to include approximately 500 individuals across the United States, Europe, and Japan. In addition, an approximately 36-week study in participants with overweight or obesity is expected to include approximately 275 individuals across the U.S. and Europe. Let me now turn it back over to Ray Stevens. Ray? Thank you, Blai. Thank you, Mark. In summary, and on slide 23, on the top row, GSBR-1290 was designed from the start using our structure-based drug discovery platform to be a true once-a-day oral small molecule medicine with a promising safety and tolerability profile. We're very aware that to be successful in this area, one has to win on the molecule design, the formulation, and the titration schema. Based on what we're seeing today, with up to 4.9% placebo-adjusted weight loss after four weeks with once daily dosing and no AE-related discontinuations in our 1b study, we believe we've selected the right molecule. In addition, we're pleased to report today that there were no study drug discontinuations due to adverse events in our blinded phase IIa obesity cohort, up to and including 120 mg and after 12 weeks of dosing. We're also completing our six- and nine-month tox studies with no issues observed to date, and we'll report this data together with a type 2 diabetes phase IIa clinical study later this year. In summary, we believe we have a promising drug in GSBR-1290, which reinforces my confidence that it has the potential to be a best-in-class oral agonist for the GLP-1 receptor for the treatment of type 2 diabetes and obesity. We look forward to the phase IIa data coming out in the latter half of Q4, in the first half of next year, as well as the initiation of our phase IIb studies in obesity and type 2 diabetes in 2024. Beyond GSBR-1290, in the middle row, we're making progress with our dual GLP-1/GIP dual agonist. Hits have been identified and lead optimization is underway, with a plan to deliver a DC in 2024. On the bottom row, our amylin program, we're also making good progress with our oral small molecule amylin receptor agonist. Hits have been identified and lead optimization is underway with our partner, Schrödinger, using their free energy perturbation technology. This will accelerate our program with an intent to deliver a DC in 2024. At the very bottom of the screen, you'll see our thinking on the evolution of the incretin metabolic space and life cycle management for us to be a major player in the fight against diabetes, obesity, and related diseases. One last item to note is that we're very pleased to have concurrently announced this morning a $300 million private placement. As I noted, the GLP-1 space is competitive, and we believe this financing provides us with the capital we need to continue advancing GSBR-1290, as well as our other programs, as expeditiously as possible. With this positive phase Ib data, we strongly believe that we have a potential best-in-class molecule in 1290, backed by a strong portfolio with our combination programs. It is a top priority for us to move these forward rapidly. We would like to thank you all, all of our investors, for your support. Thank you for listening. I would now like to turn the call back to the operator, so we can start the Q&A. Thank you. As a reminder, to ask a question, you will need to press star one, one on your telephone. Please stand by while we compile the Q&A roster. Our first question comes from the line of Roger Song from Jefferies. Great. Congrats for this impressive data and successful financing. A couple from us. First one, maybe Ray, you can kind of set, maybe update your expectation for the weight loss for your 1290, given at four- week already achieved the previous guidance of 5% placebo-adjusted weight loss, which is very impressive compared to the field. Maybe that's my first question, and a few... I have two others follow-up. Thank you. Yeah, absolutely, Roger. Thank you for the question. I'm going to turn that question over to Dr. Blai Coll. Yes. Thanks, Roger, for the question. We're encouraged by the data at four weeks, but we also want to recognize that it's early in an obesity-related study. And so we are keeping our indication in terms of what we expect from the phase IIa study. Of course, the data that you've seen is encouraging, and we're very much looking forward to have the results of the phase IIa study. As a reminder, we power the phase IIa study to detect at least a 5% reduction at the end of the 12 weeks, and we remain excited about this, and we're looking forward to share the results with you in the latter half of this quarter. Excellent. Okay, so maybe two other questions related to the tolerability kind of profile, given we know GLP-1 is not just for the efficacy as a chronic treatment. So the first one is the GI tolerability. I think you mentioned a little bit about the potential dosing optimization can further improve the GI tolerability. Maybe just give us a little bit color around that. Also, I want to confirm you have not down titrated your patient in your obesity cohort in both phase Ia, IIb, and phase IIa. I have another question related to the heart rate increase. Thank you. Thanks, Roger. I'll take that. So let's just start with the down titration first, just to clarify. So in the four-week study that we just presented, there were no down titrations or subjects putting on hold due to tolerability issues, and as you've seen, there were no discontinuations due to adverse events. In the phase IIa data, the cohort of subjects with overweight or obesity, we remain blinded, but we can share with the group that we have not seen discontinuations due to adverse events. We have down titrated subjects that have been down titrated in that 12-week study, but as I said, we remain blinded, and we will report the results once they're available. In terms of your first question, and thanks for bringing up the gastrointestinal tolerability, because as you can imagine, it's front and center for our program. So what we are constantly looking is in ways to optimize that tolerability, and we see the results that we've presented today as an encouraging and early signs of target engagement. Of course, that tolerability can be optimized and can be improved, and we'll take these data along with the phase IIa data sets to inform how to best design the titration schemes for the phase IIb, that Dr. Bach presented to you in his opening remarks. And so that's how we looked at the tolerability, taking the learnings from these phase Ib and phase IIa studies, to help us inform what would be the best starting dose, what would be the best titration scheme, and also to inform the target dose that we will pursue in the phase IIb studies. Hope this clarifies your question. Excellent. Thanks a lot. Maybe just a very, very quick last one. In terms of the heart rate increase, four-10, within this four-week, how should we contextualize this magnitude and the kinetic of the heart rate increase, particularly compared to other small molecule GLP-1 specific kind of compound? Thank you. Thanks for your question. Definitely an important topic. So what we know from the field of GLP-1 receptor agonist and also for others in the incretin space is that it's commonly reported that increase in heart rate, especially in the short-term studies phase Ib, IIa, and that's been reported previously. You mentioned other small molecules in the field, and there's been a range of increases in heart rate, placebo-adjusted from other programs between five and 13 beats per minute. Just as a reminder, we saw an increase of four-10 beats per minute, placebo-adjusted. So we think that it's comparable. Again, we interpret this as a sign of GLP-1 receptor engagement. What we also know from the field, and we're confident that we're going to see a similar pattern, is that with longer exposures, there's tachyphylaxis phenomenon, and that increase in heart rate subsides and gets back to the baseline situation. Looking forward to continue surveilling, and we'll of course have a close look into the future programs on the heart rate, and we'll report the results accordingly. Perfect. Thanks a lot for all the color. Congrats again. Thank you. Thank you. One moment for your next question. Your next question comes on the line of Yasmeen Rahimi from Piper Sandler. Good morning, team, and congrats to the data. A few questions. I think the first one is, why unveil the data, MAD data today? I think you've been very, very consistent over the last few months saying: We're going to wait till year-end and put the data all together instead of, you know, maybe just sharing ahead. Obviously, the data looks really great, but, but just the rationale, why, why change the communication? That's question one. Question number two, a lot of clients are interested on understanding if any liver enzyme excursion occurred, even... were, were liver enzymes measured, were they sustained at normal range? Was there any cases of, you know, excursion, even as greater than twofold upper limit? And then a couple, two more, follow-up questions for you. Hi, Yas. Thank you for the question. Appreciate it. So I'll handle the first question, and then I'll let Blai handle the second question. So the first question that you asked is, why release the data now? And, and you're correct. We have all along been messaging that we would release the 1b data together with the 2a data at the end of this year. When we realized that there would be a delay in releasing the obesity cohort for the 2a data, we made the decision to unblind the 1b data. When we unblinded the data and we saw the efficacy up to 4.9% placebo-corrected weight loss, we realized that that was materially relevant, and we needed to disclose that information. So that, that was the logic behind the disclosure. So what this also does is this allows us to now release the 1b data today. Just to remind everybody, we'll be releasing the type 2 diabetes cohort 2a towards the end of the year, and then we'll be releasing the 2a obesity cohort in the first half of next year. Blai, you want to take the second question? Yes, thank you. And Yasmeen, thanks for the question. In regards to the liver enzymes, we've presented earlier in slide 15 the mean change from baseline to day 28 in ALT and AST. And as you can see in the table, there's no clinically meaningful changes in any of the two liver parameters in any of the groups receiving GSBR-1290. More importantly, and I think you're spot on in your question, we also looked into the dataset to identify any participant with a threefold increased upper limit normal in any of those liver function tests, and we did not find any participant fulfilling that condition. So we're confident about that. And of course, we'll continue monitoring. That's part of the safety surveillance, and we'll continue monitoring, but this data is positive up until now. Thank you. And then two quick follow-ups. One is just the site, the one site that had 24 patients, that they didn't measure weight, which is quite insane. If you think about it, they're running a weight loss study. Is that-was that site involved in the 12-week obese cohort at all, or they just only ran the obese diabetic cohorts? If you could clarify that, that would be great. And then one last one for you. Yes, I'll take the site question. So that site is also participating in the type 2 diabetes. When the event happened and we got notified from our CRO, we of course conducted a deep dive surveillance and analysis of the whole study, and we can assure you that there's no other systematic omissions, and so the data will be accurate, and we are confident about the integrity of the results and the integrity of the data. Thank you. And then the last- Yas, sorry, just for one more piece of clarity. So just to confirm, we have four different sites all in the United States, because that's a question that we received. Got it. Thank you. And then last question is, I think a lot of investors are now wondering, you know, what's the kinetics of weight loss going to look like for the product? And I know you powered the study for 5%, but you got about, you know, almost 5% at month one. So could you maybe remind us the kinetics over time with the other oral GLP-1? and what we should see, like, if, if you got five at month one, you know, I think a lot of the expectations may shift in a different, higher direction. So we'd love to hear, like, your thoughts on this. Do we just can we, can we, you know, beat this further at the longer time point? And I'll jump back into the queue, and I appreciate you taking all my questions. Thank you for the question, Yasmeen. So the kinetics of weight loss is, your question is really spot on. As we said in the beginning, we see those results at four weeks as encouraging, but we also know that at four weeks is a short period of time to see the full effect and to see the full dynamic and kinetics. When compared to other small molecules in the field, data has been presented up to four weeks with a placebo-adjusted rate, weight reduction of around 3.6%. As we presented, we achieved a 4.9%, and that gives us confidence to look forward for the type 2 diabetes, where we will have the 12-week data. And, as we said, we will present the results at the end of the quarter. It's difficult at this point to speculate what will be exactly the kinetics, because of the early signs at four weeks when it comes down to weight. Thank you so much. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Seamus Fernandez from Guggenheim Securities. Great, thanks for the question. So, a few questions here, and, you know, congrats on the, the four-week data. Maybe, first off, just, if you can clarify for us, exactly, what is going to be included, in the phase IIa presentation of the diabetes patient population, and will you share the baseline characteristics, of that patient population ahead of time? The only reason that I ask that is because, in prior studies, HbA1c, you know, where it has been materially higher, has negatively impacted weight. So, you know, and for obvious reasons, because of the, the, the glucose storing capabilities and insulin catalyzing benefits of GLP-1. So just wanted to get clarification on that. And then, second question is, as we, you know, think about the full presentation of the phase IIa data in the first half of next year, can you just help us understand, how the groups and the data will be presented, you know, for the patients that, I guess, will need to be excluded from the weight loss data at 12 weeks? What will be included from a safety perspective, at 12 weeks? So, we'll—I assume we'll get all 64 patients, presented in that data set. And then separately, just interested to know if we'll see the full 64-week patient data at eight weeks, because it's my understanding that those data were collected for weight loss, up to that point. I have a couple other follow-up questions. Blai? Yeah. Thank you, Seamus, for the question. So let's talk about the first one, and this is in active discussion right now. We're well aware of that connection between potential discrepancies in HbA1c at baseline and how that influenced the weight loss signal. So we're constantly discussing this, and we appreciate the recommendation. We'll get back to you, but certainly, this is an option that we can implement. In terms of the second question on what is going to be presented, so in the latter half of this quarter, we'll present the full cohort of subjects with type 2 diabetes. This is a study of 54 subjects with type 2 diabetes, in which we tested two different doses of GSBR-1290, 45 and 90 versus placebo, with the primary endpoint of safety and tolerability, but also importantly, the secondary endpoints then to assess the decrease in HbA1c, the changes in weight, and also the dose responses and exploratory analysis. So all these data package, we're on track to present it by the latter half of this quarter. In terms of next year for the cohort with overweight or obese and, and due to the omission of the data, as you've heard, we are planning to replace those 24 subjects. So what we will have is a data set of efficacy that will encompass the 40 subjects up until 12 weeks with efficacy data. But of course, we'll have data in terms of safety, in terms of tolerability, labs, and ECGs out of 64 participants. And so in a way, we're expanding that cohort to 64 subjects, and so we'll have a better sense in terms of safety and tolerability. Your question about the weight measurement, we do have weights collected up to week eight, as indicated per protocol of the original 40 subjects. And so we remain blinded to that data, and we want to keep blinded after deciding to replace those 24 subjects. We don't want to contaminate the study, and so we will remain blinded. Right now, the team is laser-focused to replace those 24 subjects as soon as possible, and as I said, we'll report the efficacy data out of the 40 subjects in the first half of 2024. Hope that answers your two questions, Seamus. Yep. No, that's super helpful. And then, you know, I guess one point is just the 90% confidence interval that you disclosed, and thanks for including that. I think not a lot of companies would include that, but I believe Lilly did also disclose this in their four-week data. Confidence intervals here look very consistent, but the breadth of the 90-mg confidence interval on weight just wondering if you might be able to help us understand that in terms of the patient who, you know, lost considerably less weight. Was this a patient who was uniquely, you know, overweight? And so we might have some learnings in terms of the dose-exposure relationship in that regard from this study. So just interested to know if there's any dose exposure information that you've learned from this original, I guess, four-week data set. That's obviously very, very abbreviated, so I'm guessing no, but question. Thank you, Seamus, for the question. This is top-line data, so the team is looking at the data as we speak, and we're very much looking forward to look into the PK/PD, and that will be a focus of work for the team in the following days. And yes, you're spot on. I think the variability, we're interested in providing that confidence interval because it's the right thing to do, especially when we're talking about a study of 24 subjects overall. And we see, we expect to see that kind of variability. I think what is important as a bottom line is that even when you looked at absolute change in weight percentage and placebo-adjusted, the data is pointing in the same direction, and there are clear early signs of efficacy. Great. Last question, and I guess this is for the Ray and the team overall. You know, we're seeing, I think, really good early results here. We also know that there is some complexity to the structural backbones that get used between these different oral agents. Just hoping you could help us understand your thoughts around the targeting of biased molecules versus unbiased molecules, what you believe you're seeing in these results, and should we be thinking about GSBR-1290 as a backbone, you know, sort of structural molecule, you know, such that an agonist-agonist rather than a co-agonist profile may, in fact, make more sense, both from a manufacturing perspective as well as a future kind of design and planning perspective, as you advance the rest of the pipeline? Thanks so much. Yeah. Thank you, Seamus, for the question. And if I don't fully answer your question, if you could rephrase it, 'cause the first part, I understood. The second part, I was a little bit confused by. So on the first part of the question, we do believe that biased signaling is important for this class of drugs. As many of you know, what biased signaling means is that we want to only signal through one pathway, the G protein pathway, and we want to avoid the pathway which causes receptor internalization. By avoiding this receptor internalization, it leaves the receptor more on the cell surface. This allows the drug to act longer, which means that we can get the dosage lower. So that's the hypothesis behind the biased versus non-biased signaling. The second question that you asked, I wasn't quite clear on. If you could rephrase, please. So there's, I guess, two ways to proceed, you know, sort of your next-generation assets, whether it be amylin or, or GIP. One is an agonist-agonist approach, where it's two separate molecules, but where GSBR-1290 is your sort of structural backbone molecule. Alternatively, you could develop co-agonists. Just trying to get a better understanding of what you think the most realistic approach is going forward and how you're, you know, sort of evolving your pipeline from here. It strikes me that 1290 and kind of the complexity of manufacturing some of these assets, you know, you wouldn't want to necessarily mess with that too much when you're generating data like this, and perhaps an agonist-agonist approach might make the most sense. Just trying to better understand what you think is the most realistic, best approach here and how you're thinking about 1290 with at least these preliminary data? ... Yeah, absolutely. Now I understand your question, Seamus. Thank you so much for clarifying, and it's an area that we're very excited about with small molecules. So we're taking both approaches. It's what we call the sort of fixed dose, where we can make two different molecules and combine them. But we're also taking the approach with our structure-based drug discovery, structure-based drug design, where in our GLP-1/GIP, we have a single molecule that hits both receptors, very similar to what we've seen in the peptide space as well. So it's still early days. We're parallel processing the co-formulation approach versus the single molecule for GLP-1/GIP. In the case of amylin, amylin is quite uniquely different than GLP-1 or GIP, and so because there's enough differences, that's likely going to be one that is combined, where we have two different molecules that are combined together. Excellent. Thanks so much, and congrats again. Yep. Thank you, Seamus. Thank you. One moment for our next question. Our next question comes from the line of Evan Seigerman from BMO Capital Markets. Hey, guys. This is Keith on for Evan. Congratulations on the data. Just have a few questions for you. The first is, can you remind us what you think might be driving the excellent tolerability here? Would it be, you know, I guess, in order of priority in terms of drug exposure, baseline characteristics, meaning obese versus type 2 diabetic, and then also the drug design, and then I assume the four-week data is a bit too early to observe the benefits of the biased agonism. Would those start to show up meaningfully at week 12? And then could you compare the dosing titration schedules across 1b and 2a? And I just have one follow-up. Yeah, Keith, I'll take the beginning of the question about the drug design itself, and then I'll let Blai answer the following questions that you asked. So in terms of the drug design, you know, what we believe is we've tried to optimize a molecule for safety, tolerability, and efficacy, trying to combine all of those. GLP-1 class of drugs with the on-target effects that we've been talking about today, we really believe that you have to balance tolerability as well as the efficacy, and obviously safety always being at the top. So from the very beginning, we tried to design a molecule that optimized for all three of these, where we would really be able to improve on the tolerability challenges that's faced, as well as, we're very proud of our safety profile. We've taken this molecule all the way to 1000 mg per kg in rat in our NOAEL. So very safe molecule, designed for improved tolerability and of course, the high efficacy, and as you heard from the previous question, you know, we do believe biased signaling is important to help in terms of getting the dosage as low as possible. Blai, you want to handle the second part of the question? Yes. Thanks, Keith. The titration schema for the type 2 diabetes cohort is very similar to the one that you've seen here in cohort one. We have weekly titrations, and the fold increase is very similar. The only thing that we added there in the top dose, in the top arm, was the 90 mg step, and those subjects will continue for eight weeks on a 90 mg target dose. That's the high dose arm of that cohort. We're also, and have another cohort with a target dose of 45 mg, and they started the same, starting dose 5 mg. Of course, the titration for that 45 is not as high, and the increases are lower, but it's a 5 mg, 10 mg, 20 mg and 30 mg, and then remain on 45 mg for the remaining of the study. So it's a weekly titration on both cohorts for the type 2 diabetes, and then for the obesity, it's also a weekly titration, and we're targeting a higher dose there at 120, and subjects remain on 120 for the last six weeks of the phase IIa study. Hope this clarifies the question. It does. It does. Thank you. And then, I guess, given the impressive tolerability, could you just walk us through expectations, I guess, of improvement on, from the capsule to tablet PK bridging study? And then lastly, could you just, maybe talk about the expenses or the impact of expenses for re-enrolling of the 24 patients? Are you guys covering that? Is the CRO covering that? How should we think about that? That's it for me. Thanks. Thanks, Keith. I'll take the tolerability question. Indeed, we are pleased with the data that we reported, no down titrations, no discontinuations due to adverse events. We also acknowledge this is a four-week study, and so we need to be cautious about future studies as well. We know the field and we know that tolerability in terms of gastrointestinal. It's also encouraging to see that in the 12-week study, targeting 120 mg of the overweight and obese subjects, we have not seen discontinuations due to adverse events. But I want to also put a word of caution. It would not be unreasonable, and we would not be surprised if we see discontinuations due to adverse events in the group of type 2 diabetes. This is a different patient population, more fragile individuals with concomitant conditions and concomitant medications. And so we're pleased, as I said, with the data that we're reporting, but we will continually monitoring that very, very closely. We know that this tolerability, in terms of the gastrointestinal effects, can be optimized, and this is front and center for the program. Let me turn it over to Ray to talk about the other questions.... Yeah, Keith, so the clinical site has accepted responsibility for the error that occurred, and they are covering the costs for the additional 24 study participants. All right, terrific. Thanks for answering my questions, and congratulations again on the data. Thank you, Keith. Thank you. Thank you. One moment for our next question. Our next question comes from the line of David Risinger from Leerink Partners. Yes, thanks very much, and let me add my congratulations on the phenomenal results. I have three questions, please. I'll just go one by one. First, the fact that no patients down titrated is a meaningful positive surprise. Could you add some more color on what drove that outcome and your expectation for the forthcoming phase IIa results? David, this is Blai. I'll take that question, and thanks for pointing these out. This is a four-week study. We've reached 90 mg, which is, as you've said, as you've seen, an efficacious dose. But again, I want to remind everyone that this is a four-week study. There's been other programs in the same field using selective GLP-1 with just a handful of discontinuations, one or two subjects discontinuing at the end of the four weeks. So it's not that unusual to not see a lot of discontinuations in a relatively short period of time. But again, I think we're pleased with the data that we're seeing, and we'll continually monitor that. This is a high priority for the program, and we're constantly monitoring that in order to identify strategies and tactics that we can do in order to improve them. Thank you. Then, thanks for sharing the comments on no grade 3 ALT or AST elevations, Blai. Could you also comment on grade 2, plus share your perspective on 1290's liver tox differentiation versus Pfizer's danuglipron? Yeah, thanks. So liver function test, of course, is as well front and center for the program. We interrogated the dataset from different angles. We've presented in the slide the change from baseline, and as you've seen, there's no clinically meaningful changes there. There's of course, variability, biologic variability in the measurement and we need to interpret that, but that's why we were very, very interested in looking at a more categorical threshold. And as I pointed out in the presentation, we have not seen any individual with a threefold increase, upper limit normal of AST, ALT. We are flexible in the inclusion criteria to enroll subjects with slight increases in ALT and AST. And just because of that, because there's biologic variability and we want to incorporate those subjects in the study. But despite that situation, we have not seen any significant increase in liver function test. So, I hope that addresses your question. Let me turn it back to Ray to discuss the structural potential differences. Dave, could you repeat the question? Yes. If you could share your perspective on 1290's liver tox differentiation versus Pfizer's danuglipron? Yeah, absolutely. So thank you for the question, Dave. The molecules are very different. That's about all that I can say. Very... It's very unique and different from Pfizer's lotiglipron. Okay, yeah, I was asking about danuglipron, but yeah. Sorry, very different. Also very different from danuglipron. Okay. Okay, thank you. And then one final question, Ray, could you share your thoughts on cross trial comparisons and, you know, considering those going forward as we see these additional datasets? Yeah, I'm actually going to hand this question over to Blai. Thanks, David. So we're looking at these from two different perspectives. One, from an efficacy perspective. As we've said, I think it's important to contextualize our data with other datasets at the same time. And there are programs out there with a four-week readout and small molecules seeing a 3.6% reduction in weight, placebo-adjusted. As we've presented, we achieve a 4.6% and a 4.9% reduction in weight. So we see these as encouraging results, and we very much looking forward to look at the data from the type 2 diabetes cohort at the end of this quarter. There's also, as you know, 12-week datasets from selective GLP-1 orally available, achieving an efficacy that ranges from 4%-7% in a subject population with type 2 diabetes. So that's how we frame the space, and that's how we want to present our data. The other angle that we want to stress as well is the discontinuations due to adverse events. We've seen a variety of results up to 12 weeks. The discontinuation rate ranges from 10%-35% in some programs, from 18%-54% in other programs. We, as you know, wanted to provide the flexibility for those participants to be able to down titrate if there's any tolerability issues, but remaining in the study. That's what we're doing, that's what we've implemented. Based on these results and that flexibility in the protocol, we remain confident that we can provide good results in terms of this continuation due to adverse events. Great. Congrats again. Thank you, Dave. Thank you for your questions. Thank you. One moment for our next question. Our next question comes from the line of Yasmeen Rahimi from Piper Sandler. Hi, team. Thank you for allowing me to ask a question that I think a lot of our clients are submitting to us is: Given that the data is very strong at week four and came in earlier than expected, why do the private placement ahead of the data? Like, or conjunctive with the data. Why not? Like, if you could just elaborate on how that's... Because I think a lot of our clients, they had a little bit more time to do work on the name, so it caught them quite by surprise of having this data out. So I'd love to hear your thoughts, as many clients that are listening to this webcast would love to learn a little color. That would be helpful. Absolutely, Yas. I'll, I'll let our Chief Financial Officer, Jun Yoon, answer that question. Hey, Yas, this is Jun. Thanks for the question. So, you know, with the unblinding of the 1b MAD data, which was not anticipated at all, and the exciting results that we saw, we view this as a stepwise financing strategy. You know, we knew we were gonna need to raise the capital, and this was an opportunity for us to raise the capital in the short term and really allow us to accelerate the activities we have ongoing and be in a position to run additional studies in parallel with the 2b studies that are planned next year. So, the other thing is, we've got exciting momentum around the incretin metabolic franchise, including the dual GLP-1/GIP, as well as the amylin agonist. So we wanted to make sure we had the cash on the balance sheet to be able to continue the momentum on those programs with discovery preclinical activities on that. And then lastly, this does extend our runway through the end of 2026. And this is, again, an opportunity for us to increase our balance sheet with this data. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Seamus Fernandez from Guggenheim Securities. Oh, great. Thanks, Yas. So just wanted to ask, just a couple quick follow-ups. You know, as we've gotten some questions incoming, wanted to just get a better understanding of how you see the needs from a financing perspective going forward, should the program require a broader acceleration in 2024, and then certainly in 2025, with the DC candidates potentially moving to IND, and then into broader programs overall, is this something that, you know, you see Structure managing on your own or potentially pursuing as a partner? That's my first question, and then I just have one follow-up. Yeah. Jun? Oh, yeah, in terms of your question, you know, we wanna make sure we have enough funds to be able to carry out all the different activities for the phase 2b. So there's gonna be a number of additional parallel studies, drug-drug interaction studies, hepatic renal studies, really position this molecule for us to go into phase III. This is a large market, and so, you know, we do anticipate seeing the potential for a partnership in late-stage development commercialization. But at this time, you know, it's really being in a position to raise the capital that we need to pursue and position the 1290 program in the best way for pivotal trials that we anticipate going into 2026. And then, you know, regarding the franchise effort, you know, as that program advances further, you know, we'll be doing, you know, phase I studies for the GIP and the amylin agonist going into 2026. So, anticipate potential financing to make sure we continue that momentum for those efforts. Seamus, I was just gonna add that Jun gave you the CFO answer. I'll give you the CEO answer. It's really about acceleration. Yeah. Great. And then just last question, Ray. As we think about acceleration and potentially competition with some others, the manufacturing complexity of 1290, can you just update us? I know Lilly's orforglipron is quite complicated. Maybe just remind us what, you know, how you view your molecule comparing from a number of chiral centers, you know, versus orforglipron, and how the number of chiral centers can actually negatively impact yield, you know, as we think about the manufacturing complexity of your molecule versus some others. Yeah. Thank you, Seamus, for the question. So as, as you know, and many of you know on the call, you know, we, we built this company really around accessibility to all, to be able to take biologics and replace them with orally available small molecules. And so your question, about affordability or cost of goods is a, is a really important question these days. So from the very beginning, you know, when we designed the molecule, we thought very carefully about the synthesis and the number of steps, that it would take to make sure that, you know, manufacturing this molecule would come in, in the range of traditional small molecules. And so we spent a lot of time, you know, on the CMC component, making sure that the cost of goods is very reasonable. And then your second part of your question, in terms of chiral centers, the more chiral centers that you have, this is for any. You know, I'm gonna make a generalization. The more chiral centers, the more complex the synthesis is, and so one wants to minimize that where they can. Thanks so much. Yep, absolutely, Seamus. Thank you. Thank you. I would now like to turn the conference back over to Dr. Raymond Stevens for closing remarks. Thank you. Thank you all for joining our call today, and we look forward to continuing our programs and making these medicines more accessible to all. This concludes today's conference call. Thank you for participating. You may now disconnect.