Ladies and gentlemen, thank you for standing by. Welcome to Structure Therapeutics webcast and 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 would need to press star one one on your telephone. You would then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Due to timing, we ask each analyst to please limit to one question. Please be advised that today's conference is being recorded. I would like now to turn the conference over to Danielle Keatley, Head of Investor Relations for Structure. Please go ahead. Thank you and good morning. Earlier today, we issued a press release providing top-line results from Structure Therapeutics GSBR-1290 obesity program. 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, and Dr. Blai Coll, Vice President of Clinical Development. Dr. Mark Bach, our Chief Medical Officer, Dr. Xichen Lin, our Chief Scientific Officer, and Jun Yoon, our Chief Financial Officer, are also on 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. 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 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. I will now turn the call over to Dr. Raymond Stevens, CEO of Structure Therapeutics Good morning, everyone, and thank you for joining us. Today, we are pleased to announce positive top-line results from Structure's GSBR-1290 obesity program. These data, which we will go through in detail on this call, provide us with the conviction that GSBR-1290 can become a potential key treatment to significantly change the obesity landscape. As an oral non-peptide small molecule, GSBR-1290 has the potential to reach hundreds of millions of people, and this is absolutely central to our mission at Structure Therapeutics, making medicines more accessible to all. As a leader in the field of oral small molecule incretins and related targets, GSBR-1290 is our selective GLP-1 receptor agonist, the foundation and lead program of our broad metabolic franchise. We believe data that we'll be presenting today strongly position GSBR-1290 as a potential best-in-class oral GLP-1. First, we are showing competitive efficacy compared to other selective oral GLP-1s, given our differentiated PK properties you will hear more about later on this call. We demonstrated statistically significant and clinically meaningful placebo-adjusted mean weight loss of 6.2% in the phase II-A study and up to 6.9% in the capsule- to- tablet PK study at 12 weeks, with room to do even better in the future. As is known in the field, not all people respond the same to GLP-1s. We are pleased to see, in a 12-week study, more than half of the participants had at least an 8% decrease in weight and one-third lost at least 10% of their body weight based on a primary efficacy estimate. We continue to emphasize the differentiated safety profile of GSBR-1290. More than 200 patients have now been treated with GSBR-1290 across various studies for up to 12 weeks. From this data, I would highlight that we observed no clinically important liver findings, and we have a large safety window that gives us the opportunity to go higher in dose if we want to. In terms of tolerability, the low AE-related study discontinuation rate of 5% in our phase II-A study and 11% in our capsule- to- tablet PK study are very encouraging and significantly lower than for other drugs in this class at 12 weeks. Our PK properties are optimized to adequately engage with the receptor for 24 hours, clearly confirming once-daily dosing, as does the efficacy we are seeing. And very importantly, we believe we have the ability to manufacture GSBR-1290 at scale today to deliver treatment to more than 120 million patients, which is aligned with our accessible to all mission, and the scaling has the potential to only get better. With these strong data, we are well on our way to reaching our goal of being a best-in-class oral GLP-1. Let me now turn the call over to Dr. Blai Coll, our Vice President of Clinical Development, to present the data. Thank you, Ray. The results from our phase II-A obesity study exceeded all the study objectives, as did the results from the capsule- to- tablet PK study, both in terms of compelling efficacy along with positive results from a safety and tolerability perspective. Now, I'd like to share with all of you the details of the two studies. Let's just start with the study design of the phase II-A obesity study. This was a proof of concept study using weekly rapid titration to achieve a target dose of 120 mg within 12 weeks of exposure. We enrolled 64 participants overall, including the 24 replacements, as we announced back last year. 37 participants were randomized to GSBR-1290 and followed a weekly titration, starting at 5 mg to reach 90 mg for two weeks and continuing at the 120 mg target dose for the remaining of the study. Additionally, 27 participants were randomized to placebo. The primary endpoint was safety and tolerability, and the secondary endpoint were change in body weight from baseline to week 12. The efficacy analysis was done based on a primary efficacy estimate, which takes into account the definition of intercurrent events as specified in the statistical analysis plan. Turning to the baseline characteristics, you will see that these are balanced between the GSBR-1290 and the placebo groups. Average age was between 44 and 45 years old, well-balanced number of female participants between groups, with a representation of the Hispanic or Latino population between 43% and 48%. Baseline body weight was 90-92 kilos, and average baseline BMI was approximately 31, both balanced across groups. HbA1c was in the normal range as required per protocol. Let's now review in detail the magnitude of weight loss seen in the study, one of the key pieces of data being presented today. We are very pleased to show a statistically significant weight reduction over 12 weeks, with an early clear separation compared to placebo. As you can see in the graph, the blue line depicts the participants receiving GSBR-1290 versus the gray line showing placebo. Participants on study drug achieved a 6.2% weight reduction at the end of the 12 weeks, with no plateauing in weight loss, whereas the placebo group did not experience any change in body weight. Placebo-adjusted weight loss remains at 6.2%, with a statistically significant and clinically meaningful difference between the two arms. This clinically meaningful and statistically significant body weight reduction in 12 weeks, considering the rapid weekly titration steps, is very encouraging and supports the continued development of GSBR-1290. To better characterize the treatment effect, we also looked at the weight change responder analysis, the number of participants who achieved various thresholds of weight reduction at the end of week 12. Starting on the left, two-thirds of participants lost at least 6% of their body weight. More than half of participants lost at least 8%, and remarkably, one-third lost at least 10% of their body weight within 12 weeks. Overall, from an efficacy perspective, we are very encouraged by these results at an early time course of 12 weeks, and we are confident that this positions GSBR-1290 to be a potential best-in-class oral GLP-1 receptor agonist, with potential for weight loss to meaningfully continue to increase as we move to longer studies. Let's now discuss in detail the weight changes observed in the capsule-to-tablet PK study. This study enrolled 54 participants, randomized 15 to 3 to GSBR-1290 tablets or placebo. The objectives were to assess safety and tolerability, the PK comparability of the capsule-to-tablet formulation, and explore weight changes during the 12 weeks of the study. There were three GSBR-1290 arms, varying in starting doses from 5mg - 15 mgs and following either a weekly or biweekly titration. As you can see in the study schematic, two of the cohorts reached a target dose of 120 mg, and the third had a target dose of 60. The baseline characteristics were balanced across groups, and the BMI was around 30. On slide 12, you see the results of body weight reduction with the tablet formulation. Consistent with the phase II-A study, we saw clinically meaningful and statistically significant weight reduction in this study. The placebo group is in gray, showing a 0.5% weight gain at 12 weeks. The light blue line shows the 60 mg cohort, and the darker blue lines show the 120 mg groups. In this study, we also see a clear separation of the curves very early on, and that continued through the course of the study. At the final week 12 reading, we saw body weight reduction in the range of 5.8%-6.4%, equating to a placebo-adjusted weight reduction of 6.2%-6.9%, as shown in the table. The weight reduction in all three of these cohorts was statistically significant and again, shows clinically meaningful weight reduction with GSBR-1290, consistent with the previous study and supporting the advancement of GSBR-1290 into further clinical development. Now that we have summarized the weight reduction seen with GSBR-1290, it's appropriate to contextualize the efficacy data. Here we show a cross-trial comparison of percent body weight reduction, placebo-adjusted at 12 weeks across different programs with other oral selective GLP-1 receptor agonists in participants living with obesity. On the left-hand side of the slide, our own data with body weight reductions ranging from 6.2%-6.9%. Next, the results of the top doses of two different small molecules with efficacy ranging from 6.5%-6.6%. The graph shows orforglipron at the top dose in the 36-week phase II-B study and extrapolate the weight loss at 12 weeks. And also danuglipron, given twice a day, 12-week data reaching a 6.6% weight loss. I need to caveat here that these are cross-trial comparisons. The studies use different titration schemes that could potentially impact the efficacy readout, and as mentioned, for some of the programs, the results shown in the slide were extrapolated at 12 weeks. Caution should be exercised when comparing data across the studies, but even with the limitations described above, we're confident the efficacy of GSBR-1290 positions the program competitively to move forward into later stages of clinical development. Safety and tolerability are key aspects of the treatment of patients with chronic metabolic conditions. Let's review in detail the safety and tolerability results. We continue to see low rates of the study discontinuation due to adverse events at 5.4% for the final 12-week analysis, which is two participants discontinuing the study. There were two participants who experienced gastrointestinal-related adverse events and discontinued study within the first two weeks. Per protocol, we also allow participants to remain in the study and reduce, hold, or discontinue doses if needed for tolerability reasons. Over the course of the study, the same two participants that discontinued study previously discontinued study drug. 15 participants had a dose reduction and remain in the study at any dose of GSBR-1290, and two participants had a temporary dose hold. Taking into account the weekly titration in this 12-week study, we are encouraged to see the low number of study discontinuations. Turning to the adverse event profile, there were no serious adverse events observed in this study. All adverse events were mild or moderate in severity, and most adverse events were gastrointestinal related, as you would expect for the GLP-1 receptor agonist class of drugs. Nausea and vomiting were the most commonly observed adverse events. I would point out, though, that this table indicates the number of subjects with at least one event reported. So to better characterize the tolerability profile, we analyzed the weekly incidence of participants with nausea in the right-hand side of the slide. As expected, we saw higher rates in the dose titration phase, with rates starting to subside when patients were maintained on the 120 mg dose. Also note that rates of nausea do not increase over the course of the study, despite increasing doses of GSBR-1290, potentially indicating initial signs of tolerability. The study also observed a similar pattern on other gastrointestinal-related adverse events. Let's now wrap up the safety section. Liver test assessments are a focus of safety surveillance for the GLP-1 receptor agonist to small molecules, and as you know, we have been carefully monitoring liver enzyme activity in both the phase II-A study shown on the left, as well as the capsule- to- tablet PK study on the right-hand side of the slide. Most notably at the top, we have not seen any drug-induced liver injury in either of the two studies. We have also not seen any increases in hepatic enzymes, as reported as adverse events in any arm in either study. We also show the mean change from baseline to week 12 for the two hepatic enzymes, ALT and AST, where you can see biologic fluctuation, but not clinically meaningful changes in any of the parameters. Lastly, we looked at the number of participants who have elevations of at least 3, 5, or 10 times the upper limits of normal for ALT or AST. At the 3 times the upper limit of normal, there were three cases, one in the GSBR-1290 capsule, one in the placebo arm, and one in the 120 mg tablet arm of GSBR-1290. We'll go through these cases one by one. The first in the phase II-A study, this was a female participant with a sporadic increase in ALT of 3.9 times and in AST of 2 times the upper limit of normal at day 44. The investigator, and following the regulatory guidance, continued dosing the subject and repeated ALT and AST four days later, when importantly, both parameters came back to normal values. Turning to the placebo arm, there was one male participant with an increase in both ALT and AST at day 30, most likely related to a viral syndrome. Then the third case was in the capsule to tablet PK study. The male participant had an isolated increase in AST of 4 times the upper limit of normal on day 84, the last day of the study. This was associated with an increase in creatine kinase, most likely due to previous physical exercise and pointing to the muscle as the potential source of the increase. I will also highlight that we have not seen any cases of 5 or 10 times the upper limit of normal increases in these studies. In summary, on safety, we continue to see very encouraging results, which provide confidence as we go into longer studies and potentially higher doses. Now it's the right time to discuss in detail the molecular and PK characteristics of GSBR-1290, a question we have repeatedly heard from all of you, and that we're pleased to share the results of all the data up to date. As you will see, the PK characteristics support the efficacy data presented and once-daily administration, and gives us confidence for the design of the upcoming phase II-B. Let's just start with a graph showing the plasma concentration of GSBR-1290 using different formulations, tablet and capsule, and doses of 60 mg and 120 mg. First, at 60 mg, we see comparable exposure between tablet and capsule. Second, the exposure is generally proportional between 60 mg and 120 mg. Third, the concentration at 24 hours is above 10 ng/mL for the 120 mg groups. The average concentration identified in the non-human primate studies is achieving maximum insulin secretion. Those three observations enable the program to continue with the tablet for the phase II-B and opens the possibility to test higher doses than 120 mg. We're confident those aspects are favorable to continue maximizing the efficacy of GSBR-1290 into the dose range finding study. In the table on the right, you can see the PK characteristics in detail at the different doses and with the two formulations studied. In summary, we see adequate levels of exposure determined by the AUC and Cmax comparable to other small molecules in development. We also observed delayed Tmax, then in conjunction with a half-life observed, up to 8.5 hours, supports appropriate target engagement during the majority of the dosing interval. As mentioned in the previous slide, suitable drug exposure at 24 hours. The molecular and PK properties described indicate that GSBR-1290 is a once-a-day drug. From an efficacy perspective, let me summarize some key aspects. We have reported statistically significant body weight reduction at 12 weeks. GSBR-1290 is a full agonist with minimal beta-arrestin signal and favorable free drug concentration. Our exposure response model identifies exposure, AUC, as the main driver for efficacy. We see proportional exposure across the doses explored at higher doses in phase II-B, and we see plasma concentration at the nanogram threshold, which reassures target engagement during the once-a-day dosing interval. All these observations support the level of efficacy achieved in the two studies presented today and sets a strong foundation for the design of the phase II-B. From a safety and tolerability perspective, GSBR-1290 has ample safety margins with minimal tissue accumulation in preclinical studies. As you're all aware, there is ongoing formulation work that can potentially modulate some of the PK characteristics. With the favorable molecular and PK properties of GSBR-1290, let's move into next steps and key learnings from the studies presented today that will be incorporated in the design of the upcoming phase II-B. On this slide, we show the incidence of nausea in dark blue and vomiting in light blue on the Y-axis over the first two weeks in the study at different starting doses. As you can appreciate, the group of participants starting at 5 mg had the lowest incidence of events compared to 10 mg or 15 mg. Interestingly, remaining at 5 mg for an extra week, as shown in the right-hand side of the graph, instead of escalating the dose to 20 mg or 30 mg, also showed the best results, with no events of vomiting and the lowest incidence of nausea for the second week. This is consistent with what has been seen with other GLP-1 receptor agonists, and we will apply these learnings to the phase II-B study. Overall, it is reassuring to continue seeing low number of adverse events related to study discontinuations, mostly associated to gastrointestinal symptomatology and the majority of those events accumulating during the first 6 weeks in the study. The 36-week placebo-controlled study is expected to include approximately 300 participants with obesity or overweight. We will evaluate multiple doses of GSBR-1290, with all arms starting at a lower starting dose, 5 mg, and a slower monthly titration. As previously indicated, the ample safety margins and the generally proportional exposures enables the program to explore doses higher than 120. The study will evaluate percent weight change at 36 weeks as the primary endpoint and other relevant clinical endpoints as secondary, some of them listed in the slide. I'm also pleased to share with you today that the IND for chronic weight management is on track to be submitted in the third quarter of this year, and this will enable the initiation of the phase II-B in the fourth quarter of 2024. I've reviewed with you a comprehensive report that reassures Structure's confidence to move forward with next steps. Once again, I'll share with you what these high-level achievements are. GSBR-1290 achieved clinically meaningful and statistically significant placebo-adjusted weight loss at 12 weeks across both studies, 6.2% in the obesity study and up to 6.9% in the formulation study. Importantly, the PK data confirms the dose proportionality and once-daily dosing for GSBR-1290. It also demonstrated a generally favorable safety profile, with approximately 200 participants exposed to GSBR-1290 to date from multiple studies. The safety results from these studies are consistent with the large safety margin seen in our GLP tox studies. Finally, no drug-induced liver injury or permanent elevations in liver enzymes has been observed. From a tolerability perspective, we are encouraged to report low study discontinuations related to adverse events and a tolerability profile consistent with this class of drugs. Additionally, our results endorse a lower starting dose and a monthly versus weekly titration with a tablet formulation that we are confident will further enhance the profile of GSBR-1290 in the phase II-B study, where we have the potential to explore higher than 120 mg, and that we're advancing rapidly to a start in the fourth quarter of 2024. In summary, the results presented confirm GSBR-1290 as a key molecule for further development and as a foundational backbone in Structure's portfolio. With these exciting results, let me turn it over to Ray for his concluding remarks. Thank you, Blai. We believe these data position GSBR-1290 as a potential best-in-class, non-peptide, oral small molecule, GLP-1 receptor agonist. We are pleased to share with you today that at Structure Therapeutics, we have met the key aspects of our aspirational target product profile that we established when we designed GSBR-1290 through our structure-based drug discovery platform several years ago. First, we designed a potent full agonist with minimal beta-arrestin signaling. Second, we targeted weight loss on par or better than the GLP-1 peptides. Third, we designed this drug to be once-daily dosing, targeting GSBR-1290 with potentially superior PK properties, and to have approximately 24-hour drug exposure, not longer and not shorter, with minimal tissue accumulation to make the drug as safe as possible, and in order to enable QD dosing in a very large population that would be taking this medicine chronically over many, many years. Fourth, we believe formulation work could modulate Cmax and continue improved tolerability. And last, as part of our company mission, we wanted to make sure that we had the ability to scale manufacturing to meet the needs of patients around the world. I would now like to spend a few minutes putting these results into greater business context and how we view GSBR-1290's position within the rapidly evolving obesity in GLP-1 field. Today, there's more than 800 million patients globally who could benefit from GLP-1 receptor agonist. We have done market research and know that the majority of patients prefer a daily oral medication over a weekly injectable. Given this patient preference for orals and their scalability, oral small molecules are well positioned to take a significant portion of this large, greater than $100 billion market. With GSBR-1290's product profile, it is well positioned to become a potential best-in-class oral GLP-1 option. Turning to the next slide, why are oral small molecules so important, and where does GSBR-1290 fit into the landscape of GLP-1s? There is a tremendous gap in obesity treatment today. With the significant progress and success of the GLP-1 peptides that are commercially available today, only approximately 5 million people in the United States are receiving treatment. That still leaves nearly 100 million people living with obesity in the U.S. without treatment. Over the past year, I've visited several clinics and seen firsthand the challenges they are facing with getting this class of medicines to the people who need them and being able to stay on them. Worldwide, the gap is even bigger. Simply put, GLP-1 peptide-based therapies are challenging to scale, and despite considerable efforts to scale manufacturing, these limitations and this treatment gap will remain a major issue. With oral small molecules, and specifically GSBR-1290, we believe we have the ability to address this gap. Much of this advantage comes from the ability to manufacture oral small molecules at a much larger scale than peptides. Here, we outline our ability to rapidly and cost-effectively scale GSBR-1290. Today, we have locked the synthetic route, have completed multiple GMP batches, completed manufacturing of our phase II-B GMP supply, and the ability to manufacture 6,000 metric tons of GSBR-1290 per year. This is enough drug to treat more than 120 million patients per year, which is more than the number of individuals living with obesity in the U.S. today. As we know and should not forget, as is part of our company mission, the global number is much bigger, and accessibility worldwide is even more of an issue. I shared these key takeaways from the studies at the beginning of the presentation, but they are particularly important and bear repeating. With the strong, competitive, placebo-adjusted efficacy of 6.2%-6.9%, a safety profile that demonstrates no liver liability and supports the ability to go higher in dose, a tolerability profile that led to low study discontinuation rates, once daily dosing, and the ability to manufacture at scale. The pieces of the puzzle, with approximately 200 participants to date, having received GSBR-1290, have all come together very nicely. We are extremely encouraged by the data, and we look forward to our phase II-B study, where we will apply a number of key learnings from today's studies to even further enhance the profile of GSBR-1290. Today, we are in a strong position with 12-week data establishing GSBR-1290's potential as a very competitive oral small molecule. So how do we win in the GLP-1 space in the long run? As we move to our phase II-B dose range finding study and our phase III pivotal program, based on our data to date and modeling, we believe we will see very competitive weight loss in the range of mid to high teens in phase three, meaning equal to or better than other selective GLP-1s that have completed phase III or on the market. In our later stage studies, and with longer titration schemes that are followed in the field, we expect much lower discontinuation rates and lower adverse events for the patients to have a better experience. We also feel it is important to help patients stay on GLP-1s longer than they are today. This positions GSBR-1290 as a potential key treatment and importantly, one that can be manufactured at scale to reach the large number of patients in need. Beyond GSBR-1290 as a selective GLP-1, we have our combination programs with amylin, GIP, GCG, and Apelin, with tremendous potential to unlock even more of the obesity market. To wrap up, I'll outline our anticipated catalysts over the next two years. Here is what we have upcoming. We are rapidly advancing GSBR-1290, the foundation of our broad metabolic franchise, and will start our approximately 300-participant phase II-B trial in a few months, with all the learnings from our past few years of hard work. You hear a lot about duals in the news lately. We are the leader in the field of small molecules targeting other incretin receptors. As treatments become more specialized to address specific patient needs, we believe we are well positioned with our programs, namely amylin small molecule program as a monotherapy or in combination with GLP-1, which is a very promising and exciting space. We expect to declare a development candidate for our amylin oral small molecule within the next 6 months and be in the clinic next year. Not to forget, we are quite excited about our oral small molecules for GIP and GCG, and these programs could open up additional disease indications that we would be able to even better address. We also have our muscle-sparing, selective weight loss oral small molecule with our Apelin receptor agonist, which has completed phase I studies and is now phase II-ready. With so much going on in the metabolism space, we are really looking forward to our first R&D day at the end of the year to update you on the exciting progress in these important areas. As you can see from the presentation today, we believe we have one of the deepest and strongest pipelines in the small molecule metabolism space, with a consistent flow of key milestones and inflection points over the next few years. 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. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. As a reminder, due to timing, we ask each analyst to please limit to one question. Please stand by while we compile the Q&A roster. The first question comes from Evan Seigerman with BMO. Your line is open. Hi, guys. Thank you so much for the data today, and the great presentation. I wanted to drill down a bit on some of the tolerability components, specifically the relatively high rate of nausea and vomiting. Maybe could you expand as to what we saw kind of at weeks 10 and 12? Maybe taking a step back, you mentioned a lot on the PK properties of the asset. Maybe walk us through what you can do from a PK and formulation perspective that could improve upon that. Thank you so much. Evan, this is Blai. I'll take the question, and thank you. This is an important question since we're constantly thinking about how to improve that. So the tolerability profile is consistent with what we saw and reported back in December. We saw a concentration of those events in the beginning of the study, while the subjects are going through the up titration, and then an attenuation over time, which to us indicates initial signs of the tolerability building that we know is happening with the class of drugs. You're specifically asking about weeks 10-12. The incidences are fluctuating throughout the course of the study, but there's a clear downward trend to reduce the incidences towards the end when subjects are at the top dose. The other thing that we mentioned in the in the presentation is that the incidence of nausea and vomiting, diarrhea, constipation, the majority of GI adverse events do not increase over time as subjects are getting up titrated. So that's another reassuring point that it's building the tolerability. However, we're also confident that for the phase II-B as we showed in the tablet study, starting at a low dose and going slowly in the titration and extending that period to 4 weeks compared to 1 week in the phase II-A, will have a positive impact in the incidences of those events. Did I address the questions? And then just on the formulation, I know you were talking about the PK profile and kind of ability to reformulate or improve upon formulations. What can you do there to maybe attenuate the side effect profile even more? Yeah, Evan, this is Ray. So in that regard, you know, we want to send a clear message. We're very happy with our tablet formulation that we currently have. That's why we're moving into the phase II-B, and we can see ourselves continuing this through phase III. But we're always looking for, you know, additional ways to further improve tolerability. And so in terms of formulation, as a representative example, extended release is one thing that we've looked at and we've been doing work on for the past couple of years to find ways to even further modulate the PK properties. So we see a lot of opportunity to further improve the patient experience through these additional formulation methods. Great. Thank you so much, guys. Thank you. One moment for the next question. The next question comes from Yasmin Rahimi with Piper Sandler. Your line is open. Thank you, team. I guess the first question, team, is you did a really nice job breaking down the rates of nausea, vomiting at the end of 12 weeks, or in total, on slide 16. That's for the capsule formulation. Could you maybe now talk about how this compares to the tablet? And if you have the data on hand, that would be great. I think clients are just wondering, what does the time curve look like around nausea, and more importantly, what do the overall rates look like? Just kinda in relative to slide 16. And then the second question is, given the three cases of liver enzyme elevations, I guess, what evidence is there to conclude, especially the two cases that was on the 120 mg dose group, that were just not related to drug? I know you guys went quite a bit in detail around the patients, how they have predisposition, but if you could just highlight a little bit more, like, why weren't they screened out of the study initially, if they had a propensity for liver enzyme elevations? And my apologies for asking two questions. Yes, this is Blai. Thanks for the two questions. So the first one, in terms of nausea, vomiting, and in general, the GI-related profile, comparing the capsule to the tablet, it's numerically comparable. There's, of course, fluctuation. There are different, different trials, and so numerically, they are different, but overall, it's comparable. And most importantly, we see as, as I mentioned in the question before, we see that similar temporal trend, so an accumulation in the beginning and a trend towards a diminishing incidence towards the end of the study. So we would categorize the, the two profiles in terms of GI tolerability between the capsule and tablet as comparable. The question about the liver enzyme elevation, as we've detailed in the call, we've seen two participants, one with an elevation of between 3 and 5 times upper limit of normal for ALT, and 2 times the AST in the capsule receiving 120. But importantly, that subject continued dosing for 4 days and repeat ALT and AST, and both determinations, ALT and AST, came back to the baseline values, to normality, which I think is a strong and a strong signal of the lack of association between the drug and the elevation in ALT, AST. The other subject with the tablet had an elevation of just AST at day 84 of the study, and that was associated with the previous physical exercise and a substantial increase in creatine kinase that points to the muscle as the potential source of the elevation. And then there's a third case that we also reported in the placebo arm of the capsule study that had an elevation in both ALT, AST, coinciding with a viral syndrome. Hopefully, that addresses the two questions. Thank you. Thanks, Blai. I'll hop back in the queue. One moment for the next question. The next question comes from Jon Wolleben with Citizens JMP. Your line is open. Hey, good morning, and thanks for taking the question. You guys mentioned that you had two batches of patients, and you gave us 8-week data, I believe, back in December from the first group. Can you talk a little bit about any differences in weight loss or tolerability or baseline demographics between those two groups? Yeah, thanks. Thanks, John, for an important question again. So as you know, we did not alter the protocol. It was the same inclusion, exclusion criteria. Baseline characteristics between the original cohort and the second 24 replacements were comparable. And so the only difference that we included in that second part of the study was to more closely monitor those participants that could be at risk of discontinuing or has lack of compliance due to some of the nausea and vomiting. And we did that through the electronic diaries that the participants were answering on a daily basis. That data was sent to the researcher staff that proactively followed up with those participants in order to adjust the diet, provide symptomatic treatment, to better manage the nausea and vomiting. That might have increased the degree of compliance in the replacement cohort. We saw a magnification of the treatment effect to approximately a 7.5% body weight reduction at the end of week 12. That transferred to a 9.2% placebo adjusted. Now, we need to caveat, though, that this is absolutely post hoc analysis. It's, therefore, hypothesis generating, and so that's the nature of, of that data. But it's an extra element of reassurance of, of the level of efficacy that, that can, can achieve. And we're moving forward to implement those changes in the phase II-B. You're mentioning the tolerability in those 24 replacements. We've seen two subjects discontinuing study drug, due to adverse events in those 24 replacements. Again, small sample size, but that's, that's what the data is telling us. We see also a fluctuation in terms of the number of down titrations and discontinuations of the study drug. From a qualitative perspective, nausea, vomiting, the two most common adverse events, and we also see the similar temporal trend in terms of that's been released in the overall population. Very interesting. Thanks for the color. Thank you for the question. One moment. My apologies. One moment for the next question. The next question comes from David Risinger with Leerink Partners. Your line is open. Yes, thanks very much, and congrats on the results, and thanks for the detailed presentation. So I have two questions, please. First, the weight loss moderated significantly between weeks 8 and 12. We've gotten questions on that. I just was hoping that you could comment on that. And then, second, if you could just update us on your plans for potential partnering discussions. I believe that earlier this year, you mentioned that you could have discussions following the release of this data set, so I'm just hoping for an update on that, please. Thank you. Blai, why don't you take the first question, and I'll take the second question. Sure. Dave, thanks for the question. So as a reminder, this is a 12-week study where we know that the weight changes are not robust enough to detect the full extent of the treatment effect. If you looked at other small molecule programs at 12 weeks, there's a systematic and consistent slowing in body weight reduction observed at 12 weeks compared to what's been achieved at 6 and 8 weeks. So it's not no surprise that the shapes of the curves at different time points during those 12 weeks is gonna be different. When we compare then with the 26 or 36 weeks for the same programs, you see that the body weight reduction continues growing and continues expanding. Based on the data that we've seen, we have confidence that by extending the exposure, we'll continue expanding and increasing the body weight reduction. And Dave, in answer to your second question, thank you for that. You know, we have the same goals and same timing as we stated previously. We recognize that the obesity and metabolic disease market is very large, and it will require a strategic partner to help us with the late-stage development and commercialization. So we remain consistent on that topic. Thank you for the questions. One moment for the next question. The next question comes from Seamus Fernandez with Guggenheim. Your line is open. Oh, great. Thanks for the question. So just a couple quick ones. First, can you comment on the 60 mg dose, the performance of that product in the titration study or that of that dose seemed actually quite good. I guess one of the dynamics that may be missing there is just tolerability by dose selection. Was the tolerability of the dose range with the 60 mg in the titration study better than expected? Basically, you know, sort of speaking to your start low, go slow approach. Then, in terms of the second question, really just interested to know, you know, maybe if you can reference in the slides what the LFT abnormalities were, if any, in the titration study as well. Just gotten a couple questions on that, but I believe it's in the slide deck. Thanks. Seamus, thanks for the question. So in regards to the 60 mg arm, we saw better and improved tolerability when we started that cohort at 5 mgs and then remain at 5 mgs for the second week, as shown in the slide, compared to 10 mg and 15 mg. So that was an important finding from the study that we will incorporate into the phase II-B. Overall, we saw, again, numerical differences in nausea and vomiting, but again, as we stated, similar trend in terms of accumulation of events in the beginning or during the titration phase. The performance in terms of efficacy, I think you're spot on in terms of the degree of weight reduction. But again, 12 weeks is kind of a short period of time to see if there's any dose response or any dose difference in terms of weight reduction. When it comes down to the liver, we reported one subject on the tablet receiving 120 mg that had an elevation in AST at day 84. That was 3 times upper limit of normal, and that was the subject who had some physical exercise three days before the study visit, and the AST elevation was associated with an increase in creatine kinase. So most likely the source of that elevation is related to the muscle and not to the liver. Thanks for the questions. Great. Thanks. One moment for the next question. The next question comes from Prakhar Agrawal with Cantor Fitzgerald. Your line is open. Hi, good morning. Congrats on the update, and thanks for taking my question. So, this trial had lower baseline BMI related to some of the other obesity trials. Could you talk about how movement into higher baseline BMI will change the magnitude and the slope of the weight loss curve? And could that lower baseline BMI be influencing the weight loss flattening that you're seeing from week 8 to week 12? And my second question is: could you talk about the tolerability profile of cohort 3 in the PK formulation trial that had slower titration? You disclosed nausea, vomiting is lower by week 12, by week 2, but what about the other time points? Thank you. Thanks, Prakhar. So in regards to the low baseline BMI, the most important thing is that it's balanced across the groups and placebo and drugs. So that's the first observation that I wanna highlight. The second thing, in moving forward for the phase II-B, the intent will be to have a higher baseline BMI and higher body weight. And there's, as you know, there are ways to do that, whether it's capping the number of subjects with overweight and highlighting the subjects with a BMI over 30. That has the potential to increase the effect size. We do not think, based on the data that we have seen from ourselves, our programs, and from others, that that baseline BMI can have an influence on the shape of the curves between 6 weeks and 12 weeks. But for sure, for the phase II-B, we'll have an opportunity to increase the baseline BMI based on the inclusion criteria that we're planning to do. In terms of the nausea and vomiting of cohort at 60 mg with the capsules compared to the 120 mg, as I said before, I think the most striking difference happened in the first two weeks. Overall, the tolerability was comparable with the 120 mg with numerical differences. Of course, with those small sample size in those studies, you always see some heterogeneity, but the most striking difference, as we reported in the presentation, was during the first two weeks. Thanks for the question, Prakhar. It's important. As a reminder, we ask that each analyst please limit to one question. One moment for the next question, and the next question comes from Roger Song with Jefferies. Your line is open. Thank you, and congrats for the data. I will limit my question to one. Maybe, team, if you can comment on your PK profile, this kind of mean plasma concentration meeting this 10 ng versus you wanted those that are a bit higher than 120 mg, how this will improve your overall weight loss over longer term, and and how high that those you are kind of planning to go based on your safety profile. Thank you. Thank you, Roger. Important question, of course, and currently discussing right now based on the data that we have and designing the phase II-B. So the idea here, since we have ample safety margins from the GLP preclinical tox, and also we see the proportionality and exposure between 60 mg and 120 mg, we have the opportunity to go higher than 120 mg in our phase II-B. And again, couple that with the fact that we will have the possibility as well to extend the titration to 4 weeks, as we've communicated, that can also optimize the tolerability. So when we put those two pieces together, there's the potential to increase the efficacy and to maximize that efficacy while we're optimizing the tolerability. How high we will go, this is currently under discussion. As you can appreciate, there's a lot of work in terms of the modeling and the dose identification, but certainly, that's a possibility that we have, and that's the intent of the program, to go higher in doses for the phase II-B Roger, we'll be giving an update on this in the future, once we have that number determined. Thank you for the question. One moment for the next question. The next question comes from Hardik Parikh with J.P. Morgan. Your line is open. Hi, everybody. Good morning. Thank you for the time. I was just wondering that, you know, have you guys seen any data as relating to your titration schedule that kind of gives you any insights of, y ou know, as you, as you moderate the titration, is it easier to potentially reduce the rates of nausea or vomiting, like one versus the other? Is there a specific type of leverage you can pull that kind of maybe hit vomiting more than nausea? Yeah. Parikh, this is Blai. Important question again. You know, those two events usually go hand in hand. But when you looked at the data that we shared in slide 21, I think it's very clear that there's a reduction in both nausea and vomiting in the second week of that cohort that started the first week at 5 mg. And again, as I said, this is the striking result or the most compelling result. Over time, we're seeing varying degrees of nausea and vomiting. But again, those two events are usually going together. And when we're able to reduce nausea, as a consequence, we're also reducing the incidences of vomiting. Thank you. One moment for the next question. The next question comes from Myriam Belghiti with LifeSci Capital. Your line is open. Thank you, and good morning, and congrats on the data. Thank you for taking my question. Just one question from me. Naturally, with a slower titration schedule, we will expect lower AE, but, also slower weight loss. What in your mind is the limit to how slow you can titrate GSBR-1290? As in, is there a minimum weight loss threshold by some time point that you think is important to hit? Go ahead, Blai. Yes, Myriam, thanks for the question. Of course, the objective of the phase II-B will be how to balance that optimization in tolerability while we're maximizing the efficacy. The results that we presented today gives us a lot of confidence to continue exposing subjects with longer titrations, starting lower and maximizing the efficacy. We've seen efficacy at 12 weeks, that it's comparable to others in the space. And when we then transfer those to 26 and 36 weeks, it's reasonable to expect an increase and enhancement in efficacy in the mid-teens, placebo adjusted. And that's how we're looking into the next steps and the interpretation of the current data from today. And, Myriam, I'd also sort of remind you that, everybody in small molecules does a weekly titration. We have to do this at a pretty aggressive timescale because we have that 12-week time period. But what we see is as one goes from the phase II-A, 12-week to phase II-B, we've seen this going to 26-36 weeks, and then phase III, and phase II-B, sorry, goes biweekly. And then by the time one gets to phase III, we see this transition to every 4 weeks. So we're switching to phase, in the phase II-B, we're switching to every 4 weeks earlier because we think that it'll help. And we think by increasing the tolerability, this will have a positive impact on the efficacy, as we've seen from others. Thank you for the clarification. Yep. Thank you for the question. That will end the Q&A portion. At this time, I would now like to turn the call back to Ray Stevens for closing remarks. I want to thank you all for joining our call today, and we look forward to continuing our programs and making medicines more accessible to all. Hope you all have a good day. This concludes today's conference call. Thank you for participating. You may now disconnect.