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

Ladies and gentlemen, thank you for standing by. Welcome to Structure Therapeutics webcast and conference call. [Operator Instructions] 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'll 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'll 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 IIa study, and up to 6.9% in the capsule-to-tablet PK study at 12 weeks, which proves 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 1/3 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 IIa 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 IIa 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 2 studies. Let's start with the study design of the Phase IIa 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 milligrams for 2 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 to 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 1290 versus the gray line showing placebo. Participants on the 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 remained at 6.2%, with a statistically significant and clinically meaningful difference between the 2 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, 2/3 of participants lost at least 6% of their body weight, more than half of participants lost at least 8% and, remarkably, 1/3 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 these positions 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 64 participants randomized 15:3 to 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 3 GSBR-1290 arms, varying in starting doses from 5 to 15 mg and following either a weekly or biweekly titration. As you can see in the study schematic, 2 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 IIa 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% to 6.4%, equating to a placebo-adjusted weight reduction of 6.2% to 6.9%, as shown in the table. The weight reduction in all 3 of these cohorts was statistically significant and again shows clinically meaningful weight reduction with 1290, consistent with the previous study and supporting the advancement of GSBR-1290 into further clinical development. And now that we have summarized the weight reduction seen with 1290, it's appropriate to contextualize the efficacy data. Here, we show a cross-trial comparison for 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% to 6.9%. Next, the results of the top doses of 2 different small molecules with efficacy ranging from 6.5% to 6.6%. The graph shows orforglipron at the top dose in the 36-week Phase IIb 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 used 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 are 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. So let's review in detail the safety and tolerability results. We continue to see low rates of study discontinuation due to adverse events at 5.4% for the final 12-week analysis, which is 2 participants discontinuing the study. There were 2 participants who experienced gastrointestinal-related adverse events and discontinued the study within the first 2 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 2 participants that discontinued the study previously discontinued the study drug. 15 participants had a dose reduction and remain in the study at any dose of GSBR-1290 and 2 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 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 1 event reported. So to better characterize the tolerability profile, we analyzed the weekly incident 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 rate 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 IIa 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 2 studies. We have also not seen any increases in hepatic enzymes as reported as adverse events in any arm in either study. We also showed a mean change from baseline to week 12 for the 2 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 10x the upper limits of normal for ALT or AST. At the 3x the upper limit of normal, there were 3 cases, 1 in the 1290 capsule, 1 in the placebo arm and 1 in the 120 mg tablet arm of GSBR-1290. We'll go through these cases one by one. The first in the Phase IIa study. This was a female participant with a sporadic increase in ALT of 3.9x and an AST of 2x the upper limit of normal at day 44. The investigator, and following the regulatory guidance, continued dosing the subject and repeated ALT and AST 4 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. And then the third case was in the capsule-to-tablet PK study. The male participant had an isolated increase in ASP of 4x the upper limit of normal at 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 10x 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. And 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 in once-daily administration and gives us confidence for the design of the upcoming Phase IIb. Let's just start with the graph showing the plasma concentration of 1290 using different formulations, tablet and capsule, and doses of 60 and 120 mg. First, at 60 milligrams, we see comparable exposure between tablet and capsule. Second, the exposure is generally proportional between 60 and 120 mg. And third, the concentration of 24 hours is above 10 nanograms per milliliter for the 120 mg groups. The average concentration identified in the nonhuman primate studies is achieving maximum insulin secretion. Those 3 observations enable the program to continue with a tablet for the Phase IIb and opens the possibility to test higher doses than 120. 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 2 formulations study. In summary, we see adequate levels of exposure determined by the AUC and Cmax compared to other small molecules in development. We also observed delayed Tmax when in conjunction with the half-life observed up to 8.5 hours supports appropriate target engagement during the majority of the dosing interval. And 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 identified exposure of AUC as a [indiscernible] driver for efficacy. [indiscernible] proportional exposure [indiscernible] to explore [ effective dosing ] in Phase II [indiscernible]. And we see plasma concentration at 24 hours [indiscernible] threshold, which reassures target engagement during the once-a-day dosing [indiscernible]. All these observations support the level of efficacy achieved in the 2 studies presented today and sets a strong foundation for the design of the Phase IIb. From a safety and tolerability perspective, GSBR-1290 has ample safety margins with minimal tissue accumulation in preclinical studies. And 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 IIb. On this slide, we show the incidence of nausea in dark blue and vomiting in light blue on the Y axis over the first 2 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 or 15 mg. Interestingly, remaining at 5 for an extra week, as shown in the right-hand side of the graph, instead of escalating the dose to 20 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 IIb 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 1290, with all arms studying at a lower starting dose, 5 mg, and a lower monthly titration. As previously indicated, the ample safety margins and the generally proportional exposures enables the program to explore doses higher than 120. This 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 IIb 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 1290 to date from multiple studies. The safety results from these studies are consistent with the large safety margins seen in our GLP tox studies. And 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 the tablet formulation, that we are confident will further enhance the profile of 1290 in the Phase IIb 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 confirms GSBR-1290 as a key molecule for further development and as a foundational backbone 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 a weight loss on par or better than the GLP-1 peptides. Third, we designed this drug to be once-daily dosing, targeting GSDR1290 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 to improve tolerability. And last, as part of our company mission, we wanted to make sure that we have 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. And 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. And 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 IIb GMP supply and manufactured 6,000, 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% to 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 IIb 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 IIb 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 III, meaning equal to or better than other selective GLP-1s that have completed Phase III or on the market. In our latest phase 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's 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. And 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 2 years. Here is what we have upcoming. We are rapidly advancing GSBR-1290, the foundation of our broad metabolic franchise, and we'll start our approximately 300 participants Phase IIb trial in a few months, with all the learnings from the 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. And 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.

[Operator Instructions] The first question comes from Evan Seigerman with BMO.

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? And 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?

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 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 to 12, the incidences are fluctuating throughout the course of the study. But there's a clear trend to reduce the incidences towards the end when subjects are at the top dose. The other thing that we mentioned 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 titrated. So that's another reassuring point that it's building the tolerability. However, we're also confident that for the Phase IIb, 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 IIa 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?

Yes, Evan. This is Ray. So in that regard, 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 IIb, and we can see ourselves continuing this through Phase III. But we're always looking for 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.

The next question comes from Yasmeen Rahimi with Piper Sandler.

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 kind of relative to Slide 16? And then the second question is, given the 3 cases of liver enzyme elevations, I guess, what evidence is there to conclude, especially the 2 cases that was on the 120 mg dose group, that it was 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 this screened out of the study initially and they had a propensity for liver enzyme elevations? And my apologies for asking 2 questions.

Yes. This is Blai. Thanks for the 2 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 trials. And so numerically, they are different. But overall, it's comparable. And most importantly, we see -- 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 2 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 2 participants, 1 with an elevation of less than -- between 3 and 5x upper limit of normal for ALT and 2x the AST in the capsule receiving 120. But importantly, that subject continued dosing for 4 days, and repeat ALT and AST and the -- both determinations, ALT and AST, came back to the baseline values to normality, which I think is 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 shortage 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 2 questions.

The next question comes from Jon Wolleben with Citizens JMP.

You guys mentioned that you had 2 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 2 groups?

Yes, thanks. Blai?

Thanks, Jon, 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, and we saw a magnification of the treatment effects 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 that data. But it's an extra element of reassurance of the level of efficacy that, that can achieve. And we're moving forward to implement those changes in the Phase IIb. You're mentioning the tolerability in those 24 replacements, we've seen 2 subjects discontinuing the study drug due to adverse events in those 24 replacements. Again, small sample sites, but that's what the data is telling us. And 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 2 most common adverse events, and we also see the similar temporal trend in terms of what has been released in the overall population.

The next question comes from David Risinger with Leerink Partners.

Congrats on the results, and thanks for the detailed presentation. So I have 2 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.

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 no surprise that the shapes of the curves at different time points during those 12 weeks is going to 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. And so 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. 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 that it will require a strategic partner to help us with the late-stage development and commercialization. So we remain consistent on that topic. Thanks for the questions.

The next question comes from Seamus Fernandez with Guggenheim.

Great. So just a couple of quick ones. First, can you comment on the 60 milligram dose? The performance of that product in the titration study or of that dose seems 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 milligram in the titration study, was that better than expected, basically, sort of speaking to your start low, go slow approach? And then in terms of the second question, really just interested to 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 of questions on that, but I believe it's in the slide deck.

Seamus, thanks for the question. So in regards to the 60 milligram arm, we saw better and improved tolerability when we started that cohort at 5 mg and then remained at 5 mg for the second week, as shown in the slide, compared to 10 and 15. So that was an important finding from the study that we will incorporate into the Phase IIb. 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. And when it comes down to the liver, we reported one subject on the tablet receiving 120 milligrams that had an elevation in AST at day 84, that was 3x upper limit of normal, and that was the subject who had some physical exercises 3 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.

The next question comes from Prakhar Agrawal with Cantor Fitzgerald.

Congrats on the update. 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 and vomiting is lower at by week 2, but what about the other time points?

Thanks, Prakhar. So in regards to the low baseline BMI, the most important thing is that it's balanced across the groups, in placebo and drug. So that's the first observation that I want to highlight. The second thing in moving forward for the Phase IIb, 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 the 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 our sales and 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 IIb, 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 milligrams with the capsules compared to the 120, as I said before, I think the most striking difference happened in the first 2 weeks. Overall, the tolerability was comparable with the 120 milligrams, with numerical differences, of course, with those small sample size in those studies, you always see some [indiscernible], but the most striking difference, as we reported in the presentation, was during the first 2 weeks. Thanks for the question, Prakhar, it's important.

[Operator Instructions] And the next question comes from Roger Song with Jefferies.

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-nanogram, versus you wanted those a little bit higher than 120, how this will improve your overall weight loss over longer term, and how high that those you're kind of planning to go based on your safety profile?

Thank you, Roger, an important question of course, and currently discussing right now based on the data that we have and designing the Phase IIb. So the idea here is, since we have ample safety margins from the GLP preclinical talks and also we see the proportionality and exposure between 60 and 120 mg, we have the opportunity to go higher than 120 in the Phase IIb. 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 2 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 IIb.

And Roger, we'll be giving an update on this in the future once we have that number determined. Thank you for the question.

The next question comes from Hardik Parikh with JPMorgan.

I was just wondering that have you guys seen any data as relating to your titration schedule that kind of gives you any insight of as you moderate the titration, is it easier to potentially reduce the rates of nausea or vomiting, like one versus the other? Is there specific type of levers you can pull that kind of maybe hit vomiting more than nausea?

Yes. Parikh, this is Blai. Important question again. Those 2 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 milligrams. And again, as I said, there is -- this is the striking results or the most compelling result. Over time, we're seeing varying degrees of nausea and vomiting. But again, those 2 events are usually going together. And when we're able to reduce nausea as a consequence, we're also reducing the incidences of vomiting.

The next question comes from Myriam Belghiti with LifeSci Capital.

Congrats on the data. So just one question from me. So naturally, with the slower titration schedule, we will expect lower AEs, but also slower weight loss. What in your mind is a limit to how well you can titrate GSBR-1290? And then 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 IIb 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 exploring subjects with longer titration 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 in 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 time scale because we have that 12-week time period. But what we see is as one goes from the Phase IIa 12-week to Phase IIb, we've seen this going to 26 to 36 weeks. And then Phase III -- and Phase IIb, 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 -- in the Phase IIb, we're switching to every 4 weeks earlier because we think that it will help. And we think by increasing the tolerability, this will have a positive impact on the efficacy as we've seen from others.

That will end the Q&A portion. So 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.