Good day, and thank you for standing by. Welcome to the Structure Therapeutics GSBR-1290 Phase II Development Program update. 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 this session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Raymond Stevens, CEO of Structure Therapeutics. Please go ahead.
Good afternoon, everyone, and thank you for joining us today for an important update on our clinical trial plans for GSBR-1290, our oral small molecule GLP-1 receptor agonist. As we start to wrap up 2024, we're very pleased with the execution and progress we have made at Structure this year, having now begun our next phase of development with GSBR-1290. We look forward to 2025 as a pivotal year for Structure with the goal of bringing GSBR-1290 to patients as rapidly as possible. GSBR-1290 is positioned as the second most advanced oral GLP-1, with the potential to be best in class. In 2024, we've amassed a significant amount of clinical data evaluating GSBR-1290 in over 200 participants, and now we have moved into a 36-week study and an additional 300 participants.
This year, we are also significantly strengthening our management and clinical teams, and we are well positioned to carry out these GSBR-1290 studies that are underway. In addition, we plan to finish this year very strong and select our amylin development candidate later this quarter. Turning to the focus of this call, this afternoon we announced that the first patients have been dosed in our phase IIb ACCESS study of GSBR-1290. We also announced a related phase II trial called ACCESS 2, designed to assess higher doses of GSBR-1290 than previously studied. On today's call, we will share details on the protocols and the trial designs for these two studies and put these in context of what we feel is an extremely compelling profile for the compound and why we believe we potentially have the best-in-class oral GLP-1 small molecule.
Please see the first slide containing our note on forward-looking statements, including in our presentation and the risks and uncertainties which may cause our actual results to differ materially from such forward-looking statements, including risks which are also referenced in our SEC filings that I encourage you to review. I'll start with a brief overview on this slide of Structure's unique platform capabilities and GSBR-1290's differentiation. Blai will provide a recap of GSBR-1290 data that we shared back in June of this year, which was also the focus of two posters presented at Obesity Week conference earlier this month. He'll then go into more detail on the specific trial designs for ACCESS and ACCESS 2, including the titration schedule and doses that are intended to maximize the efficacy and minimize the very well-documented GI-related adverse events known to be on-target effects for all GLP-1 agonists.
We'll also discuss the higher doses we plan to study to assess further potential efficacy differentiation. We'll then conclude with a summary of our comprehensive oral small molecule franchise and next steps before opening the call to Q&A. Starting with our core competency in structure-based drug discovery and our mission of bringing small molecule innovation to areas of great unmet global need and making medicines more ACCESSible to all, we utilize our expertise to design non-peptide drugs which are orally bioavailable and can overcome many of the inherent limitations of peptide-based therapy treatments at a much lower cost point and without supply constraints. Specifically, oral small molecules have the potential to provide broader ACCESSibility. The oral formulation provides more patient options and a compelling potential maintenance solution for long-term weight loss management.
Large-scale manufacturing of oral small molecules is easier and less costly and more environmentally friendly, and we're very excited about the potential advantages for fixed dose combination therapy, which we see as the future direction in obesity treatment. The data to date shows that GSBR-1290 has the potential to be best-in-class oral GLP-1 receptor agonist with efficacy, tolerability, and safety data that could potentially set us apart from others in the market. On the efficacy side, we have demonstrated competitive in vitro potency and clinical efficacy out to 12 weeks, including more than 10% weight loss in 34% of participants. We have observed proportionality between 60 and 120 mg, and because we have ample safety margins from our toxicology program, we have the opportunity to explore higher doses of GSBR-1290 to maximize efficacy.
Additionally, clinical data to date shows that the level of efficacy with GSBR-1290 is directly related to exposure, and therefore higher doses have the potential to yield overall better efficacy. In terms of tolerability, we have initially shown that starting low and titrating slowly improves GI-related adverse events, including nausea and vomiting. This is consistent with what we've seen with other GLP-1s, including the long history of the peptides. Additionally, we have the potential to differentiate 1290 based on its wide safety margin with a greater than 150-fold window at the 120 mg dose, as well as clean safety data from more than 200 participants in our clinical studies, including no signs of liver toxicities. On these key elements of efficacy, tolerability, exposure margins, and safety, GSBR-1290 has the potential to become best in class.
With that overview to provide context, I'll now turn the call over to Blai to quickly recap the data we shared in June on the GSBR-1290 12-week studies and then move into the trial designs for the ACCESS programs.
Thank you, Raymond. I'll briefly review the key data from our 12-week studies that we shared back in June. We showed a competitive placebo-adjusted weight loss of 6.2%-6.9% at week 12. We also demonstrated a clean safety profile with no liver liability that is consistent with the lack of off-target effects in our GLP tox studies. Both pieces of data support the ability to go higher in dose. As you know, we observed low rates of study discontinuations, even though the 12-week studies followed a more aggressive weekly titration schedule that was necessary due to the short duration.
As previously discussed, I will point out that in the longer duration ACCESS program that we will discuss today, we are taking a longer monthly titration approach that will optimize the tolerability profile of 1290. In the 12-week studies, we dose daily, and the efficacy results and PK profile that we shared support QD dosing moving forward. One additional and important point: the manufacturing and scalability advantages of oral small molecules can't be ignored. Only a very small fraction of the more than 100 million people living with obesity or overweight in the U.S. have ACCESS to treatment today, and ACCESS is even more of an issue for the 800 million people globally who could benefit from a GLP-1 receptor agonist. Oral small molecules will be a critical therapeutic tool to address these patient needs, and Structure currently has the manufacturing capacity to supply drug to 120 million patients.
Let's now turn to our late-stage phase II program, which includes the ACCESS and ACCESS 2 studies. We intentionally designed the program as two separate studies. The rationale for doing this is to accelerate our timeline to phase III and, at the same time, evaluate potential further efficacy differentiation with higher doses of 1290. The data we have to date indicates that for doses up to 120 mg, the ACCESS study should lead to robust efficacy, and we want to move these doses forward as quickly as possible so we can start preparing for the phase III program. Starting with ACCESS on the left, this is a phase 2b study designed to optimize tolerability by following a start low and go slow titration. This is an established titration schedule that has been shown to minimize gastrointestinal-related adverse events that are inherent to the GLP-1 receptor agonist class of drugs.
Other programs have seen significant improvement in tolerability with longer titration periods, and our data is consistent with those findings. The dose range finding study is designed to confirm the competitive efficacy that we have seen with previously studied doses of 1290 over a longer 36-week study with patients on the target maintenance dose for at least 16 weeks. Turning to ACCESS 2 on the right, this is a separate phase II study designed to explore doses higher than 120, specifically 180 and 240 mg. The favorable dose proportionality, as well as the safety profile of 1290 up to 120 mg, enables us to study those doses for further weight loss differentiation. By doing this as a separate study, we can assess these higher doses without compromising the flexibility to move into phase III as quickly as possible with the data from the ACCESS study.
Now let's go to the study designed for ACCESS. This is a randomized double-blind placebo-controlled dose range finding study in participants living with obesity defined as body mass index of at least 30 or overweight with a BMI of at least 27, with at least one weight-related comorbidity. ACCESS will enroll 220 participants at sites across the United States, and participants will be randomized into three cohorts in a 3:1 ratio of 1290 or placebo. All three cohorts will start at a dose of five milligrams, titrating up every four weeks before reaching target doses of 45, 90, or 120 mg. As you can see, patients will be at their target maintenance dose for at least 16 weeks. Similar to our phase IIA study, the protocol allows for down titration depending on tolerability.
The primary endpoint of percent change in body weight will be measured at 36 weeks compared to baseline, with safety, tolerability, and pharmacokinetic assessments as part of the secondary endpoints. Moving to ACCESS 2 in Slide 12, this is a phase II randomized double-blind placebo-controlled study in the same patient population as we're enrolling in the ACCESS study, so participants with obesity or overweight with at least one weight-related comorbidity. This is a different design because this is our first time evaluating those higher doses. The study includes a sentinel cohort of 10 participants, which will be randomized 4:1 to 1290 or placebo following a monthly titration schedule and reaching a maximum target dose of 180 mg, which will be maintained for 12 weeks. The main study group and the sentinel group cohorts will run in parallel and will complete at the same time.
The main study group includes 72 participants, randomized 5:1 to GSBR-1290 or placebo, and follows the same four-week titration period up to the 120 mg dose. At week 28, once patients in the sentinel group have been at the 180 dose for four weeks, tolerability, exposure, and early weight loss readouts will be assessed before proceeding to randomize the main study group into three cohorts. The first will remain at 120 mg for the duration of the study, the second group will titrate up to 180 mg, and the third will titrate up sequentially to 180 and then 240 mg on a four-week interval. The primary endpoint for ACCESS 2 is safety and tolerability at 180 and 240 mg doses, with a secondary endpoint of plasma pharmacokinetics. We will be looking at weight loss as directional and exploratory to inform the dose selection process for phase III.
As we shared today, we are very excited to communicate that we have now dosed our first patients in the phase IIb ACCESS study and expect to dose the first patient in the ACCESS 2 study later this quarter. We expect expeditious enrollment and anticipate reporting data from both studies in the fourth quarter of 2025. With that, I'll hand the call back over to Ray for additional color on the rest of our pipeline and some closing remarks.
Thanks, Blai. Now that we've covered our plans for the phase II ACCESS programs, I'd like to briefly describe Structure's metabolic franchise. We believe that GSBR-1290 has the best-in-class potential with an opportunity to differentiate on efficacy and safety, which are equally important for a treatment that's going to be given chronically and that is both a monotherapy and in combination. We completed this important proof of concept stage earlier this year, and here we lay out the steps for making GSBR-1290 into a standard of care treatment for obesity and related diseases. We have now initiated our phase II dose range finding program, which we have carefully designed with the aim of ensuring dose selection and rapid progression to a phase III pivotal program.
With oral combinations being the future treatment direction, we are working on future opportunities with GSBR-1290 as the backbone to combination programs with our amylin, GIP, GCG, and apelin oral small molecules, with tremendous potential to unlock even more of the obesity market. Structure has what we believe is the most robust oral small molecule metabolic franchise today. In addition to our non-peptide oral GLP-1 receptor agonist, GSBR-1290, we also have pipeline programs targeting amylin, GIP, GCG, and APJ. We believe that various combinations of these potential medicines could have applicability in obesity and the constantly expanding list of related diseases, including Type 2 diabetes, chronic kidney disease, MASH, and even indications such as inflammation and neuropsychiatry indications. With extremely large patient populations, many of these indications can only be fully supported through the manufacturing yield, stability, and shelf life of oral small molecules.
Structure has the opportunity to design, develop, and commercialize medicines for some of the world's largest serious chronic diseases, bringing meaningful change for hundreds of millions of patients. Before wrapping up today, I'd like to briefly give you a preview of how our amylin program fits into our plans. We believe that both GSBR-1290 and our amylin oral small molecules could become backbone therapies for various patient populations. And as we have seen from the peptide amylins in development, amylin may have tolerability advantages and could preserve lean muscle while decreasing fat. Structure is in a very favorable position with what we believe to be the most advanced oral amylin small molecule in development. We plan to announce our first amylin oral small molecule development candidate before the end of this quarter.
While we have not yet disclosed which molecule we will take forward initially, we have the good fortune of selecting from multiple molecules with the desired characteristics. You'll likely see more than one DC selection from our amylin program, given the first-in-class nature of an oral small molecule here, with the first one planned for this year and potentially another next year. Please stay tuned. In closing, in 2024, we successfully conducted a comprehensive systematic series of studies for GSBR-1290 in over 200 participants and demonstrated a compelling safety profile and competitive efficacy. Based on the data we have released to date, we have confidence in the potential best-in-class profile of GSBR-1290 as monotherapy and with potential future drug combinations.
Our two 36-week studies are expected to read out by the end of 2025, at which point we'll have data in more than 500 participants, enabling us to advance to phase III as rapidly and seamlessly as possible. As you can see, we have the broadest and strongest oral small molecule portfolio, including our amylin program, where we expect to declare our first development candidate by the end of the year, which to our knowledge will be the most advanced oral small molecule amylin receptor agonist. We hope that you share in our excitement and continue to follow our story, which is only just beginning. Thank you again for sharing your time with us today, and we'll now move to Q&A.
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. In the interest of time, we ask that you please limit yourself to one question. Please stand by while we compile the Q&A roster. And our first question comes from Evan Seigerman with BMO Capital Markets. Your line is open.
Hi, guys. Thank you so much for taking my question. Really great to see the progress on the phase IIb. I'd really like to touch on some of the trial design, especially for the second trial. What do you hope to really gain from that high dose? I know that it's more exploratory, but do you think you'll be able to fully understand the benefit of, say, that 240 mg dose at the very tail end? Or is it really just helping directionally talk about where this will be in the phase III? I'm just trying to get a handle as to how that fits in with this phase IIb as you think about a potential pharma partner.
Thanks, Evan.
Yeah, I'll take the question. Thanks for the question because, of course, it's an important one. For the 180 and 240 from ACCESS 2, we're planning to take three things. One is to use the level of exposure and how different that exposure could be compared to the 120 mg, and directionally, how much additional weight loss we are able to achieve with those higher doses. Your question is spot on, though. It's four weeks, good enough. We're confident that that's the case, especially if we can see the levels of tolerability that are acceptable and the exposure that it keeps getting proportional. In four weeks, the efficacy data, at least directionally, we may be able to read out that, and the level of confidence is coming from the capsule-to-tablet bridging, where we saw with two or four weeks at 120 mg a substantial reduction in body weight.
We feel confident that that's the right design to inform how to move forward with phase III. I hope that I answered your question.
Thank you. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.
Good afternoon, team. Thank you so much for all the great updates. I guess, based on your modeling of existing data and this dose optimization or dose titration differences between study one and study two, what would you extrapolate the magnitude of weight loss in discontinuation rates to be between ACCESS 1 and ACCESS 2? I guess if you modeled both out and you both powered them, could you talk about your expectation both from a weight loss magnitude as well as the GI tolerability of one versus two?
Yeah, thanks for the questions, Blai again. The idea entering into the study is that we have confidence based on the data that we have up until now that 120 may be one of the doses moving forward into phase III, and so that's the starting point based on the data that we have. By extending the titration to four weeks and starting at five milligrams, we're also expecting a significant improvement in the tolerability. That means a reduction in the number of participants having GI issues and also a reduction in the number of participants that will need to be accommodated to a down titration or drop out, so the tolerability will improve while we're maintaining or expanding on the efficacy. Now, providing specific metrics, now I think it's very complicated, and it would be very risky for us to do so, but that's the starting point.
Of course, if we keep the proportionality in the exposure at 180 and 240 with the times that we have, it's reasonable to assume that we can see directionally at least a 1.5 to 2% difference in body weight reduction between the higher doses compared to 120. And so that's the assumption that went into the design of the two studies, ACCESS and ACCESS 2. And the most important thing, yes, is I guess the question is pointing out to, do you guys have the right design of the phase II in order to move to phase III with enough confidence? And we do. With that range of doses from 45 to 240, we have a wide range of dosing to move into phase III. And that's the most important thing. But again, just to reiterate, 120, we feel it's a dose that most likely will move into phase III.
And so what additional weight loss? That's what we need to do the two studies. Thanks for the question.
And yes, also to add on that we're very comfortable with 120. We think that 120 is competitive with the other oral small molecules that are out there. We're in the unique position that we can go up even further. And so that's one of the things that we're excited to explore.
Thank you. Our next question comes from Roger Song with Jefferies. Your line is open.
Great. Congrats for starting the phase IIb. And then thank you for taking the question. So maybe just a follow-up on the previous question. So given you have a multiple dosing regimen to test, can you clarify the potential phase III going to look like? You will move forward to one dose regimen or multiple? Will this phase III dosing regimen coming from this ACCESS and ACCESS 2? Or given you will have a longer duration for phase III, you may test different regimens for higher dose if you choose to? Thank you.
Thanks, Roger. So the plan that we're considering is to have multiple doses for phase III, and this is something that, of course, it's not unique. And the hypothesis there is that we could move 120 into that phase III as expeditiously as possible. We would have the opportunity to also identify a lower dose. There's patients that cannot tolerate the required dose, and that's something that we're learning from different programs, including the injectables. And we want to have that flexibility to also have a lower dose in a phase III. But the difference here that we're optimizing and we're taking advantage of is due to the safety margin that we have and the proportional exposure to explore higher doses to see how much additional weight loss we can achieve. And so it's also reasonable to assume that we'll bring a higher dose than 120 into the phase III.
So that's how we're looking into this. And by designing those two studies, it keeps the options open for us because we may be able to move into Phase III with 120 as a top dose from ACCESS. But also, depending on the results of ACCESS 2, we may be able to incorporate a higher dose that can offer some additional potential to be differentiated from the other oral small molecules.
Thank you. Our next question comes from Prakhar Agrawal with Cantor. Your line is open.
Hi. Thanks so much for taking the questions and great progress on all the phase II design. Maybe just talk about the stat plan on how it will incorporate the dose reductions due to tolerability and how will it compare versus orforglipron phase II trials and add a couple of more.
Yeah, thanks, Prakhar. So the plan is to do the same statistical approach that orforglipron did in their Phase IIb studies, and so we'll be around the primary efficacy estimate, and of course, the detail of how we're planning to define the intercurrent events is key, and what we can share with you today is that the definition of intercurrent events will be the same that orforglipron used, so all the participants that will require a down titration will be part of the statistical analysis as part of the primary efficacy estimate, and so that's something that orforglipron did in their 36-week study, and since we have that long exposure in ACCESS and ACCESS 2, we're planning to do the same.
Got it. And lastly, given all these different ongoing trials, what are the implications on your partnership discussions, and when would be the right time to get a partner on board? Thank you.
Yeah, Prakhar, I'll take that question. So as we've consistently said, our goal is to have a partnership for GSBR-1290 for late-stage development and commercialization. So right now, we are laser-focused on Phase II execution. We are fortunate to have the resources and team in place to successfully execute ACCESS and ACCESS 2 so the timing of the partnership is not driven by these factors.
Thank you. And our next question comes from Seamus Fernandez with Guggenheim. Your line is open.
Thanks so much. So actually interested to ask a few questions on the pipeline. Ray, just hoping to get a better understanding. You have a number of Phase II ready assets. Do you see an opportunity to advance additional exploratory studies with your apelin molecule in combination prior to potentially seeing some advancement towards your amylin as your amylin DC moves forward? And just also, you mentioned a number of other potential programs, glucagon as well as GIP. Just interested to know where you're most excited to see a next molecule potentially emerge or where we might see a next molecule emerge within the incretin portfolio.
Yeah, Seamus, thank you for the question. So we are in the very fortunate position that we have small molecules against all these incretins and related receptors. So we're currently conducting our six and nine-month tox study for our apelin, and we're following BioAge very carefully, the study that they're doing with their apelin receptor agonist together with Eli Lilly. At the same time, we're continuing to progress our GIP and glucagon programs. But the one that's most advanced, to specifically answer your question, is amylin. We're now just about at the end of the year, and we've consistently stated that we believe we will declare a development candidate for amylin, and we're right on track for that. We had a poster at Obesity Week. I guess it was about two weeks ago. Very well-received poster. Very excited about that.
Again, we believe we have the first oral small molecule for amylin. And lastly, on the amylin note, don't be surprised if we have multiple DCs. This is a first-in-class for an oral amylin, somewhat reminiscent of six or seven years ago when the oral GLP-1 started coming out. And so there's a lot of opportunity to explore amylin calcitonin axis, biased signaling. And so we've been working really, really hard on that for the past two years. So we'll declare our first amylin DC before the end of this year. And the intention is to move that into the clinic by the end of next year. But we'll also follow up with multiple DCs to really map out to make sure that we have not only first-in-class, but also best-in-class. Our goal is to be the leader in oral small molecule amylins.
Thank you. Our next question comes from Myriam Belghiti with LifeSci Capital. Your line is open.
Thank you, and congrats on the progress. I was wondering how much better you think you can get the tolerability with the start-low, go-slow approach. Do you have a target profile in mind for the 120 mg dose and higher for what you want to see in terms of GIAE discontinuation or dose hold?
Yes, Myriam, this is Blai. Thanks for the question. As I said in the beginning, I think it's still too early to commit to certain percentages. But of course, when you looked at the titration schemes by extending to four weeks and doing that very gradually, I think we could expect it's very reasonable to expect that we'll see an improvement in the number of participants with those GI and also the number of participants that may require eventually a down titration. When you looked at previous data, for instance, from other small molecules in the field, they had a range between 10%-21% of discontinuations to adverse events. And that's what we will be closely monitoring during the study in order to beat those numbers and be much better than that 10%-21% range.
And with the current design and starting at five milligrams, we're confident that we can do better. But again, it's still very early to commit to certain metrics on that end.
Thank you. I'm showing no further questions at this time. I would now like to turn it back to Raymond Stevens for closing remarks.
Thank you all very much. So again, as you can see, we have the broadest and strongest oral small molecule portfolio, and we're very excited about the future. We hope that you'll share in this excitement and continue to follow our story, which again is only just beginning. Thank you all, and I hope you have a good day.