We're gonna get started. My name is David Risinger. I cover diversified biopharmaceuticals for Leerink Partners, and it's very much my pleasure to welcome Ray Stevens, the CEO of the company. Very much appreciate you traveling to be here, and the timing is excellent. The company issued its 10-K on Friday, had new disclosures, and Ray is going to set the stage with an initial brief presentation to bring us up to date on the latest. So Ray, let me turn it over to you.
Thank you very much, Dave, and thank you to Leerink for hosting this conference in beautiful Miami. So I'd like to spend the first couple of minutes just to sort of highlight. As Dave mentioned, we did file our 10-K on Friday, and we also updated our corporate presentation on our website just yesterday morning, in preparation for this particular sort of conference. So I wanted to just spend a couple of minutes before I sit down with Dave, as part of the sort of fireside chat, to highlight a couple of points that are in the 10-K. So as everybody, you know, I think many people sort of know Structure Therapeutics, our mission is really about converting highly validated biologics and using structure-based drug discovery to convert them into oral small molecules.
This slide that you're seeing up here, you know, at the very beginning, as a reminder, is on the left-hand side, that red object in the top right, that's GLP-1 peptide. In the background, squiggly object, that's the GLP-1 receptor that sits on your cell surface. By visualizing that with three-dimensional structural information at high resolution, atomic resolution, we're able to see what are the most important binding interactions. From that, we're able to then design the smallest possible molecule on the right-hand side that you're looking at. By making it a small molecule, we believe that that provides patients with options. It's more convenient. You take a pill, you know, in the morning instead of the injectables. We believe this will lead, for some patients, to better compliance, lower cost of goods.
One of the things that I'm gonna highlight today and we're really excited about is for the first time, we're gonna start disclosing some of our manufacturing capabilities as we sort of move into larger trials. So lower cost of goods. Stable, no cold chain requirements with these, and we're also able to, going after a validated target, we're able to really take advantage of improved properties, in particular with the GLP-1 receptor, highlighting biased signaling, where we do not cause receptor internalization, we focus on the real function, the cyclic AMP signaling. The market itself, everybody's heard about GLP-1s in the news. It's constantly in the news, and the tailwinds just continue to grow. I'm even amazed. I've been in the field of GLP-1s for about 15-18 years in terms of getting the three-dimensional structure.
We had the breakthrough in 2013 by getting the first incretin structure, the glucagon receptor, and then in 2017, published in Nature, the three-dimensional structure of the GLP-1 receptor. I did not see the size of this market continuing to grow. There's really a big need right now. With the injectable therapeutics, which are life-saving and pioneered and led by Novo and Eli Lilly, right now, they're currently servicing about 5 million patients in 2023 numbers. They're scaling, they're gonna continue scaling this, but the scaling of the production, as well as the fill finish with the injectable pens, continues to be a challenge and will continue to be a challenge.
The real need right now, servicing 5 million people in 2023 in the United States alone, we see the real need growing to over 100 million in the United States alone. The current need is over 133 million. That is an enormous gap to fill. Patients need more options. They need to get access to these medicines. So one important slide in our investor deck that we posted yesterday is we're now starting to update everybody in terms of our advantage that we have, in terms of manufacturing. So what you're looking at here on this particular graph is the green line that you're looking at. We've been able to bring the cost of goods down significantly, over 100x. In parallel, our ability to scale has gone up tremendously as well. This was all part of the design.
When we designed GSBR-1290, this is our selective oral GLP-1 receptor agonist, biased agonist. We designed it obviously with tolerability and efficacy in mind. Safety, we believe that these medicines are gonna be used by such a large number of people, safety has to be at the highest level. So in December, we were very pleased to announce our 6- and 9-month tox data, taking the rat NOAEL all the way to 1000 mg/kg, the highest dose that you go. And in non-human primates, we were capped at 20% weight loss in the lean non-human primates, and that was at a 30 mg/kg number. So with those numbers in mind, and thinking about our sort of scaling, scaling was our fourth pillar in terms of our goals. We designed the molecule to be scalable, manufacturable.
We currently have capacity to manufacture 6,000 tons per year. 6,000 tons, to put this in perspective, of 5,000 tons, would provide 40 billion tablets, which is 100 million patients. We have the ability today to service the needs of the participants or the patients that are in need of these medicines. So very excited about our ability to scale and manufacture this at the scales that are needed, for society. I also wanna highlight one other thing in our 10-K that was released, on Friday, and that is, we're not only working... We built this company not only around GLP-1, we've invested deeply for the past 15 years on the broader incretin in metabolism.... So the combination therapies, GLP-1, we believe, is going to be the backbone, a foundational element of any type of, therapeutic treatment.
But in combination GLP-1, we already know about tirzepatide, which is a GLP-1 GIP injectable peptide, doing wonderful things for patients. We recently heard last week from Novo about the great results with amycretin, a combination of GLP-1 together with amylin peptides, and those results were quite remarkable. What we've been able to do, using our platform with structure-based drug discovery, visualizing and getting all the structural data over the past many years, as well as building our incretin small molecule library, is we have small molecule programs, not only in GLP-1 receptor, but also in GIP, amylin, as well as glucagon receptor. All of these are candidates for combination. We believe a combination of GLP-1 plus glucagon is a great combination for diseases like MASH. We believe the future of weight loss is a combination like GLP-1 with amylin.
So we're very excited to also update everybody in terms of another piece in our 10-K. And this is this particular sort of image, where we have the three-dimensional structure of the amylin receptor, which is more complex than GLP-1. We've been working on this for about 5 years. We had a big breakthrough last year in this area. What you're looking at on this particular graph is the blue, blue and turquoise lines are the typical semaglutide. You see the 15-18% weight loss. Quite significant. This is in a DIO mouse model, which does translate, incretin metabolism does translate well into human studies. When we add on our oral small molecule, amylin small molecule, we see this tremendous decrease further of weight loss all the way down to 28%.
We think this combination of GLP-1, together with our oral amylin molecule, will be a next-generation therapeutic for weight loss. This is based on the recent results that we've seen from Novo Nordisk last week in terms of their amycretin molecule of a GLP-1 plus amylin itself. This candidate, our amylin small molecule, oral small molecule, we will. We feel very confident in declaring that we'll have a DC, development candidate, by the end of 2024, and we'll be in the clinic by the end of 2025. Excited about that. Our oral GIP molecule will follow this. We expect to have a DC in early 2025, with the DC being in the clinic in early 2026, and then our glucagon molecule is also in discovery stages right now.
So very excited about the oral small molecule amylin used together with oral GLP-1s. So with that, Dave, you know, my last slide before we, you know, chat about the, in the fireside chat, is a very exciting pipeline. GSBR-1290, our highly selective oral GLP-1. We will be having data coming out in Q2 of this year. This will be the 2A obesity data, and we feel very confident in terms of that data coming out in Q2. That'll be both a combination of the 2A obesity data, as well as our PK bridging study, converting capsules into tablets. The reason why we're doing this, scalability. Everything for us at this stage, besides the efficacy and tolerability and working on that, is getting ready for manufacturing and scalability.
So we'll be doing the transition over to tablets for our phase II-B study, and phase II-B study will be initiated in Q4 of 2024. In addition to the oral GLP-1, as I've already mentioned, the oral amylin, the oral GIP coming at the end of the year in early 2025. And then lastly, one other program that I want to mention is apelin receptor, and this is in selective weight loss area. We have an apelin receptor agonist that was, that is now phase completed phase I and phase II ready. In this, we're evaluating options in terms of combination with GLP-1s for selective weight loss, where we maintain muscle with apelin, but have the fat loss with the GLP-1 mechanisms. And based on preclinical studies already, we're feeling very good about this combination working.
We also have one other program that's going to be going into the clinic in Q2 as well, and that is our LPA-1 receptor antagonist, and that is for IPF. So with that, Dave, I'm looking forward to having a fireside chat with you.
Excellent. Thanks very much, Ray, and thank you for the updates. So, you obviously have a much broader portfolio than investors have focused on previously. You know, I wanted to go into that in some more detail, but maybe we could take a little time on phase II-A trial that's going to read out. I know that that's not new news, so you didn't focus on it, but you know, that's a key event in the second quarter. At a high level, you know, the diabetes results in December were on the lower end of the efficacy that you were hoping for.
Yeah.
Could you just speak to the obesity readout that is ahead, frame it for us, and then just speak to your level of confidence in compelling weight loss?
Yeah, absolutely, Dave. So, you know, the December data, we were in fact quite excited about. As a small molecule drug hunter, one of the things that you always wonder about, the real risk, you know, we don't take risk on biology. We love GLP-1 because it's a highly validated target, minimal risk in biology. The risk in small molecules is always tox. You're wondering, what are you going to sort of pick up? That's the real risk that we're sort of taking in terms of the business model of converting biologic into small molecules. And so the data that we released in December, we showed our 6 and 9 month tox data. Again, as I mentioned in the opening comments, you know, 1,000 mg/kg in rodent, and then going up to 30 mg/kg, 20% weight loss in lean, non-human primate, those are remarkable results.
Very excited about our safety profile. The obesity data that we shared, the eight-week interim data that we shared, was also very positive. If you look at the slope of the line, downward trend, you know, if we look at what's the expectation, the expectation is that 5%-7% range of weight loss. We've powered this to be 5% minimum, so I want to emphasize the word minimum, 5%. We feel confident, to your question, Dave, that we're going to be there in Q2 when we release the data. So that gives us sort of confidence in terms of our, our December release. You did mention the diabetes data, and I agree with you, it did underwhelm. We feel that there's work to be done there, and it really educated us tremendously in terms of, did we leave efficacy on the table?
Yes, we can go up in dosage. Do we need to titrate, change the titration, modify it? Yes, that's an opportunity for us. So there's a lot of places where we can improve. Where we really see ourselves stepping on the gas, and what really has us excited, is moving full steam ahead into obesity. We believe that this is the largest market. It's where the real need is. There's also a need in ob-- in diabetes, but in terms of pushing the programs forward, we're full steam ahead in obesity. That's why we'll be starting our phase II-B study in Q4, with data readout in Q4 2025 for that phase II-B study. So feeling very, excited about that development, and we'll do some additional work in diabetes.
Excellent. So just on that, could you just talk about the advantages of, you know, going straight to obesity and pursuing, you know, applications in obesity before diabetes?
Yeah, I think, you know, what we've seen in the field is diabetes was the initial focus for most studies, and this has started to change just in the past year or two. What I mean by that, you look at Viking, who released their data two weeks ago, very promising results, focusing on obesity. The real gap, and I should use the word gap, not need, is the real gap is the obesity population. We need to move faster to get these medicines to those patients, those individuals that need them. We asked ourselves the question: how can we go faster? How can we get this to market faster? One of the obvious approaches is we should push obesity forward at a more accelerated rate.
So that's why we will be in our phase II-B by the end of this year. It's not that we are not working on diabetes. We believe that diabetes, chronic kidney disease, MASH, all these adjacencies, they all are, you know, seen as, you know, having connections to obesity. And so pushing obesity forward first and then following up very quickly with these other opportunities is a very strategic and smart way to get to market as quickly as possible. That includes our manufacturing, and then also following up with these other diseases, where there's a big need.
And obviously, the FDA requires cardiovascular outcomes trials to be initiated before approval of a diabetes drug, but that's likely not the case for obesity.
Dave, that's a great point, and thank you for bringing that up. By prioritizing obesity right now and then quickly following with the other diseases, that allows us to get this to market without requiring the cardiovascular outcome studies. So again, it's about efficiency and getting to market as fast as possible.
Excellent. And then I think it'd be helpful for you to just frame the numbers for people so that when they see the phase II-A obesity results, they have a sense for, you know, how the numbers are going to flow in terms of patients and how you're going to conduct the analysis, et cetera.
Yeah, absolutely. So I'm going to break this down in the categories of... We designed the trial to try to make sure that patients stay on study as long as possible. So we allow patients to stay on. If they discontinue or they down titrate, we can continue to keep them on study because we want to continue collecting the safety data, the laboratory data, and everything, as well as understanding the effects of tolerability. So one of our goals is to have discontinuations be as low as possible in our study. In our data that we released in December, we were very pleased. In our obesity study, our discontinuation rate was 0. In our diabetes study, it was 2.8%. This is a remarkably low number in terms of discontinuations.
Now, did we, you know, because we allowed for down titration, did we leave some efficacy on the table? Yes, most likely. As we down titrate, there's less drug, there's less effect on the body. But we think this, we think it's really important to keep patients on the study as long as possible, so we can collect all that data. So discontinuation rates, we're hoping to be very low. It was low in December. We're hoping that it'll continue to be low. The second number, obviously, efficacy. Everybody's, you know, this is a weight loss, chronic weight management medicine, after all. And so we've powered this, as I've noted, we've powered this 5% minimum, hoping to do better than 5%.
We believe the range is 5%-7%, but we've powered it to be 5% minimum, so the expectation in Q2 will be there.
Excellent. Why don't we talk a little bit about the oral peptides, which has garnered a lot of, a lot of attention. Obviously, Novo conveyed its early data on its oral amycretin, but isn't yet moving it into the next stage of development as it awaits subcutaneous results later. Could you just talk about and compare and contrast the oral peptides to the oral small molecule approach?
Yeah, absolutely, Dave. So last week, Novo announced their amycretin data. That was their oral GLP-1 with amylin combination, a single molecule. We were excited about this data because it showed amylin in human data, not just sort of preclinical studies, but in human data, the combination of a GLP-1 with amylin is really powerful. So that data for us was great. The piece that wasn't sort of really focused on manufacturing an oral peptide, the scale, the amount of material that one will need is tremendous. The current needs aren't being met today with the injectables that use, you know, low, you know, milligrams sort of amounts. Going up to hundreds of milligrams per week is gonna be a big, big challenge in the future.
And so, you know, the study, the amycretin study that was announced last week, exciting because it really validated amylin as a combination with GLP-1. We have an oral amylin molecule that we showed, so very excited about that. For us, it was validating, very validating, and we're excited 'cause we have an oral small molecule. And as I highlighted in the opening slides, the manufacturing, being able to scale these oral small molecules up, again, we think about manufacturing, safety, tolerability, and efficacy altogether. We're very excited about being able to scale this to really meet the needs of 100 million patients that need these medicines.
Excellent. And could you just add a little more quantification on the, you know, injectable approach, either with just, you know, a straight GLP-1 or with, you know, amycretin as they conveyed it, versus a small molecule? Or sorry, injectable GLP-1 versus oral peptide GLP-1, or injectable amycretin versus oral amycretin, just to contextualize the volume that is such a challenge for the peptide manufacturers.
Yeah. So I think, you know, I look at it sort of this way. The current injectables, I'm just gonna use a rough number, 5 milligrams-10 milligrams or 2 milligrams-10 milligrams are used per week. When you scale these up for an oral peptide, again, you're talking about a few hundred, 300, 400 milligrams of material per week. That's a big scaling challenge. So I think that's where it's gonna be, it's gonna be challenging, you know, to scale up these peptides. Now, a question that you didn't ask, but I think is important: What's the real goal here? The goal is to get these medicines to patients and to give them options. I think the injectables are gonna be preferred by a certain subset of patients. We... You know, there's many of these marketing analyses are being done.
What percentage of patients will want oral small molecules? What percentage will like the convenience of a once-a-week injectable? And this is an important question. Nobody knows what that number is gonna be. You know, it's still being sort of, you know, I think, analyzed and debated. Until the orals get on the market, we're really not gonna know the real answer to that question. But what's important is that we give patients options. Some patients will prefer an oral pill. Whether it's an oral peptide and you can scale at that level, that's gonna be the big challenge. We know that we can scale an oral small molecule.
Excellent. And could you speak to liver tox concerns? So you know, there have been, you know, concerns that were obviously accentuated by Pfizer's cancellation of its lotiglipron program, you know, a few liver excursions for orforglipron in its phase II data.
Yeah.
It'd be great to get your take on, on that topic, and then specifically the differentiation of 1290 versus orforglipron.
Yeah, absolutely, Dave. So, sure, and again, I mentioned this earlier, the thing that you always worry about with a small molecule is tox. You know, this is the real challenge that you wanna make sure that, you know, you have a safe molecule. And so we've taken a lot of time ourselves, so I can really, you know, primarily speak to our own data. We feel very comfortable in regards to liver tox. We did have one case in our diabetes. So by the way, I don't think anybody's seen in healthy overweight individuals any liver tox issues. Individuals living with diabetes, they are more medically complex. That's the reality. They've had diabetes in our trial for an average of 10 years. They're on, you know, an average of 1.5 grams of metformin.
Many of them are on different other medicines, such as statins. And so all these things make it, you know, individuals living with diabetes more challenging. One of the reasons we're moving full steam ahead in obesity is it allows us to go the fastest possible because it's less medically complex population, so we can really accelerate and get to market quickly. So that's the way we see it. In terms of your question of similarities, we are absolutely nothing like. You mentioned lotiglipron. You know, we're nothing like that scaffold at all. We have elements. We use structure-based drug discovery for the discovery of our molecule. It's GLP-1 receptor. It's a peptide receptor.
Peptides are big molecules, and so, the molecules, you know, we took elements of different designs that we've seen in the past and used them, but we used structure-based design, elements of orforglipron, elements of other molecules to combine into creating GSBR-1290.
Excellent. And just from the ability to dose up versus orforglipron, could you comment on that?
So we follow the protocol of Eli Lilly in terms of allowing down titration and then also allowing people to then up titrate as well. And the reason why we believe this is the right approach, and this is still oral GLP-1s, just like the injectable peptides in 2005. It's early days. We're learning how to use these medicines, and we're balancing tolerability as well as efficacy. So we think in tolerability, it's about the patient experience. What really happens in the doctor's office? If you feel nauseous and you tell your doctor you're feeling nauseous from this, the physician's gonna say, "Cut the dose in half," or, "Skip a dose today and then go back on it." They'll work with you to try to make that experience. The whole goal is to tolerate the medicine.
You're asking the body to change as you're going along. You know, trying to think of the mechanism in terms of we're reducing the gastric emptying.
Yeah.
We're having other effects on the body. So how do you help the body go through that transition? That's really, really important, and so being able to sort of tolerate this. So allowing one to sort of go down in titration or down in dose and then go back up, we believe that's the real-world scenario. That's what really happens in the physician's office. That's what should happen in the clinical trial as well, to try to achieve the maximum tolerability, the maximum efficacy. And then one of the things that we also see, traditionally, you know, we did a 12-week study, where we'll be reporting out a 12-week study. The reason it's 12 weeks is because we had, at the time, three months of tox data.
When we switched to phase II-B, we now have 6 and 9 months of tox data, and so with that 6-9 months of tox data, we have our phase II-B study that's in the corporate deck that we just released, we're gonna be able to go to 36 weeks for that study. In that 36 weeks, we're able to titrate instead of weekly, going up in titration, we're able to go to biweekly titration. And then we think in phase III, what's likely to happen in phase III is, and what we've seen in the whole class of GLP-1s, you know, now since 2005, the history of this, one typically settles on monthly titrations. They go with a dose, you're able to sort of titrate up in a month, and you keep going that way.
That allows the body the best time to sort of adapt to these medicines, to ultimately get to what we refer to as the maintenance dose. In our particular case, in our 12-week study, that's 120 milligrams.
Excellent. Could you just, you obviously highlighted the other assets of the company, which, you know, don't appear to be reflected in the stock price. But, you know, the rubber is gonna be meeting the road on them over the next few years. Could you just go through them in terms of the order of when each will enter the clinic?
Yeah, absolutely. So, you know, obviously-
I'm thinking about the obesity assets first, and then we'll do LPA-1 after.
Yeah. Yeah. So, obesity assets and metabolism assets first, obviously, 1290, we'll have in Q2. We're gonna have both the readout of the phase II-A obesity study, as well as the bridging capsule tablet transition. That'll read out in Q2. We will enter the, or we will initiate our phase II-B. That'll be initiated in Q4, and that will read out Q4 2025. The amylin molecule will declare a DC by the end of this year, and the amylin molecule in combination either as a monotherapy or in combination with the GLP-1, that'll enter the clinic in 2025. Then, on its heels is the GIP program. And then we're also right now looking at and evaluating the opportunity of combining apelin receptor agonist together with GLP-1 for selective weight loss. So that's the metabolism, obesity sort of market.
So that's the layout. So we have a lot of catalysts between right now, catalyst in Q2, and there'll be continued catalyst all the way through Q4 of 2025. So quite a few catalysts over the next year, year and a half. In terms of the non-obesity, when we started the company, we were focused on... We're 75% focused on metabolism, but with this powerful platform in converting biologics into small molecules, we focused on: Where was the big global unmet needs? Metabolism, clearly, is a priority. We get 75% of our bandwidth goes to that area. The other is pulmonary, IPF, and that's where both LPA-1 and apelin have both been seen in IPF. So we'll be entering the clinic in Q2 with our LPA-1 receptor antagonist.
This, by the way, you're probably familiar, BMS announced data last year at ATS, a little over a year ago, a little less than a year ago, positive data with their LPA-1 receptor antagonist. We're very excited about ours. We believe that it has potential to be best in class. We really optimize potency and, and minimizing some of the, some of the off-target effects. Amgen just recently announced as well, that they're moving forward with their Horizon acquisition of their LPA-1 receptor antagonist. So, we're excited about LPA-1 entering a phase I study. This will be a safety study, traditional SAD/MAD study, and that will finish in 2025.
Excellent. And can you just talk... Well, actually, why don't we move to the final question? I was gonna ask about the differentiation. Clearly, you've designed it to be much more selective and potent. And I think Bristol has had to be a little more careful with its dosing. Anyway, I guess my final question is, could you talk about you know, the potential for strategic discussions and how you're thinking about that and the potential timing?
Yeah, absolutely. So we've been very clear since we started this company, and as we've seen this market grow, we're not naive. We know that we're gonna need a partner for commercialization. That's just a fact. That's the reality of the world. And so if we back calculate from that, we know that any partner is gonna want to be very involved, if not managing the phase III study that goes into commercialization. Again, that's the reality. You continue to back calculate from there, that means any strategic partnership discussions are gonna need to start as we transition phase II-A phase II-B. When is that time? Well, that time is now, 2024. We had not had any discussions in 2023 or earlier. We felt like we really wanted our programs to mature.
In 2024, we're gonna start having those discussions, trying to find the right partner that can really help us see GSBR-1290 make it to market in the fastest way possible. On that, you know, in regards to that, we also feel we do not need to rush it. We have close to $500 million in the bank, at the end of 2023. We announced our financials just last week, and so we feel very comfortable in terms of our financial position, so we don't have to rush. We feel very comfortable. We'll have the data in Q2 the phase II-A and initiating phase II-B, so we're very comfortable and confident there. But we think the timing to start having those strategic partnership discussions is in 2024, and we're looking forward to those discussions.
What are the possibilities, meaning what are the potential tracks?
Could you rephrase or clarify?
Well, I mean, would you just monetize the asset? You know, would you partner it and expect a royalty? You know, what are sort of some of the options?
Yeah, absolutely. So, you know, for us, we're looking at maximizing the value for shareholders, as well as getting this medicine to patients as fast as possible. So we're looking at it that way. We have a tremendous board, you know, Dan Welch, Ted Love, Eric Dobmeier, all former CEOs that, you know, worked with and had partnerships, M&A. So we're considering all the different options in terms of, you know, how we'll proceed forward. We don't have sort of one specific, you know, idea in mind right now. We're looking for the right partnership to help us get this, get GSBR-1290 to market as fast as possible.
Excellent. With that, we're out of time. Thank you so much, Ray, for joining. Appreciate you being here.
Thank you, Dave.