All right, everyone, I think we'll get started with our next event. Welcome to the 2025 Cantor Healthcare Conference. I am Michael Bell with the Cantor Biotech Equity Research Team, and I'm very excited to introduce Septerna, which will be sharing a presentation today to overview the company and to share updates around its next-gen PTH1R agonist, which it just PR'd this morning. So please join me in welcoming Jeff Finer, CEO and co-founder of Septerna. All right, thanks, Michael. Can you guys hear me? Okay. And thanks to Cantor for the opportunity to give everybody an update today. My presentation will include forward-looking statements, so please take that into consideration. So for those of you learning about Septerna for the first time, I'll introduce you to our Native Complex platform, which is a new way of doing drug discovery for G protein coupled receptors, or GPCRs. I'm going to spend the majority of time today focused on our portfolio. Our portfolio strategy from the outset has been to focus on well-validated targets, one with biological and, in many cases, clinical validation. Early clinical readouts are important for us, as well as significant market opportunities. We're sitting in a well-capitalized position. We did an IPO last fall. A few months back, we announced a new deal with Novo Nordisk, and we're sitting with operating capital that should put us into at least 2029. Today, I'll focus most of the time on our two lead programs. As Michael alluded to, we announced this morning the selection of our next-generation parathyroid hormone receptor small molecule agonist called SEP-479. We'll introduce that to you today. Our second program focuses on a target called MRGPRX2, which is a mast cell target. We've got a compound called SEP-631 that recently started in phase one. And I'll very briefly mention a discovery stage program called the TSH receptor, thyroid-stimulating hormone receptor, focused on Graves' disease and thyroid eye disease. and last but not least, as I mentioned, we formed a deal with Novo a couple of months back that's focused on a series of incretin receptor agonists, as well as a couple of additional targets. so just to set the context for everybody, GPCRs have been by far the most fruitful target class in small molecule drug discovery history, leading to hundreds of approved drugs. There are hundreds of GPCRs, each represented by a branch on this tree. and everywhere where you see a dot on this tree is where there's an approved drug. The bigger the dots, the more approved drugs there are. so you can see that there's a big concentration of the large dots on the upper branch. In fact, more than 70% of all GPCR drugs target just six small subfamilies of GPCRs. But we think there's a huge amount of untapped opportunity space, and we think we can unlock a lot of that opportunity space with our Native Complex platform. So regarding the platform, when we first started the company a few years back, GPCR drug discovery was limited for a whole variety of different targets. And we thought that one significant limitation in the use of modern drug discovery tools was the inability to isolate fully functional GPCRs. And that's where the Native Complex platform comes in. So what is a Native Complex? A Native Complex includes the receptor, shown here in blue, a transducer such as a G protein shown in green, and a ligand, all in a lipid bilayer. And in that setting, the receptor has all of its natural binding partners. And in that setting, it also retains its natural structure function dynamics. With those native complexes, we can do a few things, one of which is structural biology. We've taken a very hard, traditionally hard drug discovery class GPCRs and actually made them quite tractable from a structure-based design standpoint. We've also found new ways to find chemical matter using a variety of different approaches, including computational docking into pockets on our proteins, as well as complementary biophysical approaches that use DNA encoded libraries, from which we've been able to find compounds with pretty much any mechanism of action that we want so far. These two things come together: the ability to find new compounds, as well as the ability to do high-resolution structures in a very rapid and efficient structure-based design process. have, for each of the programs that we'll talk about today, been able to move from starting medicinal chemistry to very potent compounds in animals in less than a year. Just to expand just very briefly on the structural biology side, we use a technology called cryo-electron microscopy, and we found ways to not only get GPCR structures, but to get them at extraordinary speed. So if we've got a new small molecule for one of our targets, we can get a structure as quickly as within a week or two. This allows our chemists to do true structure-based design for the very first time. Each of our programs will typically have between 10 and 20 plus structures. Those are shown on the right, where each column represents a different GPCR. Each bar within each column is a new high-resolution structure with a different ligand. You can see by the color coding and the mechanisms there that this is a generalizable approach that applies to all GPCR mechanisms. Now pivoting to our portfolio, as I said, I'll spend most of the time on our two most advanced programs, the SEP-479 program for hyperparathyroidism and SEP-631 for mast cell-driven diseases. But I want to draw your attention to the therapeutic areas. Our platform is one that's applicable to a whole variety of therapeutic areas. We've initially focused on endocrinology, immunology, inflammation, and metabolic diseases, but you can see from the fourth line there that we have a lot of different research areas. We've got early-stage efforts in neurology, as well as other areas listed there. The other thing I want to draw your attention to are the modes of action in the first column. Between the PTH receptor program, as well as our incretin receptor program, we've been very successful at finding small molecule agonists for receptors whose normal ligands are peptides. This has been a historic drug discovery challenge and one that our platform has been very effective at. Another historic challenge for GPCRs has been finding allosteric modulators. We've got a couple of allosteric modulator programs listed here. What is an allosteric modulator? An allosteric modulator is a compound that binds outside of the normal ligand binding pocket, and it acts as a tuner. A negative allosteric modulator, as shown here, dials down the activity of the endogenous ligand, and a positive allosteric modulator, which we've been able to find as well, increases the activity of the endogenous ligand. We think this is, again, a generalizable approach to GPCR drug discovery. Down in the lower half of the figure, partnering has become an important part of our strategy as well. We've got an undisclosed program with Vertex and then the recent Novo deal. Okay, so jumping into the PTH program, where I've got some significant updates to share for the very first time today. To level set, in terms of hyperparathyroidism, you really have to understand some of the basic physiology. So the parathyroid glands are located within the thyroid gland in the neck. They release a hormone called the parathyroid hormone, or PTH. PTH has its effects downstream on the bone, where it increases calcium release from bone, on the kidney, where it increases calcium resorption. And the effect on the kidney also leads to an increase in vitamin D, which has an effect on the GI tract to increase calcium absorption. So all roads lead to increases of calcium. So in this way, PTH is a master regulator of blood calcium levels. Hypoparathyroid patients are missing, in most cases because of some surgery, their parathyroid glands. This leads to a loss of PTH, hypocalcemia, and a whole variety of side effects, including muscle cramps, tingling, brain fog, and other debilitating conditions. It can also lead to life-threatening complications. Because of the role of calcium in the heart, it can lead to cardiac arrhythmias. In the case of calcium in the brain, it can lead to seizures. So it's quite a serious condition. Traditional standard of care for many, many years has been high-dose calcium supplements and high-dose vitamin D supplements. Those are not only burdensome, but they actually have consequences themselves. Given the physiology I just described, if you take high-dose calcium supplements and you've got the effects on the kidney shown here, you end up cranking out extra amounts of calcium into the urinary pathway, and that can lead to kidney calcifications and eventually renal failure as well. Many of you, I'm sure, are aware of the injectable peptide therapies that have been approved and in development, most notably Yorvipath from Ascendis that was approved and is now, whatever, a good fraction of the first year into their launch. These are all injectable therapies, and they will unfortunately require lifelong injections, in many cases, possibly daily injections. So our strategy has been to functionally replace PTH instead of with an injectable peptide with an oral small molecule. So our Native Complex platform has been very fruitful. So the PTH receptors have been a historically challenging target. A number of pharmaceutical companies have tried to hit this target, find activators for many years, and completely struck out. The receptor, which is shown here in magenta, if you look at it in green, is the PTH peptide. It's got a long extended binding site. It's been very hard to mimic that with a small molecule. But with our Native Complex platform, we've been quite successful. We found not only one way to activate the receptor, but multiple ways to activate the receptor. Through our rapid iterative structure-based design process, we've taken at least two of those series to the point of being very potent selective oral small molecules with activity in animal models, PK profiles that would support full-day calcium control and good safety in preclinical studies. SEP-786, for those of you guys who aren't familiar with our story, was our first PTH receptor oral small molecule in the clinic. It, unfortunately, ran into unexpected events in phase 1 that were increases in unconjugated bilirubin. I'll have more to say about that on the next slide and our investigation into that. But we had to discontinue that. In the meantime, we're bringing along a second-generation compound. And again, we're announcing this for the first time today. SEP-479 is our new development candidate. It is structurally completely unrelated to SEP-786. It does not show the same off-target effect that I'll describe to you in a moment. And in addition, it has some bonus features. It looks like it's active in animal models at significantly lower doses than 786 was and projects to have a longer human half-life as well. So first on 786, I wanted to share that story because we've had some learnings from it. SEP-786, as I said, was discontinued in phase one because of a couple of severe cases of increases in unconjugated bilirubin. When people think about bilirubin, they often think about liver injury. Just to be clear here, this compound did not cause liver injury in either of these healthy subjects. It was reversible. And it also didn't lead to cholestasis or hemolysis. These are other mechanisms for increases in bilirubin. On the more positive side, 786 was a good proof of principle for us that a small molecule can do what a peptide does in healthy volunteers. We saw decreases in PTH. A healthy volunteer has an intact parathyroid system and an ability to react in real time. So we saw decreases in endogenous PTH, increases in serum calcium as well. The observed half-life for 786 was about 18 hours, which should have supported once or twice daily dosing. With regard to our investigation of the off-target effect, it's important to know a little bit about bilirubin metabolism. Bilirubin gets taken up into hepatocytes with a couple of transporters called OATP1B1 and OATP1B3. It gets taken into hepatocytes and then gets conjugated to conjugated bilirubin using an enzyme called UGT1A1, and then gets excreted into the bile with another transporter. Through our investigations, we actually have a very clean smoking gun here. 786, we found, is a very potent UGT1A1 inhibitor, which is a clearly known mechanism for increases in unconjugated bilirubin. Unfortunately, we didn't catch this earlier. We didn't catch it earlier because UGT1A1 is not routinely checked preclinically unless your compound is believed to be a substrate of that enzyme. We also had another finding in our subsequent analysis after the clinical trial was stopped, is that we saw in a monkey study, and I'll have more to say about that in a few minutes, we saw that SEP-786 does increase bilirubin in monkeys, so there was a distinct difference between monkeys and humans and rats and dogs, unfortunately, so moving on to our new compound, SEP-479. This is a potent selective molecule. The way we evaluate this initially is a rat surgical model of hypoparathyroidism, where we surgically remove the parathyroid glands. These animals develop hypocalcemia, hypoparathyroidism. And the idea is if we dose our compound, could we reverse that? What we're looking at here is serum calcium levels and serum phosphate levels. The normal levels are represented by the gray bands that you see there. These are 28-day studies where we're looking at detailed time courses on four days. You can see that we're able to, with the dosing of this compound, get into the normal range on both calcium and phosphate. I want to bring your attention to the line at the bottom, which is the dose. SEP-479 showed this effectiveness at a dose of 0.15 milligrams per kilogram once a day, whereas to get very comparable data with SEP-786 was three milligrams per kilogram twice a day. It's about 40-fold lower dose. Significant improvement in that regard. It's also got a pharmacokinetic and pharmacodynamic profile that we're excited about. The PK side, I'm showing some of the data here, again, comparing to SEP-786. 786 was actually pretty good. It had oral bioavailability in about the 50% range. PK across species was in the four- to eight-hour range. This led to a predicted human half-life in the 9-27-hour range. Now that we can share what we learned in phase 1, we saw that it had a half-life in about 18 hours of about 18 hours. Our predictions were about right. Now, using that same predictive model, if you look at SEP-479, it's got significantly higher oral bioavailability, longer half-life across species, and projects to a human half-life in somewhere in the 40-80-hour range. We'll have to see what it's like once we're in the actual clinic. With regard to pharmacodynamics, we did something with this molecule that we hadn't previously done with SEP-786, was a detailed study, PKPD study in healthy cynomolgus monkeys. We did that to initially help us predict what things might look like in healthy volunteers. As I mentioned earlier, healthy volunteers have an intact PTH axis. What you would expect to see and what we indeed saw in these cynos was that this is a once-a-day dosing for seven days. We saw an immediate decrease in the PTH levels, as you can see over on the figure on the bottom right, all the way down about 80% just after the first oral dose of our compound, which is great. We also saw increases in serum calcium, as you can see in the figure on the left. What's a relevant calcium level that we would hope to see? Fortunately, we've got the PTH peptide data results that have been published ahead of ours. A relevant amount of calcium to increase is on the scale of about one milligram per deciliter. That dose level should be about the right range. If we see that in a healthy volunteer, it should be about the right range for seeing efficacy in hyperparathyroidism patients, and that's exactly what we're seeing with this molecule, so we're excited about this data, but what's left with 479? Just to kind of reflect on the mechanism for 786, we see no UGT1A1 inhibition, which is great. We saw no hyperbilirubinemia in any of our preclinical studies, including that seven-day monkey study I just showed you. We've already completed 28-day GLP-tox studies in rats and dogs, and 479 was well tolerated, and we decided to go the extra mile and do an add-on, a third GLP-tox study in cynos just to be certain that we don't have any effects there, so that study is kicking off. Assuming that study is successful and manufacturing and other regulatory work goes well, we're hoping to be back in the clinic with our PTH program and this molecule in the first half of next year. Jumping to our second program, we're targeting going after a target called MRGPRX2, which is an emerging target for mast cell diseases. In terms of the mast cell pathways, the traditional mast cell activation pathway that everybody thinks of is the allergen pathway, where IgE and an allergen combined bind to a high-affinity IgE receptor. That leads to degranulation, release of a whole variety of inflammatory mediators, including histamine, tryptase, and others. MRGPRX2 is a relatively newly appreciated target that has a different pathway. It is activated by a whole variety of different endogenous peptides and protein activators listed up there in the upper right corner and leads to actually a release of a different subset of granules from mast cells. There is evidence that non-IgE-mediated pathways are involved because in many of these mast cell-driven diseases, there are refractory patients that aren't responding to the traditional anti-IgE drug, so one of the diseases that we're interested in is chronic spontaneous urticaria, but there are several other indications as well. Our strategy has been to develop what we're calling a negative allosteric modulator, and ideally one with an insurmountable profile, and we've got exactly that. This highlights a couple of the key features of our compound. SEP-631 potently inhibits activation of the receptor by all endogenous agonists that we've thrown at it. It also has this insurmountable profile. So what does that mean? When the compound binds to the receptor, it effectively turns the receptor off in a way that it can't be outcompeted by excess amounts of endogenous agonists. It also has a very slow off-rate. When our compound is on the receptor, it's on there for hours. Preclinically, unfortunately, MRGPRX2 is not well conserved across species, so we had to make a knock-in mouse, remove the mouse's gene, replace it with a human gene. And we've developed a model system that we think is actually quite relevant to urticaria. That involves dosing the mouse with our drug, also administering a blue dye. The blue dye has the effect of tinting the blood blue. And then we do an intradermal skin challenge with an MRGPRX2 agonist, in this case, Compound 48/80. At the site of that intradermal injection, we get extravasation of the blue dye into the skin, so the animal basically gets a little blue hive, and ideally, with our compound, we would completely inhibit this, and that's exactly what you see in the graph here. The Y-axis is fold over vehicle, and we're seeing basically complete inhibition of the extravasation with our compound. The best human translational model that we can get our hands on is primary human mast cells, and you can see from this that we're able to completely inhibit the activity of substance P-induced tryptase release with our compound as well, so summarizing some of the key features that I've already mentioned, we've got a very potent compound, broad inhibition, good oral bioavailability and PK properties, great effects in both the in vitro and in vivo pharmacodynamic models. We've completed 28-day GLP-tox studies in rats and dogs, and it was well tolerated. All of this data is supported moving forward in the clinic. I want to introduce you today, again, for the first time, our phase 1 trial design. We're doing a randomized placebo-controlled single ascending dose and multi-ascending dose design. We're using oral tablets of SEP-631 in the MAD portion of the trial. This will be daily dosing. We could have up to 150 healthy volunteers in this study. On the pharmacodynamic side, we decided to do a skin challenge in these healthy volunteers as well. In this case, we're using a drug called Icatibant. Icatibant is an approved drug that's normally dosed subcutaneously. Everybody who gets that drug has basically a wheal and flare response. And we've been able to, and what we're hoping to be able to show in our phase one trial is that we can inhibit that wheal response with SEP-631. So Icatibant is known as a known agonist for MRGPRX2. And so we're viewing this as basically a pharmacodynamic readout in the phase one. If all goes well, we're hoping to be able to share our SAD and MAD data also in the first half of next year. Quickly, just introduce you very briefly to our third program, thyroid-stimulating hormone receptor, targeting both Graves' disease and thyroid eye disease. Both of these diseases share a common pathophysiology where there's autoantibodies that bind to the TSH receptor in either the thyroid gland to increase thyroid hormone release or the orbital fibroblast behind the eyes to increase orbital fat, which leads to the characteristic eye bulging and proptosis that are seen in thyroid eye disease in these patients. Each of these diseases is treated separately. Graves' disease treatments don't prevent thyroid eye disease, and thyroid eye disease treatments don't inhibit Graves' disease. Our goal is to develop a universal therapy to treat both these conditions with a single small molecule. One of the challenges is that each patient has their own autoantibodies. In many cases, they're high affinity and even polyclonal. So one of the first experiments we wanted to do was to show that we can inhibit a range of different autoantibodies. This was a study we did with an academic collaborator where we found that we were able to fully inhibit the activity of a whole variety of different patient samples. So for lack of time, I won't go into the details here. We've also developed an animal model that we think is a novel model for Graves' disease. What we do here is we take a patient-derived antibody. We found one that cross-reacts with the mouse's receptor. We treat the mouse for about six weeks. The mice all develop characteristic Graves' phenotype, increases in thyroid hormone levels. The thyroid gets enlarged, and the eyes begin to bulge as well. And the idea is, in the setting of continuing with that autoantibody, can we reverse these symptoms? And this is exactly what we see. We were able to see good reversal of increases in thyroid hormone levels, shrinkage in the thyroid, as well as a reversal of the eye bulging that we've seen. The eye bulging that you can see in the middle of two photos is significantly reduced in the larger samples. We're not a development candidate quite yet with this program, but we're making good progress. The last thing I wanted to just touch on was our Novo Nordisk collaboration. Prior to the collaboration, we had done some work with a series of different incretin receptors and shown that we'd identified a novel binding pocket that could be activated by even single small molecules across all three incretin receptors. This collaboration involves a total of five targets, those plus two undisclosed targets. We're doing a total of four programs at a time. Importantly, we received $195 million upfront back in July. We've got a good milestone in the royalty package outlined there, as well as an opt-in right for a profit share, but most importantly for us in the near term is that Novo is supporting all of the R&D costs going forward. So that's also helped to kind of reduce our burn rate associated with this program. So we're excited about this, and hopefully, between us and Novo, we'll have more to share in the future. Finally, just in the last minute or so, I just want to talk about the company. We've got a very experienced management team in the room today. We've got our President, Chief Operating Officer, Liz Bhatt, as well as our Chief Financial Officer, Gill Labrucherie. We've got an experienced board of directors, as well as world-class academic co-founders and a drug discovery advisory board that's made up of a number of individuals from the pharma industry. Just to wrap up and leave a couple of minutes for questions, just to again reemphasize, our platform has been a fruitful one. It's led to a portfolio of programs that we're excited about, each with significant market opportunities. And we're sitting in a well-capitalized position with good operating capital, at least into 2029. So saved about two minutes for questions. Yeah. What we're looking for is no surprises. So we know from our seven-day study that it was well tolerated. We know it was well tolerated in the other species. We're just hoping for no new off-target surprises that we weren't aware of otherwise. No, unfortunately. So, discovery stage programs and all future communication is going to be Novo is going to have to participate in that communication. No. In fact, we've tested it with 631. Yeah. Yeah. Question in the back? Not that we know of. We don't have the details about that. All they released was that it was a preclinical finding, and they released that preclinical finding in the setting of a phase two trial that was ongoing. So it was presumably some sort of chronic tox study, but we don't know. And they haven't published any results related to that. Okay. Well, anyway, if there's no other questions, again, I want to thank the Cantor team for inviting.