Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tess Romero, and I'm one of the Senior Biotech Analysts here at JPMorgan. Our next presenting company is Septerna, and presenting on behalf of the company, we have co-founder and CEO Jeff Finer. Jeff, over to you. Okay, thanks, Tess. I'm excited to share an update on Septerna with everybody here today, and as a quick note, my remarks will include forward-looking statements, so Septerna, for those of you learning about Septerna for the first time, we're a company entirely focused on a class of cell receptors called G protein-coupled receptors, or GPCRs, and we've developed a new way to do drug discovery for GPCRs that we call the Native Complex Platform. I'll introduce that to you briefly. That platform has quickly yielded a very rich portfolio of programs that we'll go over. Our portfolio strategy from the outset has been to go after targets with significant degrees of validation: biological validation and ideally some clinical validation. Each one of our programs that we'll talk about today has an early clinical readout, meaning that in phase I, we'll know whether or not our compound is doing what we hope it will do. Each also represents a significant unmet need as well as a significant market opportunity, and we're well capitalized. We completed our IPO in October of 2024, as well as a deal with Novo last summer that has put us in a strong cash runway position with operating support all the way into at least 2029. So we'll spend most of today talking about our two lead programs. The first is called SEP-479. It's a parathyroid hormone receptor agonist going after a disease called hypoparathyroidism. This one is wrapping up IND-enabling studies and should be entering phase I trials in the first half of this year. The second program I'll introduce you to is SEP-631. It's going after a target called MRGPRX2, which is an emerging target in mast cell diseases, and our profile here is a negative allosteric modulator, or NAM. You'll hear me say that a few times. This is in a phase I trial that's in the home stretch right now. The trial's wrapping up soon, and we announced yesterday that we'll be in position, we anticipate being able to share the data on this trial at the AAAAI meeting coming up in March, so we're excited about that. Two earlier stage programs I'll mention very briefly. One is a thyroid-stimulating hormone receptor, also a negative allosteric modulator. This is going after both Graves' disease and thyroid eye disease, and we believe we've got a mechanism that could be disease-modifying for both of those conditions. This is a program that's in lead optimization, but we're starting to have line of sight to a development candidate, and finally, the last program I just mentioned very briefly is we've got an incretin receptor agonist program. This is one that formed the basis of our Novo collaboration that I just mentioned. Here we identified a very novel binding pocket within the incretin receptors that allow us to activate not just a single receptor, but multiple receptors at the same time. Okay, just kind of to frame the whole GPCR landscape, GPCRs have been by far the most productive target class in drug discovery history, leading to about a third of all FDA-approved drugs, literally hundreds of approved products, and these span literally hundreds of different GPCRs. The tree diagram that we're looking at here represents about 400 non-olfactory GPCRs, and everywhere where you see a dot is where there is a GPCR with at least one approved drug. The bigger the dots, the more approved drugs there are. And you can see that the top branch of the tree has a large number of these dots and large ones. And we think there's a tremendous amount of untapped opportunity space. The success today has been highly concentrated, so much so that about 70% of all GPCRs target just six small subfamilies. The focus of the company has been to try to unlock those difficult-to-drug GPCRs with our Native Complex Platform. The Native Complex Platform I'll introduce you to very briefly. When we first started the company about five or six years ago, one thing was very clear: modern drug discovery technologies were barely being used for the GPCR target class. And we asked ourselves why that was, and there was really a fundamental question. In order to use many of those modern drug discovery technologies, you need to be able to isolate the GPCRs outside of cells in a fully functional form. And that's really where our Native Complex Platform comes in. So what is a Native Complex? A Native Complex is a reconstituted system that consists of a GPCR, represented here in blue, a transducer such as a G protein there in green, and a ligand, all reconstituted in an artificial lipid bilayer that mimics a cell membrane. So in this setting, the receptor is surrounded by all of its natural binding partners and retains all of its natural structure, function, and dynamics. Once we have these Native Complexes, we can actually do multiple things with them. One of the important ones is finding structures and solving high-resolution 3D structures. The GPCR target class has traditionally been one of the more challenging ones. We found a way to solve structures actually very routinely now with GPCRs. We've solved over 150 structures so far in the company, each with different ligands. And what we've learned from those is we're identifying novel binding pockets and novel ways to modulate GPCRs in the way that we want. We've also got approaches of using these Native Complexes to screen literally billions of compounds. We've got complementary approaches. One includes a computational approach where we dock literally billions of virtual compounds into pockets on these structures. The second uses DNA-encoded libraries to biophysically screen for binders to these Native Complexes. And through the combination of these methods, plus some traditional high-throughput screening approaches, we found with each of our targets to date a compound with exactly the mode of action that we wanted. These two components of the platform come together in a really very productive way: the ability to find new chemicals, the ability to get structures. They come together in a rapid and iterative structure-based design process where whenever our chemists want to answer a question about a compound, we can get a new structure within a week or two. This has led to very, very fast optimization, so much so that for each of the programs that we've started to date, from the time we started medicinal chemistry to the time we had active compounds in animals, has been less than a year. This is an overview of our portfolio where we'll spend the rest of the time today. I mentioned these at the outset, but a couple of things to highlight here. In terms of the therapeutic areas, this platform and our approach as a company is therapeutic area agnostic. With that said, we are focused initially on endocrinology, immunology, and inflammation, as well as metabolic diseases. But if you look at the fourth line there, there's a number of research areas. There are GPCRs involved in all aspects of physiology, and we have a number of earlier stage programs as well in other therapeutic areas. The other thing I wanted to highlight are the mechanisms of action, because they represent, this is in the first column, they represent very traditionally difficult drug discovery programs or challenges for GPCRs. One is finding small molecule agonists for peptide GPCRs. We've done that with the parathyroid hormone receptor program. I'll say more about that in a moment. And also with the incretin receptors. The MRGPRX2 program and the TSHR program are examples of negative allosteric modulators. So first off, what's an allosteric modulator? An allosteric modulator is a compound that binds outside of the binding pocket of where the natural ligand of the receptor binds. An allosteric modulator either dials up the activity or dials down the activity. Negative allosteric modulator dials it down, and we'll talk about a couple of examples there as we go. So hopping in first to the PTH receptor agonist program, we're going after a condition called hypoparathyroidism. And just to level set here, the parathyroid glands are located within the thyroid gland in the neck. They release a hormone called PTH. That PTH has its effects downstream on the bone and the kidney primarily. In the bone, it causes increases in calcium released from the bone. In the kidney, it causes increases in resorption of calcium. Also in the kidney, it leads to increases in vitamin D production, and that leads to increased absorption of calcium from the diet through the gut. So as you can see, all of these effects lead to increases in calcium. So in this way, PTH has become basically the master regulator of blood calcium levels in the body. Hypoparathyroidism patients have lost their parathyroid glands in most cases, usually through some sort of neck surgery, and as such, they've lost the ability to make this critical hormone, and they can no longer control their blood calcium levels, which go low, and they get hypocalcemia. Patients with hypocalcemia develop a number of challenging side effects: muscle cramps, tingling, brain fog in many cases. It can also lead to life-threatening complications because of the importance of calcium in the heart and in the brain. It can lead to cardiac arrhythmias and seizures as well. Standard of care for many, many years has been just take more calcium, take more calcium and vitamin D. But these individuals have to take huge amounts of calcium, often many times a day, often waking up in the middle of the night to take additional doses of calcium, and it doesn't always resolve all of their symptoms. And it's got an additional effect, which is if you take a lot of calcium and you don't have the parathyroid hormone, it causes increases in calcifications in the kidney because a lot of calcium is going through the kidneys. More recently, there have been injectable PTH therapies that have been approved. These look very, very promising. However, they're injectable, and a number of the patients that we've talked to are very young, and they would prefer to have an oral option. So our strategy has been to develop basically a functional way to replace PTH, but with an oral small molecule instead of an injected peptide. This receptor has been one that the pharmaceutical industry has gone after for many, many years. Many companies have tried and struck out and have been able to find tractable small molecule chemical matter. The receptor here is shown in magenta, the PTH receptor. The PTH peptide is a long helical peptide shown in green. It starts in the transmembrane domain, goes up on the extracellular domain of the receptor. In blue is the G protein. But what we've found with the help of our Native Complex Platform is not just one way to activate this receptor, but actually two independent ways. So we've taken this very historically challenging target and cracked it not just once, but twice. We've used our Native Complex Platform to optimize compounds from both of these binding pockets, as I mentioned to you before. This led to multiple candidate quality molecules, very potent selective oral small molecules that, as I'll show you in a moment, normalize serum calcium in animal models. Importantly, they have also demonstrated in all of our studies to date very comparable effects to PTH peptides, both cell-based assays and animal models. We're seeing exactly the same effects. We are functionally replacing PTH. Our lead molecule here is a compound called SEP-479. This is not our first PTH receptor molecule to go into the clinics, but it's the second. For those of you who were following our story for a while, we earlier last year had a first-generation compound called SEP-786 that unfortunately ran into an unexpected off-target effect in the phase I trial. We had to discontinue that trial back in February of last year. 479 represents a completely unrelated structural series, binding to the other binding pocket, and we have figured out what the mechanism was for that off-target activity for 786, and 479 does not have that activity. I'll show you that 479 also has very, very favorable pharmaceutical properties. I'll show you in a moment a monkey PK/PD study, which is showing very promising results, very similar to what we'd expect to see in a healthy volunteer patient study, and this compound also has very good pharmaceutical properties, as we'll go over in a moment, so a little bit on the animal data. We started with a rat surgical model of hypoparathyroidism where we surgically removed the parathyroid glands, much like in the patients I mentioned to you. When those parathyroid glands are removed, these animals have hypoparathyroidism. They get hypocalcemia. And the idea is, can we dose our compound and functionally improve these hypoparathyroid rats? What we're looking at here are both serum calcium levels and serum phosphate levels. The normal levels are represented by the gray bands, and the gray dots represent the hypoparathyroid animals. So you can see that serum calcium levels are low, represented by the gray dots, and serum phosphate levels are actually high. This is a 28-day study where we're looking at detailed time courses on four of the 28 days. And you can see that we're able to get into the normal calcium range and the normal phosphate range all day long. And we're able to do this with a pretty low dose of the compound, just 0.15 milligrams per kilogram once a day. This is a study we're particularly excited about. This is a monkey seven-day healthy pharmacodynamic study. The reason we did this study was to simulate what a healthy volunteer study would be. In order to help you guys think about this, one thing I wanted to point out is that a healthy volunteer and a healthy monkey is actually very different than a hypoparathyroidism patient. What's different about a healthy animal and a healthy human is that we all have intact parathyroid glands and the ability to actually secrete the parathyroid hormones. What happens when calcium starts to increase in a normal person or a normal monkey is immediately endogenous PTH levels are decreased, so much so that the feedback is so efficient that the very first thing we will see is decreases in endogenous PTH. That's shown here on this figure on the left. This is remarkable that after just a single dose, single oral dose, we're able to get endogenous PTH levels down about 80%+. Once PTH levels are bottomed out, then serum calcium levels can start to rise with increasing doses of the compound, and so that's shown on the right figure where we're having increasing doses of serum calcium or increasing levels of serum calcium. Now, a fundamental question here is, what level are we looking at, looking for? And fortunately, there's lessons to be learned from the PTH peptide therapies that have been in development ahead of us. If you look back at the approved peptide therapies or the ones that are in late-stage development, the doses in a hypoparathyroidism patient that are effective therapeutically, if you look back to what those doses look like for those same agents in their phase I healthy volunteer studies, we learned that the relevant amount of calcium in a healthy volunteer study is about 0.5-1 mg/dL calcium increase. And so that's what we'll be looking for when we eventually do our phase I study. I mentioned the compound has great pharmaceutical properties. 479, we've done PK studies in a number of species, and this has led to a projected human half-life of about 40-80 hours. We think this will support once-daily oral dosing. So as I mentioned, 479 is wrapping up its IND-enabling studies. Here, we did three 28-day GLP tox studies: rats, dogs, and cynos. Very clean profile in all of these. What we did see in each of these studies was on-target effects of hypercalcemia, exactly what we would expect for a PTH agonist. It's an on-target effect. And if you have an animal that has hypercalcemia for 28 days, you start to see some consequences of calcifications. We'll never go up that high in a human or a patient. And we did not see any effects of hyperbilirubinemia, which was the side effect that we saw with our first molecule, SEP-786, or inhibition of this enzyme that was the cause of 786's effects, UGT1A1. Drug product manufacturing is progressing well and tracking to finish up soon. And as I mentioned, we're tracking towards starting this phase I clinical trial in the first half of this year. We're planning to do a single ascending dose, multiple ascending dose design. We're planning to do that trial in Australia. Our first trial with 786 was in Australia. It was a well-run trial. And so we're going to go back and do it exactly the same way. Our goal in this first study is to look at, obviously, all phase I studies are designed to look at safety, tolerability, PK. That's table stakes for this. But what we want to see is on-target effects. We want to see exactly what I showed you in that monkey study a moment ago. We want to see decreases in endogenous PTH and increases in serum calcium. We expect this study to run about six to nine months. So depending on when we get started, we anticipate having top-line results from this later this year or early next year. Okay, moving on to our second program, SEP-631. This is an oral small molecule targeting MRGPRX2 for mast cell-driven diseases, including chronic spontaneous urticaria. So as I mentioned at the outset, MRGPRX2 is an emerging target. It represents a different mast cell degranulation stimulation pathway than the more traditional IgE and allergen pathway. Both of the pathways can lead to degranulation. MRGPRX2 has a number of endogenous ligands. Some of those are listed up in the upper right-hand corner. Each of these pathways leads to degranulation and the release of overlapping inflammatory mediators, including histamine and others. The mast cell degranulation can lead to a whole bunch of additional effects. And the idea is that our hypothesis is that a lot of diseases are driven by MRGPRX2-driven endogenous ligands. And our hope is to go after a number of different diseases. We're viewing this as a pipeline and a product opportunity. There's a number of skin conditions, including chronic spontaneous urticaria, chronic inducible urticaria, prurigo, atopic dermatitis, but there's also some non-skin conditions where there's increasing evidence of mast cell involvement, including asthma. Interstitial cystitis is a new indication that we're quite interested in, as well as migraine. CSU is the first indication that everybody thinks of in the mast cell space, represents a significant unmet need, results in chronic itchy, painful hives. It can be debilitating if somebody has these all day, can't sleep at night in many cases. First-line therapy is high-dose antihistamines, but there's a number of patients that are refractory to high-dose antihistamines, and there's currently a significant unmet need for new second-line treatment options for all of these patients. So our strategy has been to go after a negative allosteric modulator, and I'll explain a little bit more about the profile next. SEP-631, we think, has a differentiated profile, has a number of very positive features. It's a very potent compound, single-digit nanomolar to high picomolar in all the assays that we've tested. It broadly inhibits every MRGPRX2 agonist that we've thrown at it. It has a profile that we call an insurmountable negative allosteric modulator. What that means is when the compound is bound to the target, it completely turns the receptor off. It turns it off in such a way that it actually can't be outcompeted by other excess amounts of endogenous ligand. And our compound also has a very slow off-rate, very long residence time on the receptor. It's on there for hours. Our profile, as we'll share, we believe is a once-a-day drug. And in fact, in our phase I trial, we only did once a day. I'll show you on the next couple of slides a little bit of pharmacodynamic data. And then in terms of safety, our IND-enabling studies were done in rats and dogs. Compound was well tolerated. And we decided to go the extra mile in terms of thinking ahead to phase II. And we've already started our chronic toxicology studies with the goal of completing both six-month rat studies and nine-month dog studies before we start phase II. So I'm going to show you a little bit of pharmacodynamic data. MRGPRX2, unfortunately, presents a preclinical challenge in that it's not well conserved across species. So we had to make a human knock-in mouse. So we took the human MRGPRX2 gene, replaced the mouse's gene. And the study that I'm going to show you in a moment is one that we think is quite relevant to urticaria. We take this knock-in mouse, we treat it with our compound 631, we then administer a blue dye, and then the next thing we do is we inject into the skin an MRGPRX2 agonist, in this case, Cortistatin-14. At the site of that injection, what we get is a little blue hive, so the animal develops an extravasation in the skin at the site of that X2 agonist injection, and theoretically, if we were able to completely turn off this receptor, as we think we can do with SEP-631, we would ideally see no skin extravasation, and that's exactly what we see. This middle figure shows you that we've been able to completely dampen down the skin extravasation to really zero. The y-axis here is fold-over vehicle, so the dashed line there is basically the zero extravasation line. The closest we can come in terms of a human translational system is primary human skin mast cells that have been isolated from skin donors. Here, we're stimulating these cells with a different X2 agonist, substance P in this case, and we're looking at tryptase release, and you can see that we're potently inhibiting that with our compound as well. Our phase I trial, as I mentioned, is wrapping up. This is a trial that is a single ascending dose, multiple ascending dose design. In the MAD portion of the trial, we're doing an intradermal skin challenge. In the MAD portion of the trial, we're doing once-a-day dosing with these oral tablets for a 10-day period. The skin challenge I wanted to walk through, because this will give you a little bit of a preview of the data that we hope to be able to share in about two months now. This involves injection of a drug called icatibant. Icatibant is an approved drug for hereditary angioedema. It's known to have an off-target effect hitting this particular receptor. It causes a skin reaction in virtually every patient that it's injected into. What we're doing is an intradermal skin challenge. That leads to a wheal response. The idea is to do a skin challenge with a couple of doses of icatibant, a negative control, which is saline, a positive control, which is histamine. Do that skin challenge before we start dosing SEP-631. We've done that. Then again on day nine, after nine days of treatment with our drug, where the drug is now at steady state. So in this case, each of the subjects in the MAD portion of the trial is their own control. And what we're hoping to see is a dampening down of the icatibant skin challenge, much like in that mouse study that I showed you, hopefully down close to the saline baseline. All right. And as I mentioned, we'll be sharing that data at the AAAAI meeting on March 1st. A couple of quick programs now. The TSH receptor negative allosteric modulator, again, going after Graves' disease and thyroid eye disease. Both of these conditions are autoimmune conditions caused by an abundance of autoantibodies that bind to a very large extracellular domain on the TSH receptor. These activate the receptor in both the thyroid gland, leading to hyperthyroidism, as well as in orbital fibroblasts behind the eyes. In orbital fibroblasts, this stimulation leads to expansion in the orbital fat and the characteristic proptosis of thyroid eye disease. Each of the current approved therapies for Graves' disease and thyroid eye disease treats one condition or the other. The Graves' treatments, which are standard anti-thyroid drugs or removing the thyroid gland or radioactive iodine to ablate the thyroid gland, they treat the Graves' disease. They don't do anything to thyroid eye disease. On the converse, the approved thyroid eye disease therapies don't do anything to Graves' disease, and our hope is to find a universal therapy that will be disease-modifying for all Graves' patients and thyroid eye disease patients. One challenge is that each patient has a unique autoantibody. They're different from person to person. They're actually also polyclonal, where within a patient, there's often several autoantibodies. Our strategy here has been to develop a negative TSHR modulator. This is completely analogous to what I just mentioned to you in our MRGPRX2 program. Our profile here is also an insurmountable negative TSHR modulator. We've identified such compounds. We've identified selective, potent, insurmountable negative TSHR modulators for this receptor. We've shown in preclinical studies that I don't have time to share with you that we can inhibit a diverse range of patient autoantibodies. In fact, every patient sample that we've gotten our hands on, polyclonal serum samples from Graves' patients, we've been able to inhibit the activation of those on primary human skin cells, primary human orbital fibroblast cells. We've also reversed Graves' disease in an animal model that I'll show you right now. In this case, we had to come up with a novel animal model. And this is a mouse model where we dose the mouse over and over again with a Graves' patient-derived antibody. This Graves' patient antibody, if you treat the mouse over and over again for a six-week period, causes basically a Graves' phenotype. These animals have hyperthyroidism, high thyroid hormone levels, the thyroid gets enlarged, and the animals also showed signs of proptosis with the eyes bulging. The idea is in the setting of continuing to dose that antibody that causes this phenotype, could we reverse it with one of our TSHR NAMs? And we're seeing exactly that. And this is now, with just one week of treatment, we're able to take thyroid hormone levels shown in magenta in the gray bar all the way back down to the normal levels. These animals also have increases in thyroid size. The thyroid weight is increased, also represented by the second graph. That's also where we're able to start to get some normalization of that as well. On the right figure, you're now looking at proptotic animals with thyroid eye disease. The middle two photos in the second row there show that these animals have more prominent bulging eyes than the vehicle control animals listed above or shown above. We're able to see some reversal of that as well. This is an exciting program. It's still in the lead optimization stages, but as I mentioned earlier, we're starting to have line of sight to develop mechanics. I hope to be able to say more about this program later in the year. Last but not least, I mentioned our metabolic programs and our findings here of novel binding pockets in the incretin space. This led to our Novo Nordisk collaboration. Just a little bit on the collaboration for a moment. It includes these three receptors: the GLP-1 receptor, the GIP receptor, and the glucagon receptor, plus two undisclosed targets. We signed the deal last May, closed it in July, received the upfront payment. Good economic terms, good milestone royalty packages, as well as an opt-in for a worldwide profit share on a program of our choosing later. One important feature here is that Novo covers all R&D costs going forward. All right. Just to quickly wrap up our team, I'm joined up here today by Liz Bhatt, our President and Chief Operating Officer. She's going to join me in the Q&A session that we're about to start. Gil Labrucherie is in our audience here, as well as our CFO. And we've got a very experienced team across the board. We've got an experienced board of directors, a couple of members in the audience today, and academic co-founders that are world leaders in thinking about GPCR biology and a drug discovery advisory board, including some very experienced people from the pharmaceutical industry. And with that, I'll leave this slide up to kind of start the Q&A. This is just a summary of our pipeline. Okay. Okay, great. I don't think my mic is on. Okay, there we go. Jeff, thank you so much for the presentation. I thought I would start with a little bit of a bigger picture question here. How do you think about balancing investment across the portfolio and picking the right places to go leveraging your platform? And secondly, how can you minimize potential off-target side effects with novel binding pockets? Yeah, both really important questions. So as I mentioned, there's a tremendous amount of opportunity space in the GPCR space. And we've gone after targets again where we think there's a significant unmet need. Ones where they've proven to be small molecule challenges, ones where we think our platform can actually work and make a difference, and importantly, ones that have early clinical readouts. In terms of balancing resources, we're sitting in a well-capitalized position, as I mentioned. Right now, obviously, the priorities are our lead programs and getting to good clinical data on those as quickly as we can. But we are continuing to invest in early stage programs as well as our platform. We're continuing to add to platform value there as well. To get to your question about minimizing off-target effects, we're discovering novel binding pockets, as you just mentioned. Each one of these represents a new frontier. We don't know exactly what it's going to do. But as part of our drug discovery program, we've got very robust systems to look at selectivity across different GPCRs. So we'll look at literally 100 or so different GPCRs to gain confidence in selectivity. So that's one thing. If we don't have selectivity or questions about that, we're able to use the platform to further drive selectivity among receptors. We also have a very robust set of preclinical studies to look for off-target effects in our preclinical models. Okay. Okay. And in the eight minutes that I have, I'm going to do some quick hits here. Let's see how much we get in here. Go for it. So for SEP-479, what are the gating factors to entering the clinic? And maybe can you give us a little bit of a framework with respect to the right way to think about your overall development plan? And how quickly can you kind of move from phase to phase? And what would a trial there look like? Yeah, great questions. So what's gating for 479 to get in the clinic at this point is honestly just regulatory. We need to prepare the regulatory documents, get them approved, get the site started, and all of that. So we're going to be in that phase I trial in the first half of this year. We're excited about that. If you think about the overall program, we think that the phase I data is going to be value-creating in itself. Every compound that has been in a phase I trial in hypoparathyroidism that has worked in a healthy volunteer has also worked in hypoparathyroidism patients. So we want to pivot quite quickly from a healthy volunteer study into patient studies as quickly as we possibly can. That will obviously involve multiple sites, multiple locations. We're doing some pre-thinking for that with the hope that we'd be able to actually start that study not too long after seeing hopefully promising results in healthy volunteers. Okay. And maybe you could talk a little bit more about what your view is of the evolving market for HP and what have you learned from the first commercial players and from the development landscape? Yeah, so I'll go ahead and take that one. So the hypoparathyroidism market is changing. So it is still very robust with about 70,000-80,000 patients within the United States. Currently, standard of care has been high doses of calcium and vitamin D. With the new players, with the peptides, we are seeing certainly uptake of those programs. Right now, those are probably being used mostly for the more uncontrolled patients, patients who can't get their serum calcium to the normal range. What we believe with SEP-479, that it is really going to be addressable to all types of patients. People really want oral options. As Jeff mentioned, these patients are relatively young when they get diagnosed. They're going to be treating their disease for decades. And so they're going to want an oral option that's going to be convenient for them. So someone who potentially is naive to therapy might be interested in an oral option. Somebody who's on an existing therapy may be interested in switching. There's a lot of patients out there who actually aren't interested in injectables. They're interested in really kind of maintaining their disease with oral options. The other thing to mention is with hypoparathyroidism. Again, patients currently take so much calcium right now that's really long-term really not healthy for their kidneys. And so having PTH replacement therapy, we really believe most patients should be on PTH replacement therapy. And so having various options, whether it be peptide injectables or whether it be an oral option, we think that 479 really has a broad opportunity across the space. Okay. Segueing here, Jeff talked a little bit about the mechanism of SEP-631. Can you talk a little bit more about how it differentiates from other targets for mast cell disorders? And how de-risked do you believe the target is at this point from either internal or externally generated evidence? Yeah. In terms of 631, we have what we believe is a very differentiated mechanism on the target itself. It's got this insurmountable negative allosteric modulator profile as I mentioned, does completely turn the receptor off. And as I mentioned, it's got a very slow off rate, which we think should translate to better clinical efficacy. In terms of target validation from others, we know that depleting mast cells can have effects on a number of different diseases. So there are mast cell depleters out there. In terms of the X2 mechanism, fortunately, we're learning from Evommune, who's ahead of us in this space. They showed some promising data in their chronic inducible urticaria study showing that inhibiting this mechanism can be effective in that setting. We do think there may be some opportunities to do a bit better than that. Hopefully, if we've got a compound that does completely turn off the receptor, we've got opportunities to show improved efficacy. Okay. Okay. And assuming the phase I goes well, zooming ahead here, is CSU the priority indication for development, or are you contemplating other diseases at this point? So one of the things that excited us about X2 when we chose that target is really the breadth of opportunity with mast cell-driven diseases. There is a lot of different indications, as Jeff had mentioned, a lot in dermatology, whether it be CSU, CIndU, atopic dermatitis, but really the emerging data on allergic asthma, potentially interstitial cystitis, evidence in migraine as well. There's a lot of different areas to go. So we've actually been spending quite a bit of time thinking about some of those indications that are potentially a little less validated, but very exciting with huge unmet needs in terms of how do we think about preclinical work in that space? How do we think about signal-finding studies in those additional spaces as well? And so we'll start probably with CSU, but I think begin to think about how we can quickly explore some of those in a capital-efficient way as well. Okay. And maybe just touching on the TSHR program, how close are you to the development candidate selection here? We're getting there. TSHR is represented a very challenging target. It's a multi-parameter optimization where we need a very potent compound, a very selective compound, also one with very good pharmaceutical properties. And a number of companies have been in this space, and it's actually a very hard optimization problem. We think we've got line of sight to cracking that finally with our latest series. The hope is that we're getting there, and the hope is that we've got a little bit more to say about that later this year. Okay. How do you protect your efforts from an IP standpoint? Yeah, great question. We've got IP in terms of our platform. We know to date it's been able to find very novel binding pockets on these receptors. And those novel binding pockets have led to novel chemistry. So from an IP standpoint, our number one approach is to protect these novel chemical structures that we've identified. So that's our number one defense there. It doesn't mean that others couldn't eventually get into this space, but we've got a long-term strategy to do backups and follow-on compounds for all of our programs and are building quite robust portfolios for each of our targets. We also just recently announced last week that we hired a new head of IP who's going to be helping us with the longer-term strategy. Okay. Okay. Last question from me. You talked a little bit about your strategic collaboration with Novo. Is further business development a priority for Septerna in 2026? Yes, we've done two deals now, one initially with Vertex and then one more recently with Novo. As we kind of think about 2026 going forward, one of our objectives as we're growing as a company is to really focus and execute on our own pipeline. The collaborations have been very important to us going forward. We're going to be opportunistic as it relates to business development. We're always in dialogue in terms of new opportunities coming forward. One of the key things about our portfolio, as it continues to grow, we're not going to be able to do everything. And so we're always going to be thinking about how can we maximize the value of our programs, what types of partnerships, and when are those partnerships make the most sense in terms of doing that. So we'll always be having BD dialogue, but really we're focusing on execution right now. Jeff, Liz, I want to thank you so much and the entire Septerna team for being here, and all the investors and everyone for joining. Thank you.