Okay, thanks, everybody. Really pleased to be here, at Guggenheim's second annual Healthcare Innovations Conference. I'm Seamus Fernandez, one of the biopharma analysts here at Guggenheim. Really pleased to be joined by Jeff Finer, who's CEO and co-founder of Septerna, and the team in the audience as well. Thanks for joining. You know, I'm going to turn it over to Jeff, who's going to basically just orient everybody to the story. And then, we're going to dive right into Q&A. So, Jeff, turn it over to you. Thanks so much for joining us. Okay. Yeah, great. Thanks. Thanks, Seamus, for the intro. For my remarks, we'll have forward-looking statements. I need to say that. The company is, for those of you who aren't familiar with Septerna, is a company focused entirely on G protein-coupled receptors, or GPCRs. We've discovered a new way to do GPCR small molecule discovery, using a platform that we call the Native Complex platform. This has quickly yielded a portfolio of products. We'll talk about a few of those today. All of our programs have validated targets, early clinical readouts, and significant market opportunities, and we're well capitalized. We put out our quarterly report just this morning that indicates we should have operating cash runway into at least 2029. We'll spend today talking about a couple of the programs primarily. Our SEP-479 program, which is a parathyroid hormone receptor agonist focused on hyperparathyroidism, similar to the condition that you guys heard about in the meeting just before this. Second program, SEP-631, is an MRGPRX2 negative allosteric modulator, or NAM. You may hear me say NAM a few times. That's what that means. Both of these programs are advancing. The 479 program, we anticipate getting into the clinic in the first half of next year. SEP-631 program, we anticipate sharing data from our phase one clinical trial in the first half of next year. We've got an earlier stage program, a thyroid-stimulating hormone receptor program focused on Graves' disease and thyroid eye disease. We have also got an incretin receptor agonist program. This is one where we've identified a novel binding pocket, and that became the subject of a collaboration, a very significant collaboration with Novo Nordisk that we announced in May, which officially launched in July. That collaboration included $195 million upfront, and importantly, they are supporting and paying for all research and development costs on top of that. I want to orient you guys to two of our programs here. The first is the 479 program for hyperparathyroidism. This has been a historically difficult small molecule target. I'm showing you here the receptor in magenta, the peptide, PTH peptide in green, the G protein in blue. Many companies have tried to find small molecules for this target and just completely struck out, and our platform has actually solved this problem actually more than once. We've identified two novel binding pockets to both activate the receptor with novel small molecules. Another feature of our platform is our ability to optimize and with structure-based design very, very quickly. We took both of these forward to clinical candidate quality molecules. The first compound, for those of you that have been following our story for a while, it was a compound called SEP-786. It was in phase I trials, moving along quite nicely. From this program, we actually learned that a small molecule can mimic the activity of a peptide with decreases in endogenous PTH and increases in serum calcium. It's exactly what we wanted to see. Unfortunately, we had to discontinue this trial. There were a couple of subjects in this trial that had unanticipated increases in unconjugated bilirubin, very significant levels there. Fortunately, after we discontinued the trial, we were able to figure out what the mechanism was, and the mechanism is a very clean one. The 786 targets a bilirubin conjugation enzyme called UGT1A1, and it has just a very clean effect there. Unfortunately, it did not have legs to move forward. SEP-479, which we will spend most of the time talking about today, is our next generation candidate. It is completely structurally unrelated to 786. It does not have the UGT1A1 inhibition. As a special bonus, it actually has significantly improved pharmaceutical properties and ones that we think could be compatible with once daily dosing with full calcium control. Here, I am going to show you a little bit of data in a rat surgical model of hyperparathyroidism. We surgically remove the parathyroid glands. These animals develop hypoparathyroidism, hypocalcemia, and the idea is, could we mimic the effect of that PTH and correct this with our oral small molecule? What we are looking at here are serum calcium levels and serum phosphate levels. These animals end up with low serum calcium levels, as represented by those gray dots, and high serum phosphate levels. This is a 28-day study. We're looking at detailed time courses over four of the 28 days. You can see that we're able to normalize both serum calcium and serum phosphate, getting into that gray band that's represented on the figure there. Importantly, the dose needed here was actually quite small. It was only 0.15 milligrams per kilogram once a day, which is actually significantly lower than similar doses for 786. We've got great pharmacokinetic properties, good oral bioavailability, as demonstrated across these four species, half-lives starting at about seven hours in a mouse, all the way up to much longer than that. We've got a predicted human half-life in the 40-80 hour range, which, again, we think should support once daily oral dosing. Here's some data that we're quite excited about on the pharmacodynamic side. This is a seven-day PKPD study in healthy cynomolgus monkeys. The purpose of this study was to try to simulate what 479 might look like in a healthy volunteer study. What is important to understand is that healthy volunteers have intact PTH calcium feedback loops. If you look at the right figure there, what we're looking at is endogenous PTH levels. This is a seven-day study, once daily oral dosing, followed by a five-day recovery period. You can see after just a single dose, we're able to take endogenous PTH levels all the way down 70-80%. Once PTH is bottomed out, the next effect is you can start to see some calcium increases. We're seeing what we think are clinically meaningful calcium increases. What's clinically meaningful? If we look at the PTH peptides that have been ahead of us in clinical development, and you look at what the starting doses were in hyperparathyroidism patients, and then look back at what those drugs did in phase one, the relevant amount of calcium increases about 1 milligram per deciliter, somewhere starting dose around half of that, around 0.5 milligrams per deciliter, up to titration a little bit north of that. We think we're at the right levels. 479 is currently wrapping up its preclinical development studies. We've completed 28-day GLP-tox studies in rats and dogs, very well tolerated. The dose-limiting effects were hypercalcemia. This is on target and to be expected. We decided to go the extra mile, just based on our prior experience, and do a third GLP-tox studies, this time in SNOs. Like I said earlier, if this is on pace, it should be in the clinic the first half of next year. Just briefly, I want to introduce you to the second program, SEP-631. This is going after a mast cell target called MRGPRX2, and we think it has relevance to a whole slew of mast cell-driven diseases, including chronic spontaneous urticaria. We think we've got a compound with an attractive profile, high potency, single-digit nanomolar to high picomolar, depending on the assay, broad inhibition. We've got a really unique profile that we think is differentiated from others that are in this space. It's called an insurmountable negative allosteric modulator. What it basically does is when 631 is on MRGPRX2, it turns the receptor off. Not only does it turn it off, but it turns it off for a long time. The compound is on the receptor for hours at a time, which we think is quite differentiated. PK profile suggests once daily oral dosing should be sufficient. On the next slide, I'll show you a little bit about pharmacodynamics, and then it had a good safety profile as well. In terms of pharmacodynamics in translational models, MRGPRX2 presents a challenge in that it's not well conserved across species. We had to make a knock-in mouse, knock in the human gene in place of the mouse's gene. What you're looking at here is a mouse model that we think is quite relevant to urticaria and also our phase one trial design. These mice are given our compound, administered a blue dye that goes into the bloodstream of the animal, and then they're given an intradermal skin challenge with an X2 agonist, in this case, Cortistatin 14. The idea is that those animals that do not have our drug will have extravasation of the blue dye, get a little blue hive. Theoretically, if we are able to fully inhibit X2, we will inhibit that extravasation. This is exactly what you are seeing here. We have shown complete inhibition of extravasation, basically none, when our compound is on board, which we are excited about. The only thing we were able to do in terms of human translational models was to get a hold of some primary human skin mast cells. These are treated with a different X2 agonist, substance P in this case, and we are looking at tryptase release, and we are able to potently inhibit that as well. Right now, we are in a phase one trial, as I mentioned. This is both a SAD, MAD trial. The MAD portion of the trial involves 10 days of oral dosing. In the MAD portion of the trial, we're doing an intradermal skin challenge, much like in that mouse model I just showed you. In this particular case, we're injecting an approved drug that's known to be an X2 agonist and have that as a side effect. It's called Icatibant. At the site of that injection, if you inject that into a healthy volunteer, the healthy volunteers will develop wheals at that site. The idea is we're going to do a skin challenge pre-dose and then again on day nine of the 10-day dosing period. We hope to be able to share this data in early 2026. With that, I'll wrap up and we can move on to Q&A. Great. Maybe I'll just leave our pipeline up there just for the rest of the— yeah, super helpful. Maybe just to start us off, Jeff, the 479 program and again, your prior lead 786, can you just compare and contrast the two for us? Other than the safety issue that emerged with bilirubin, let's just sort of take that aside, but how would you compare 479 to 786 in terms of just the it seems like 479 is actually a superior molecule in some ways. Yeah, I think in terms of the rat data that I showed you just as an example, both molecules work equally well. It's just that 479 works equally well at about 40 times lower dose. So it does have better pharmaceutical properties in that regard. The half-life also is longer. We projected for the first compound a half-life in the 9-27 hour range. It ended up being about 18 hours, so our prediction was quite good. This should be a significantly longer half-life. I think with that gives us better confidence that this should be a once-a-day drug. Okay, great. Just in terms of maybe back to the unconjugated hyperbilirubinemia from the phase one, maybe just reemphasize the learnings from 786. It feels like a little bit of belt and suspenders, but the reason that you're doing the NHP program and what you hope to learn from it. Yeah, with regard to the learning from 786, I think the number one learning is that a small molecule can mimic what a PTH peptide can do. That is by far the number one learning. With regard to the bilirubin side effect, we do not have any reason to believe that the second compound will have that. I should say that in a subsequent study, after we discontinued 786, we did a monkey study and we were able to see bilirubin increases there, even though it did not previously show up in rat and dog safety studies. That is why we decided to go the extra mile and do the study there. We think doses are going to be lower, half-life is going to be longer. Lower doses, if nothing else, are going to give us just a lower chance of having another random off-target effect. Okay. Just in terms of the work that was necessary to show that 479 is just not hitting the bilirubin receptor, can you just help us? What did you do to ensure as much as possible that 479 was not selecting for that? Yeah, as we were studying the mechanism for SEP-786, we looked at bilirubin transporters, we looked at bilirubin conjugation enzymes, and it was a very clean effect. We were testing 479 exactly along the way. We did all the in vitro assays. We also have not seen any effects of bilirubin in any of our animal studies. The monkey pharmacodynamic data that I showed you earlier, we went up to way over supratherapeutic doses, probably at least sixfold above where we would probably need to be. We did not see any evidence of bilirubin there as well. We are quite confident that 479 does not have that same effect. It is also just, again, a completely unrelated structural series. We did not really expect it anyway. Okay. Just sort of the predictive properties of 479 when we go from the phase one into what would be a multi-dose phase two, most of these programs, most of these products have required titration with the calcium. How would you just sort of what are the properties that you think are necessary that you'll be looking for to have real confidence that your half-life is kind of nailing a once-a-day, which is interestingly, it looks like it almost perfectly overlaps the current once-daily injection. Yeah, the once-daily injection for Yorvipath, the effective half-life is about 60 hours. If we end up in that 40-80 hour range, I think we've nailed it in terms of being able to phenocopy that. We think any half-life over about 20 hours will probably put us in about that once-a-day range. With regard to the profile, this is going to be like the peptides. It's going to be titrated on a patient-by-patient basis. That's just the way it's going to be. It's fortunate that we've been able to have the learnings from the peptides in terms of how they made the transition from phase one to phase two. I think we're going to be able to, hopefully, from that phase one trial, see efficacy in terms of being able to, again, lower endogenous PTH, increase serum calcium, and use the experience of others to predict what our starting dose should be. Great. Let's move on to X2 and the 631 asset. Some would say, "Okay, well, we now have an IPO that's been sort of catalyzed successfully with X2 for another company." We also had another asset that had issues where it came seemingly fairly far along. What do we know about the different programs and how your asset differentiates itself from other programs that are out there? Yeah, so we set out to make just the best compound we could, and we thought this insurmountable negative allosteric modulator was the ideal profile for us to go after. Unfortunately, we do not know exactly what the others' compounds are. They have not published their structures. We have made our best guesses at what their compounds could be and tested those side by side with ours, so we do have some differentiation there. With regard to what has happened with those compounds, we are generally just cheering everybody on in this space. We want patients to have as many options as possible with their drugs. We are confident so far in what we have seen from 631 that we could end up with a differentiated profile. Maybe just remind us the breadth of the opportunity for targeting X2. We just had a CSU product actually approved targeting BTK, totally different mechanism. Where do you see X2 really fitting in the treatment paradigm? What are the indications? How broad could the indication set be from your perspective? Yeah, there are a lot of mast cell indications. There's probably six to ten different indications that we could imagine going after. CSU is the first one that everybody thinks of and is likely the first one that we would pursue as well. With the CSU space, it is obviously getting crowded. There's a number of different mechanisms, some depleting mast cells, some inhibiting activation through different pathways. The evidence in CSU that there is something other than the IgE pathway important is actually quite significant at this point in time. As we start to think about the long-term treatment paradigm for CSU, first-line therapy is always going to be antihistamines, high-dose antihistamines. We think that a mechanism like this could play very well in the second-line therapy realm. Second-line therapy is going to take a little time to shake out. It has been Xolair for a long time, but we think a lot of the other mechanisms are going to come into play. We will just have to see which one ultimately ends up working best in the clinic. I know this is going in a slightly different direction, but you mentioned Xolair. How do you think about food allergy as an opportunity for X2 over time? Yeah, food allergy is interesting. I do not know that it is actually a perfect fit for the X2 mechanism. One important thing to know is that on these mast cells, not all the mast cells have equal amounts of X2 on their surfaces. There are different subsets in the body. The skin mast cells and ones in other tissues are known to have a lot of X2. The ones in the gut are actually thought to have less MRGPRX2 on the surface, so it may or may not be as effective there. Many of the more modern therapies other than Xolair have not touched the food allergy space quite yet. They have been going after other indications. I think it may be largely that there are effects. The effects are largely thought to be IGE-mediated. With that said, there has been some evidence that with X2, you can potentially dampen down some of the anaphylaxis that may occur in food allergy. It could be conceivably something that would be combined with an anti-IgE therapy down the road. Interesting. In terms of before we get to other programs, as you kind of look at and what you would like to see in your proof of principle data with X2, what would sort of the ideal path look like in 2026, let's call it end of 2026, 2027, when we might see data after you sort of initiated the program? Yeah, I mean, the first thing we want to see out of our phase one study is significant effects on that skin challenge. That's going to be important for us. If we have significant effects in that skin challenge, we will feel comfortable moving forward into a CSU program after that. We'd want to see significant efficacy in being able to decrease symptoms and some of the standard symptom scores that are used for CSU. Timing-wise, we've talked about 631 data in the first half of the year. The hope would be that we can get started on a CSU trial sometime later in the year. Maybe we can move to the TSHR. Just talk a little bit more about the challenges of developing an asset to this target and help us better understand just sort of the background of Graves' disease and TED as well. Yeah, the first thing you've got to think about with Graves' disease and thyroid eye disease is they're actually both autoimmune diseases caused by autoantibodies that target a receptor called the thyroid-stimulating hormone receptor. That receptor is present in a couple of tissues, primarily in the thyroid gland. When these autoantibodies hit that receptor, they activate that receptor and people develop hyperthyroidism. They have too much thyroid hormone. That same receptor is located on orbital fibroblasts behind the eyes. When that receptor is stimulated, orbital fat expands, and that leads to the characteristic proptosis of thyroid eye disease patients. It is a very significant unmet need. The market size is actually quite large. Traditional therapies for Graves' disease are the same today as they were literally decades ago: anti-thyroid medications, ablating the thyroid gland with radioactive iodine, or surgically removing the thyroid gland. For thyroid eye disease, it is a completely different treatment. There are anti-IGF therapies that have been around for now a handful of years. Those are working okay, but they have got some side effects associated with them, including hearing loss. There isn't yet a treatment that actually targets both diseases simultaneously. We think targeting the receptor could be quite a good approach to that. There are other mechanisms in the works to deplete some of those antibodies. We think if we've got a unique way of basically turning off this receptor, our strategy for this one is actually quite similar to what we were talking about with MRGPRX2. It's an insurmountable negative allosteric modulator. What makes this disease additionally challenging is that every patient has a different antibody. In many cases, they're actually polyclonal. How are we going to come up with a single inhibitor that actually inhibits everybody's antibodies? This negative allosteric modulator approach, we've shown in our preclinical studies that when we inhibit the receptor in a particular way, we can shut off the activation by all antibodies. We're excited about that. We're making good progress on this program. It's been one that's been in our pipeline for a while. We now have line of sight to a development candidate. Excellent. When we talk about timelines, we've talked about timelines before. You're now sort of approaching three assets, advancing from preclinical status into the clinic relatively quickly, if we're including the Novo program. How is the pace kind of matching up to your development expectations? Maybe you can just help us understand what you believe the platform is capable of. Yeah, the platform is actually even broader than this. We think it's a generalizable platform that applies to all GPCRs, and there are literally hundreds of untapped GPCR opportunities, many therapeutic areas. Behind these three programs, we actually have more. We have earlier stage programs behind those. We think we've got the potential to create a very deep pipeline of GPCR products that are each big market opportunities and high potential. We have to focus initially over these next couple of years in making significant progress on these first two or three and see where we go from there. Right. Jeff, thanks so much. Having seen you as a private company and the advances that you've made so far, congratulations on all the progress. I look forward to a lot of success for Septerna in 2026. Thanks so much for joining us. Okay, yeah, thanks, Seamus. And thanks to Guggenheim.