All right, good afternoon, and thanks once again for joining us for the TD Cowen first annual I&I Summit. I'm Yaron Werber from the biotech team, and it's a great pleasure to moderate the next session with Septerna. With us, really needs no introduction, Jeff Finer, CEO and co-founder. Jeff, thanks so much for joining us. We appreciate it. Yeah, thanks, Yaron. Appreciate the invitation. There is a lot going on in Septerna. Jeff is going to—we are going to show a few slides, and we will keep it with a lot of Q&A. The first compound, SEP-631, it is a very potent MRGPRX2 inhibitor, allosteric inhibitor. He is in the clinic now. In the first half of next year, the next compound, SEP-479, which is a—it is a PTH1 receptor agonist for hyperparathyroidism, is expected to go into phase I. Jeff, let me turn it over to you. For the audience, if you have questions, feel free to email them to me. For those of you who are plugged in, you can put it into the operator chat or the Wall Street webcasting chat, and I can ask them anonymously on your behalf. Okay, great. Yeah, thanks, Yaron. My presentation will include forward-looking statements, so please take that into consideration. Just briefly, I just wanted to introduce everybody to Septerna. We're a company focused entirely on GPCRs, or G protein-coupled receptors, and we found a new way to do GPCR drug discovery that we call the Native Complex Platform. That platform has quickly materialized into a broad portfolio of programs that all have validated targets, early clinical readouts, and significant market opportunities. We have cash runway into at least 2029. As Yaron mentioned, we've got two programs that we'll focus in on today. SEP-631 targets MRGPRX2 for mast cell-driven diseases. That one is currently in phase I. Expect to have readouts on that in the first half of the year. SEP-479 targets the parathyroid hormone receptor for hyperparathyroidism, and we anticipate that getting into the clinic in the first half of next year. We've got an earlier stage program on Graves' disease with thyroid stimulating hormone receptor, and we've also recently announced a deal with Novo around incretin receptor agonists, but do not have time to talk about that one today. Getting into SEP-631, just really briefly, just to level set, I know most of this audience thinks about mast cells a lot, but just as a reminder that MRGPRX2 is an emerging target that involves activation of the mast cells through a whole bunch of endogenous mediators, various different peptides and protein activators. It leads to mast cell degranulation through an IgE independent pathway. There's a whole variety of different inflammatory mediators that come out. Our strategy at Septerna is to target this receptor, and we found a way to do it with what we call an insurmountable negative allosteric modulator. I'll explain more about that in a moment. The profile of this compound is one that we think provides a differentiated profile. It's very high potency, single digit nanomolar to high picomolar, broad inhibition. We've shown inhibition of all endogenous agonists that we've thrown at this receptor. We've got a very slow off rate as well, which we think is distinct. Oral bioavailability is excellent, and we're projecting to once a day oral dosing. We've got some good pharmacodynamic data that I'll introduce you briefly to on the next slide, and we showed a good safety profile preclinically. I just wanted to show just one or two pieces of data here. This is a knock-in mouse model where we've knocked in the human gene to replace the mouse's gene. Then we dose with our drug, dose the mouse with a blue dye. That tints the blood a little bit blue. We do a skin challenge, which we think is quite relevant to urticaria. We're dosing with an X2 agonist called Cortistatin-14. At the site of that injection, we end up with extravasation of the blue dye. The mouse gets basically like a little blue hive or a wheal, very analogous to what an urticaria patient would get. Theoretically, if we're able to fully inhibit this target, we will completely inhibit the extravasation of the blue dye. That's exactly what we're seeing. This dashed line here is the zero extravasation line. We're completely turning off the extravasation with SEP-631. The best preclinical model on the human side that we could use for translational purposes was identifying and isolating primary human skin mast cells. These were from skin donors. Here we're stimulating these mast cells with a different X2 agonist, Substance P in this case, and looking at tryptase release, and we're able to shut that down in a potent way as well. This compound is in a phase I trial, as I just mentioned. A little bit on the phase I trial design. This is a randomized placebo-controlled trial, standard SAD/MAD design in the multiple ascending dose portion. It's once daily oral dosing for 10 days. We are doing a skin challenge, much like in that mouse model I just showed you. In this case, with an approved drug called Icatibant, which is known to have skin reactions when it is dosed subcutaneously normally. Icatibant is known to be an X2 agonist. In this setting of this trial, we're doing a skin challenge predose with a low and high dose of icatibant, a negative control, and a positive control. Then on day nine of the 10-day dosing regimen, we're doing it again. We're trying to look at intersubject differences in the response. We anticipate having this full data set ready to share in the first half of next year. Yaron, I don't know if you want to pause and have questions about this program before we move on to the next one. Yeah, no, absolutely. Maybe you mentioned a little bit high picomolar, slow off rate, which is, I think, distinct maybe from what you think Celldex or maybe Evommune, EVO-756, which actually showed some interesting initial syndue data. They do have some, I believe, two patients, sort of asymptomatic AST elevations up to even 10x normal. There was no increase in hepatic biomarkers like bilirubin. I think that's going to be now capping a little bit how they dose their drug. I think they can only go to 150, right? It's probably going to end up being even a BID dose. Maybe a little bit of what do you think just drug profile yours is going to look like? Yeah, so we're quite confident this is going to be once daily oral dosing. Our hope is that we're able to stay on the lower end of the dosing range as well. This is something that we'll obviously have to work out when we get into patients in phase II as to what the right efficacious doses are. With regard to the safety, this compound looked very safe by everything, every metric that we've looked at. We believe that those other effects, both that you've talked about with the other X2 agonists that were ahead of us, we think those were probably molecule specific as opposed to related to the mechanism. With this particular target, you can delete, you can have a knockout mouse with this gene completely taken away, and there are no significant consequences to that. Okay, so you've not seen any liver involvement at all? No, no, none at all. Do you have a sense on what's the metabolism of the drug? Yeah, of our drug or theirs? Of yours, yeah. Yeah, we know the metabolic pathways pretty well. Those are pretty well worked out. We haven't disclosed the details of that yet. Okay, okay. Got it. Okay. In the first half of next year, maybe just in terms of, you noted a little bit, this is going to be the icatibant challenge. Based on that, is the thought to move into, this is up to, it's obviously up to 150 healthy volunteers. What can we learn from this study? Yeah, so I think what we can learn from this study is pharmacodynamics. This will give us confidence that the drug is getting to the skin and that it's able to inhibit the receptor in the presence of an agonist to the receptor, icatibant. I think we'll have confidence in that. Now, with the other groups that are ahead of us, including Evommune, we know that as we start to see their data, we can actually triangulate back to what they previously saw in their phase I icatibant challenge. We think our data should at least be comparable to that. Hopefully, when we share this data, there may be some distinguishing features because we thought that there may be a little bit of headroom for greater efficacy. The data we're going to get in the first half of next year is going to be the MAD too, right? Both the SAD and the MAD? Yeah, it'll be the full data set, SAD, MAD, and skin challenge. Yeah. Right, got it. The skin challenge is done as part of the MAD study, right? Yeah, every subject that's in the entire phase I trial that is in the MAD portion of the trial is getting a skin challenge. Got it. You're looking at a baseline at day 10, or do you do it daily? It's just two time points, predose, and then on day nine. Yeah, okay, yeah. We're looking at the difference between the predose and the day nine on a subject-by-subject basis. Yeah, got it. Okay, and after that, the next step would be to go into a CSU study or a CSU and a syndue study, or kind of what you're thinking next? Yeah, a good question. We're still working out our phase II strategy. I think it makes the most sense to get to CSU as fast as we possibly can after this study. There's at least half a dozen other indications, as you guys all know, for mast cell-driven diseases. We're trying to figure out which ones we might do in addition to CSU, but our plan would be to go straight from this trial into a CSU trial. Yeah, because with an oral drug, I mean, CSU is always an opportunity. It's smaller of the market. You can move into an asthma study. You can move potentially into PN. Exactly. We're going to have data second half next year from Celldex and PN. EOE has not worked so far, right? Yeah, that's right. Yeah, there's also some other pain indications where mast cells are becoming increasingly implicated. Migraine, interstitial cystitis, to just name a couple of them, are ones where there's a thought that mast cells could be involved. Again, we're working through the full landscape of mast cell opportunities and trying to figure out which ones we will do in parallel with OPG. Got it. Got it. Okay, let's move to 479 next. Okay, great. Okay, so SEP479 is targeting the parathyroid hormone receptor. It's an agonist, a small molecule agonist for hypoparathyroidism. This has been a historically challenging small molecule target. What we're looking at here in magenta is the PTH receptor. The PTH peptide is shown here in green. It's a long helical peptide. The G protein is shown here in blue. Many companies have tried to find small molecules for this target and more or less struck out for many years. We've actually solved this receptor not once, but twice. We found two independent binding pockets where we could activate the receptor with small molecules. Our platform, the Native Complex Platform, allows us to do rapid and iterative structure-based design. In less than a year from initiating medicinal chemistry, we had potent compounds in animal models from both of these binding pockets. This led to candidate quality molecules. Our first compound was a drug called SEP-786. This is an earlier phase I candidate. On the positive side, we saw signs that a small molecule can, in fact, mimic the effects of a PTH peptide. We saw decreases in endogenous PTH, which is what you might expect in a healthy volunteer, as well as increases in serum calcium. Unfortunately, we ran into an unexpected side effect. In phase I, we had to abruptly discontinue the trial because these individuals, we had two individuals with significant increases in unconjugated bilirubin. Subsequently, after the phase I trial ended, we did an investigation, and this was a very clean effect of a very focused effect on a bilirubin conjugation enzyme called UGT1A1. It is fortunate this was not liver injury. There were no signs of liver enzyme increases, and it was reversible. While we were thankful for that, for those healthy subjects, we decided that this compound did not have enough therapeutic window to advance. Fortunately, we had a second compound that was coming up from behind on this. This is fortunately structurally completely unrelated to 786. It binds to a different binding pocket, and we have seen no UGT1A1 inhibition or no signs of bilirubin increase in any of our studies so far. In addition to that, it has improved pharmaceutical properties that we think should project well to once daily oral dosing. Whoops, what happened there? Give me a second. Sorry about that. Had the wrong slide. Sorry about that. The pharmacokinetics translate to a predicted human half-life of between 40- 80 hours, which is good. Some of the data I just wanted to share just briefly is one piece of data in a healthy animal, a healthy monkey study. This is a seven-day PKPD study where we are dosing once a day for seven days, followed by a five-day recovery period. What's important for everybody to know is that in a healthy human as well as a healthy monkey, what we anticipate seeing are decreases in endogenous PTH levels because healthy monkeys and healthy humans have an intact feedback loop. What we're seeing is after just a single dose of SEP-479 in a monkey, we're able to get endogenous PTH levels down about 80% or so. Once the PTH levels are bottomed out, we're then at the point where we can actually start to see dose-dependent increases in serum calcium. What we're looking at here is increasing levels of serum calcium. What we're aiming for clinically in a phase I trial is seeing calcium increases of about 1 mg per dL. Where does that number come from? It comes from the fact that if you look at the PTH peptides like Urivapath and others, if you look at what their starting doses were in hypoparathyroidism patients and then look back at what they did in healthy volunteers, they show increases in serum calcium of about 0.5-0.7 mg per dL. For some individuals where they need to be dosed up higher, if you look back to what those showed in healthy volunteers, it was more in the range of about 1.5 mg per dL. About that 1 mg per dL range is the right range for us. Where is 479 now? It's wrapping up its final IND enabling studies. We've completed GLP-tox studies in rats and dogs where the dose-limiting effect was an on-target effect. It was on-target hypercalcemia. This is exactly what we expected. In order to be extra cautious, we decided to add a third study, which is a monkey study looking at a 28-day GLP-tox study in monkeys. This is currently in progress. If that study ends up being clean, as we anticipate it will be, 479 should be in the clinic in the first half of next year. The monkey GLP-tox, usually you need two species. You do not need a monkey. You are just doing this because you want to cover the bases given what, again, just to rule, just to really be extra careful given 786. Yeah, exactly. So 786 in a subsequent study, I did not mention this, after the phase I was discontinued, showed increases in bilirubin in the monkey, even though it did not show up in the rat and the dog. We do not expect to see anything in the monkey because in the prior study, we did not see that. Just we would not want to be burned twice with something that showed up in a monkey study that did not show up in a rat and dog study. This is out of an abundance of caution in case there happens to be some other random off-target effect that we would see. Yeah. And just for the audience, I mean, I think some people might be wondering, can you talk about what is the FDA's requirement? Are monkeys used typically, or they're pretty expensive, very hard to come by? Those are actually not typically used for GLP-tox studies. Yeah, this is not typical. A typical GLP-tox study requires a rodent and a non-rodent species generally. Rats and dogs will satisfy that. We are doing this really just for our own confidence as opposed to an FDA requirement. Yeah. Yeah. Monkeys are very expensive, and they're very hard to come by. They are. Delays, which delays time. It can be fairly dramatic delays. Any sense, and I know it's probably way too early, is it possible to get data next year from 479, or it's probably going to be sort of first half 2027? Yeah, I think the phase I trial we're looking at is likely to be about six to nine months. Depending on when in the first half of the year we start, that would translate to data from this study in either the late 2026 or early 2027. Yeah. Got it. Okay. I know we maybe have a minute left. Maybe just I know you can't say much about the collaboration with Novo. Maybe on the TSH axis next, and you alluded to it within your pipeline upfront, that this is the NAM, the negative allosteric modulator, too. This This potentially could go into Graves or really thyroid eye disease, things like that. Any sense, kind of where are you in the discovery process? Yeah, this TSH receptor has proven to be a really challenging target, small molecule target. We are developing an insurmountable negative allosteric modulator, very analogous to what we're doing with 631. We think we've now got line of sight to a development candidate, although we haven't given guidance on timing. It's one that we, it's a program we hope to say more about next year. Yeah. I hope next year that the goal is to have a potentially DC and begin to really move through toxicology and IND enabling studies. I think so. Okay. Got it. Okay. Terrific. I think we're just about at time. Just think we're like a little bit over. Jeff, good to see you as always. Thanks so much, and we'll continue to follow closely. Okay. Thanks again for the invitation. Our pleasure. Okay.