Septerna, Inc. (SEPN) September 2026 Conference Transcript

Good morning, and welcome to the Wells Fargo Healthcare Conference. My name is Derek Archilla. I'm one of the senior biotech analysts. And starting us off for the day, we have Septurna. From the company, we have Jeff Feiner, co-founder and CEO. Jeff, thanks so much for joining us.

Yeah, thanks, Derek, and an appreciation to the Wells Fargo team for inviting us.

Well, maybe to start off, you can just kind of provide a little bit of background on Septurna, what you guys are working on, and we can get into the more detailed questions.

Yeah, great. I've got a pipeline slide that I can just share briefly here. So, Septerna is a company working on G-protein coupled receptors, and we've discovered a new way of doing drug discovery for GPCRs, which, based on the few years that we've been doing this, has proven that we can actually unlock a number of difficult-to-drug GPCRs. This includes GPCRs that have peptides as their endogenous ligands, as well as we've got a new way of finding allosteric modulators. This has led to the portfolio that you see here on this slide, which includes our lead program in hypoparathyroidism this is a PTH receptor agonist which which I'm sure we'll spend some time talking about we've got a second program targeting MRG PRX2 which is a targeted mast cell diseases both of those are clinical stage programs we've got behind that quite a robust discovery portfolio the next program that we hope to be able to share information on is our thyroid stimulating hormone receptor negative allosteric modulator which is targeting Graves disease and thyroid eye disease and just recently we announced a fourth program added to our portfolio focused on osteoporosis this is another PTH receptor program and there are actually several more programs under the surface here that we haven't talked about in in addition to that we have a deal with Novo Nordisk targeting a whole whole variety of cardio metabolic targets Excellent.

So maybe starting with 479 as the lead, it would be really good to understand what you'll actually disclose with the phase one readout early next year and what we actually learned from the original molecule 786, some of the key learnings there that you've applied to 479.

So we're tracking towards being able to share the entire phase one data set. That's the SAD and the MAD in Q1 of next year. that is that trial is moving along nicely we did disclose recently an extended half-life for the molecule we were pleasant pleasantly surprised to see that the half-life of the drug is approximately three to four days which we think will actually do a really good job of controlling day-to-day fluctuations on serum calcium levels but in terms of the full readout obviously like all phase one trials we're looking for safety tolerability that's number one. PK, we've already disclosed a little bit about the PK profile, but we'll disclose the full PK profile as well. And then for the SAD and the MAD, the two biomarkers that we're looking most closely at are endogenous PTH suppression and calcium increases. And so maybe it's worth a moment to just share that for those of you who don't think about this every day normal patients normal healthy individuals are different than hyperthyroidism patients in a very fundamental way and that healthy volunteers like you know all of us would be we have intact and an intact parathyroid glands and that allows us to control the parathyroid hormone levels the parathyroid hormones a master regulator of calcium in the body it's in the endocrine loop is so efficient it allows calcium to be controlled very steadily by dialing up or down PTH so in healthy volunteer we're looking for PTH suppression and in fact we anticipate PTH suppression well before we start to see increases in calcium so those will be the main biomarkers that we're looking for and we hope that in our full sad med data set we're able to share that can you talk about some of the precedents from you know prior molecules targeting PTH, and I guess, you know, some reference points, some benchmarks that you guys would be looking for to kind of help de-risk future trials? Yeah, fortunately, we've had the PTH peptides pave the trail for us here, and if you look back at the effective doses in hyperparathyroidism patients for a drug like uropath, as an example, and look back at what that drug did in its phase one healthy volunteer study, there are some clear learnings in terms of the magnitude of effects that we hope to see with both PTH and calcium increases to identify a dose that may translate into hypothyroidism patients and and just give you some numbers here what we're looking for in PTH suppression is a decrease of about 50 percent or so at that point that's when calcium really calcium increases generally start to kick in and we'd be looking for increases in serum calcium in the range of about 0.3 to 0.5 milligrams per deciliter. That dose should, based on precedent with PTH peptides, translate actually very well to a starting dose for hypoparathyroidism patients. Another thing to remind everybody of here is that hypoparathyroidism patients on an individual-by-individual basis need to be titrated into the right drug levels, but that starting dose is an important point because Because it does, in the case of EuropeFath, it does control a decent number of, a decent percentage of the population, and others need to probably only go up a little bit from that baseline.

Got it, so I guess that raises the question, how do you think about titration given the half-life that you've already kind of communicated, three or four days, I mean, seemingly is very good. So I guess, how do you think about titration and also phase two, do you have to look at multiple titration schedules, or will you kind of hone in on one? Like how many arms do you think that future phase two could look like?

Yeah, so the goals of that first phase two data, first phase two study in patients are pretty simple, obviously, to show that we've got pharmacology, but also to figure out what the starting dose is and that titration protocol. Fortunately, again, with our half-life being actually not that far off from YorvaPath's apparent half-life, Urvopath, you know, is a sustained release form of PTH, and while the PTH peptide itself is short-lived, their sustained release system mimics a half-life of about two and a half days, and we think with a half-life of three to four days, even if it's a bit longer than that, we should be able to leverage their learnings on how to titrate patients, and we will be thinking about ways to streamline that potentially a bit further to see if we can improve titration there.

Got it. And then in terms of 479, you know, oral convenience, a big differentiator in and of itself relative to the injectable peptides or injectable PTHs. But I guess, you know, how do you think that there's, you know, potential other opportunities or other areas of differentiation, and how would you incorporate that into Phase 2?

Yeah, in terms of differentiation, obviously oral is a big thing. We think it will allow for potentially better patient adherence, potentially better ease of use. We think, importantly, it may allow effectively PTH replacement therapies to move earlier in the disease course in terms of potentially going after more mild to moderate patients as well, just to sort of lower the barrier there. there are a number of patients who really don't want to take injectables. It's important to realize that hyperparathyroidism is also a lifelong condition, and a number of patients that may already be well-controlled on injectables over the long haul may want to switch to an oral anyway. So we think oral is not something that necessarily should be discounted, But once we show that we're able to have effects on the PTH receptor biology, we hope we're able to show additional effects beyond just calcium control. And there are some learnings from the earlier trials that may lead us to looking more closely at some other endpoints like urinary calcium and other patient symptom-based markers.

Got it. I mean, given the fact that it is an oral, I mean, how important is it to, you know, essentially recapitulate a URBPATH efficacy profile? You know, is there a margin to be even slightly less effective and still be very successful commercially?

Yeah. I mean, we're going to be aiming for that profile or better. You know, whether or not they're going to be, you know, not quite as good, I think we'll worry about that if we get there.

Fair. And then maybe just talk about CNS penetration and how important that is, or not important that you think that is, and what's kind of the level of evidence, you know, in terms of, you know, PTH therapies?

Yeah, this is a question that does come up quite frequently. We don't think there's any evidence that CNS levels are important. So there's a, we think that the main receptor for PTH's activity is the parathyroid hormone 1 receptor, PTH1R, which is present in the bone and the kidney. That's where it has most of its effects on controlling calcium. It also controls phosphate as well. That's an important thing that isn't talked about a lot. One of the reasons people have started to focus a little bit on the CNS is that brain fog is an associated symptom for a number of patients, and there is a second receptor called PTH2 receptor that's in the brain. Although PTH2 receptor is in the brain, its main ligand is actually a different peptide. It's not PTH, it's a peptide called TIP39, and TIP39 is also in the brain. So both that receptor and that ligand are in the brain, and there's no evidence to date at all of the role of PTH going into the brain and and hitting that receptor and having some effect on the other hand if you look at brain fog as a symptom a lot of it really could be explained by calcium control as well as phosphate control both of those things have been they have been shown to you know to affect cognition and memory and things like that as well got it and then maybe just to revisit, you know, the 786 experience.

So, you know, ran into some trouble on the safety side, but like, you know, you were already dosing patients, right? And so I guess, you know, what did we learn from that? And, you know, in terms of the trends that you were already seeing on endogenous PTH suppression and calcium increases, you know, were you seeing things like, was it kind of acting as you would expect from a PD perspective and, you know, outside the safety?

Yeah, 786 was tracking actually quite nicely. So although we never disclosed the actual data, we were seeing early signs of on-target pharmacology. We saw endogenous PTH going down, just as I had mentioned earlier, and calcium levels beginning to go up. We didn't think we were quite at the level that would be a starting dose when this unfortunate off-target effect kicked in. But potentially the most important thing we learned is that a small molecule can mimic the effect of a peptide. yeah and that gave us confidence going in with 479 even though 479 is a completely different molecule completely different structural series by it so a completely different binding pocket in our preclinical models it does everything like a PTH peptide got it and then again just kind of revisiting our prior comments but spelled out so I mean it's if the data look good in the first quarter I mean that's probably very predictive of you know being successful in phase two, phase three.

Is that a fair statement?

I mean, I think that is a fair statement. This is a target where there's actually been excellent correlation from animal models into healthy volunteers into patients. Every molecule that has gone along that pathway continues to work. So we do think that our phase one healthy volunteer data, if it shows the magnitude of effects that we just talked about a minute ago, we think that should bode quite well for working in hypertherosom patients. The physiology is exactly the same in the bone and the kidney in a hyperthyroidism patient as a healthy volunteer.

So maybe just you brought up osteoporosis. I remember during the IPO, you guys were talking about that, and if there were some regulatory changes and things like that, that might be an opportunity. So maybe talk about that. Your program is very early, but maybe just kind of talk about your experience with PTH and how that's all relevant to osteoporosis.

Yeah, so our learnings from having worked on PTH for a number of years, we think are going to bode quite well in this osteoporosis program. So with regard to PTH, it's well established as an anabolic therapy for bone formation in osteoporosis patients. There's injectable peptides. One of the things that we know we need to do is make a shorter-acting drug. So we now have a three to four day half-life drug for hyperparathyroidism, but for osteoporosis we need basically a short pulsatile delivery that could be anabolic to bone formation. So our team's been actively working on making shorter acting molecules, so we'll have to be a completely different molecule than 479 just for clarity. In terms of what we talked about a couple years ago in terms of regulatory changes, things have played out almost perfectly as to what we were hoping for there the FDA a little over a year ago a little less than a year ago now changed their regulatory guidance in terms of allowing bone mineral density as a surrogate biomarker and registration trials and TerraBio is has been paving the way there in terms of getting the FDA to agree to such an approach and what that does it allows a much smaller clinical trial we don't need thousands of patients we also don't need to wait into to have an event driven trial looking at

fractures so we think that's a that's a major breakthrough in the asteroporosis field and we're excited to see a lot of interest from others in the field and excited to participate ourselves I guess you know you're kind of you have to choose a development candidate you had to you know kind of move forward you know with the early stage program but is this something that you would do yourself now because it's a bone mineral density endpoint versus having a huge spend to run an event-driven trial like you know how far can you take it or I presume that there's going to be a lot more interest now you know in this space where it's been kind of left not for dead but just little innovation because it was a huge indication undertaking for small companies so yeah how do you think that will evolve and how do you guys think you guys will approach it yeah at this

point where we believe we can take it you know well well into development and and possibly possibly further than that so you know we'll have to think about what you know September as a company looks like a few years from now but I think this could fit really well into our our future portfolio you know at some point down the line we may want to have commercial partners to just you know to share in the commercial load because osteoporosis is so prevalent. But I think in terms of getting it all the way through clinical development, now with the size of trials that may be feasible, we could take it all the way.

Got it. So maybe shift gears off PTH to MRGPRX2. So we saw the readout for EVAMUNE's X2 program and prior the S-EHM data. So I guess where do you think kind of the field is now on this target? You guys have kind of thought about essentially kind of, you know, de-emphasizing or de-prioritizing, you know, some, like at least CSU, but how should we think about this asset as part of your, you know, kind of pipeline portfolio?

Yeah, so we're actually still very, very excited about this asset. We believe we've got a compound that we think has the best-in-class profile. It's got great pharmaceutical properties, once-a-day drug, 24-hour half-life, very safe in phase one. And importantly, we were able to show a very strong pharmacodynamic effect in our phase one trial. The trick with this target, though, is figuring out what the right indications are. There are a ton of mast cell-driven diseases, and they may differ from each other in terms of what the appropriate ligands are, what the appropriate amount of receptor inhibition needs to be. One reason we're excited about our comp and why we think we potentially have the best in class profiles our ability to completely turn off the receptor so this drug is a negative allosteric modulator and what we've been able to show is that the compound when it binds the receptor causes a structural rearrangement that completely blocks the receptors ability to bind to any endogenous ligand this is a receptor that also has literally dozens of endogenous ligands all kinds of neuropeptides inflammatory mediators and such and we think it could actually be really important if we can just find the right indication so where's the field I think the field is looking for the right right set of indications here although we've decided to not do a full-blown phase 2b CSU trial after even means and essence results we do think that there is pop still a possibility that a better compound could work in those indications as well as other skin indications but our strategy obviously that's that's a higher risk now but our strategy has been is now to try to kind of survey the landscape of indications as cost-effectively as we possibly can so we're looking at fairly capital-efficient signal finding trials across a variety of different indications we're looking at indications where there's there's good evidence of mass cell involvement in the disease, good evidence of the target being present in those tissues, and ideally as we select indications to survey different tissue types. So at this point we're still doing our work trying to figure out which indications to go after but hopefully to have hope to have more to say about that in the coming months. I mean what are those trials you know look like are they individual small phase two A's and or are you talking more like a basket trial like how do you kind of approach that to generate at least POC and kind of get people more excited about the next two and then the biology yeah although it may functionally be like a basket trial probably it would probably more like individual phase two ways in reality because the the indications the investigators the sites could be different from indication to indication but we're looking on the scale of dozens of patients as opposed to hundreds and as we're designing these trials we're hoping to find a pretty

clear signal in each of those indications to justify the larger investment in the in the multi-hundred patient phase two to trust okay I guess do you think you know some of the will give me getting data for atopic derm I think from even being fairly soon so I mean do you think that has solid rationale for AD or do you think that's kind of less priority for you guys in in terms of like the mast cell biology in AD?

Yeah, I mean, we've decided to not prioritize that one. Initially, obviously, if they show great data, we'll revisit that. Yeah, we'll absolutely revisit that. We thought within the skin conditions, the urtic areas had a little more rationale. However, one of the main features of atopic dermatitis is itch, and this receptor actually could play a major role in itch. So the jury's out. We'll see what their data shows and then decide where to go from there.

Got it. So I know you highlighted a little bit earlier kind of the TSHR, you know, NAM that you guys are working on. So maybe provide a little bit more detail there and kind of the opportunities that you see within potentially, you know, Graves and even beyond in TED and things like that. But, you know, I guess what has been the trick of really trying to drug this with an oral?

Yeah, the TSH receptor, which is the main receptor responsible for all the symptoms associated with both Graves' disease and thyroid eye disease, both those conditions are autoimmune conditions where patients develop autoantibodies that bind to the TSH receptor, cause hyperthyroidism in the thyroid gland, proptosis behind the eyes. this receptor's turned out to be a tricky one for us. It's one that we've been working on for multiple years. We've developed in the past a number of compounds that do exactly what we would hope to do, which is to prevent the receptor from being activated by a whole variety of different patient antibodies. So one thing that everybody should remember here is that every patient develops their own autoantibodies. They're often polyclonal as well. They're high titer, high affinity. And so you need a drug that can really turn off several things at once if you're going to do that. Although we've found those previously, we've had trouble optimizing the pharmaceutical properties and potency at the same time. We've had compounds earlier where we shared some data that worked quite well. However, the doses would have been probably too high. And so what we've worked on over the last year or two is trying to figure out how to thread that needle. How can we get the optimal potency and the optimal pharmaceutical properties to have a reasonable human dose? And we now think we've got line of sight to that that sort of development candidate and hope to have more to say about that in the coming months Understood.

I mean as you envision kind of the Development path there. I mean does that similar to what you need to do? You know with the you know four seven nine and multiple kind of trying to figure out titration and dose or do you think you'll have a better sense of kind of how to dose this, you know, because we also have kind of precedence with TSHR antibodies that are currently in development.

Yeah, that's a good question. So, you know, one interesting sort of parallel to draw with the 479 program is that we think there's gonna be phase one biomarkers that are actually quite relevant. So in the PTH program, which we just talked about, we're expecting to see endogenous PTH levels to go down. The TSH receptor has almost the same thing, but it but but just the opposite in the case of the TSH receptor TSH levels should go up with it with our drug and that's something that that that should allow us to have a really solid signal in phase one that again should be predictive of future effects once we get into graves disease patients and thyroid eye disease patients the thyroid space in terms of development is It's actually one that hasn't had a new drug approved in 30 to 50 years, I can't remember when it was. It's been a long time. And there are a number of companies now trying to establish what that development path is going to look like, whether it's Graves' disease, thyroiditis' disease is a little more established now. But on the Graves' side, this is something that needs to absolutely be figured out as we go. But we've got some ideas there that we'll share as we get further on.

And then, yeah, maybe just talking about the NOVO collaboration and some of the programs that you've generated there. And I guess how should we think about next external visible milestone that we can kind of understand where that program is kind of trending and ultimately the value that can come to SEPTERNA?

Yeah. So just maybe a little bit of reminder on what that collaboration involves. It involves five targets, three of which are disclosed. That's GLP-1 receptor, GIP receptor, and glucagon receptor. There's two other named but undisclosed targets. It involves four programs running at any point in time. And we think that this collaboration does have a lot of potential high future value for the company. We received a nice upfront payment. Unfortunately, in terms of sharing data and where we are on that, that's really in Novo's hands. So they control all external communications, which they bought the right to do. But one thing that if investors want to sort of track how things may be going in the absence of that is to track our financials. So in addition to the $195 million up front, over the course of just the first year of the collaboration, we've had over $40 million in reimbursed expenses, R&D expenses, as well as a few smaller research stage milestones that have come through. So that's one way to sort of track things. We're excited about the progress so far, and we believe that the NOVO leadership team is Got it.

So you think at least it seems like things are progressing and it remains a fairly decent priority for them?

Yeah, progressing very well.

Got it. Okay. And then just kind of from the broader platform perspective, like, I mean, you talk about, you know, new programs that you'll disclose and I guess, you know, talk about the utility of kind of your native complex platform, how versatile is it? And, you know, other types of, you know, value creating things. So whether it be developing new candidates that you guys will take forward yourself or developing partnerships around the platform?

Yeah, so we've been really pleased with the Native Complex platform. So it's a platform that we developed completely from scratch at the beginning of the company, first starting in 2020, and we continue to invest in the platform even to today. What it has shown us over and over again is that we're able to drug previously difficult to drug GPCRs. In fact, for every program that we've started to date, we've been able to find a molecule with the exact profile. that we want, and often more than one molecule. One testament to that is the PTH receptor program, where we found not only one way to activate a very difficult to drug receptor, but two completely different ways to activate it. All of our other programs, I could say the same thing. And what we found more often than not are basically cryptic-inducible pockets within these receptors that the world didn't have a way of finding previously we've got a lot of structural biology technology within within the platform in fact we've probably solved close to 200 high-resolution 3d structures of proteins at this point in time this drives structure based drug discovery in an unprecedented way so again we think a couple of the killer applications are small molecules for peptide gpcrs allosteric modulators, both negative allosteric modulators, as we've talked about in the case of X2 and TSH receptor, but also positive allosteric modulators. We've been able to find those. We've been able to find antagonists. And again, we think there's a huge number of indications. From a target strategy, our approach has been largely focused on well-validated targets, ones where there's a good biological story to it. all the programs we've talked about today at least have some solid biology behind them. We do think there's also opportunities for orphan receptors. We've got some techniques there. But for the most part, we're focused on well-validated targets. And beyond the ones that we've disclosed today, we have a handful of other programs that are at earlier stages in the works. And as they start to hit certain points of maturation, then we'll add them to the pipeline excellent I mean we get this question often but you know with the native complex platform how much you know is IP protection around the platform versus you know kind of technical know-how yeah it's it's it's both and one of the major you know forms of IP is is trade secrets and we continue to build technologies even even to this day we've got we've got new parts of the platform that we've introduced just this year and we're not talking about about those but they've enabled us to move a lot of things forward as well gotcha and then

just kind of the question like for 786 you know how did that experience you know that reset you know around that molecule kind of change the way you know you select these future candidates and how you're kind of evaluating them and you know you did a really kind of good I don't know if I want to say like post-mortem um on 786 in terms of going back really understanding how that safety signal emerged and even developing um you know more robust animal testing to kind of you know make sure that it's not going forward so yeah how have you kind of taken that experience and and are you applying it to you know new molecules yeah so we think that 786 experience is really quite molecule specific um at the end of the day we just happen to happen to run into a an unexpected

finding we'll never run into that particular unexpected finding again so we've introduced that into our system but just as we've been going you know one of the things that it does emphasize is always having sort of backup and follow-on compounds and what the native complex platform has allowed us to do is to have structurally distinct backup compounds just in case in case we happen to run into a an unexpected finding we happen to be in a great position when the 7, 8, 6 event was observed, and we want to be in equally good positions for other compounds. But another kind of set of development philosophies that as our company has matured, we're starting to integrate into all of our programs. we're we're starting to move forward chronic toxicology studies just generally earlier in our art of our development path I didn't mention this for 479 but we we have already started chronic safety studies there just it's wanted to de-risk the compound but but also importantly we think that as we get quickly from phase one you know sort of proof of biomarker driven proof of principle we want to be able to go into phase two studies with patients that we can do open label extensions and having that chronic toxicology study early will allow us to be more efficient in development there another thing that we've started to do really for all for all of our programs is to enter phase one often we'll enter that with a capsule formulation but we try to get to tablet formulations as fast as we possibly can and for six three one is an example we had a tablet formulation even before starting phase one which which we think will allow us to speed things along in development this is 479 capsule currently and you're shifting the tablet or we've got both you got both all right and that's both are those both being tested in the phase one yeah they're both being tested in phase one well you split out the data to see both and do you expect any major changes between no we don't we don't expect major changes so yeah we'll share all that data excellent anything else that we should be kind of looking forward to in 2027 you know beyond kind of 479 that seems like it's the key update but maybe just sketch out for us you know how how the next 12 to 18 months look yeah so obviously lots of folks on 479 as I mentioned we are hoping that the TSH receptor program starts to become an important one for us in 2027 and hopefully somewhere along the way we We will share some preclinical data on the osteoporosis program, as well as updates on the MRG-PREX2 program, and who knows, maybe there's another program that emerges as well. Well, Jeff, we'll leave it there. Thank you so much.

Thanks, man.