Guggenheim 3rd Annual Healthcare Innovation Conference - SEPTERNA INC

All right. Thanks, everybody, for joining us at Guggenheim's third annual Healthcare Innovations Conference. I'm Seamus Fernandez, one of the senior biotech analysts here at Guggeheim, and I'm really pleased to be joined by the management team from Septerna. Immediately To my left is Jeff Feiner. To his left is Liz Bott. And to her left is Gil Labouchere. I am really terrible. Okay, close enough. So CEO, co-founder, president and COO, and CFO. So Jeff's going to take us through, you know, just sort of a backgrounder, quick backgrounder on Septerna, but definitely one of the stories that we're particularly excited about here at Guggenheim. Yeah, thanks, Seamus, and thanks to the Gugkenheim team for inviting us. So I'm going to run through a few quick slides, and my clicker is not working. Our discussion today will include some forward-looking statements, so please take that into consideration. I want to jump right into our pipeline. So Septerna, from the outset, has been a company focused entirely on GPCRs or G-protein-coupled receptors. and we found a new way to do drug discovery for GPCRs and we don't have time today to go into our platform but it's quickly yielded a portfolio that we're quite excited about. So four programs are shown here. I'll start from the top. SEP479 is a parathyroid hormone receptor agonist, small molecule, that is in a phase one trial right now and we anticipate having that phase one readout in the first quarter of next year. Newly announced just last week is SEP204. This is a thyroid-stimulating hormone receptor, negative allosteric modulator. It antagonizes the receptor. It's a small molecule as well for Graves' disease and thyroid eye disease. I'll have more to say about both of those programs. We also have an MRG-PRAX2 small molecule negative allostatic modulator called SEP631. This one is through a phase one trial. So it's between phase one and phase two, and we are currently evaluating what mast cell indications to work on there. And then also recently announced is a fourth early but discovery stage program in osteoporosis. This is a second approach to the parathyroid hormone receptor, where we've got also an agonist, but we need to have a short-acting agonists for osteoporesis, whereas, as we'll spend, I'm sure, a bunch of time talking about. For hyperparathyroidism, we want a long-acting small molecule agonist. Below the deck there, we've got a number of earlier research stage programs, and we've also got quite a substantial collaboration with Novo. This is a program that involves five targets, four concurrent programs, is currently off the races and moving along quite well so I'm gonna quickly just give you guys a some grounding on those first two programs SCP 479 this is the hyperthyroidism program this is a very challenging receptor one that our platform did did crack multiple times so what you're looking at here is the PTH receptor in magenta the P th peptide in green G protein in blue we found multiple ways to activate this receptor with small molecules had been a historical drug discovery challenge so where our platform really showed its colors. And we ended up with SCP-479, which is a compound that we're quite excited about. I'll show you a little bit of data in a monkey, and then we'll spend most of the time talking about the phase one trial. But we've got a compound with great pharmaceutical properties, as well as a half-life now that is in the range of about three to four days. This is a health volunteer study that's ongoing. But quickly, to show you a little bit of data, preclinical data. This is a monkey study, seven-day healthy monkey study which is meant to simulate what we would hope to see in a healthy volunteer patient. So healthy patients, healthy subjects as well as healthy monkeys have intact parathyroid glands and since the endocrine feedback loop is so efficient the first thing we anticipate seeing is a decrease in endogenous PTH secretion based on the endocrine feedback. That happens actually very quickly. And then once we reach a certain level, there's a threshold, we start to see serum calcium levels go up, as you start to on the graph on the right. And if we take the lessons from the PTH peptides that have been in the clinic and approved, including urovipath, what we anticipate to see in a healthy volunteer that should map to a hyperparathyroidism patient is a decrease in endogenous PTH on the scale of about 50%, and then an increase in serum calcium on the scale of 0.3 to 0.5 mgs per deciliter. This phase one trial is ongoing. It's a standard single ascending dose, multiple ascending dosing design. It is happening in Australia. Safety tolerability is first and foremost. These are the important things we look at. PK I just mentioned, and then the two key biomarkers endogenous PTH and calcium we showed that this compound has a in the sad portion of the trial a half-life of about three to four days so we extended the duration of the multiple ascending dose portion to 14 days to try to approach steady-state dose levels and as I mentioned what we will be looking for are changes on that scale of about PTH going down about 50% and calcium going up about, let's say, 0.5. And we anticipate these results in Q1. Second program I want to just kind of kick off with and introduce you to is our new program focused on Graves' disease going after the thyroid stimulating hormone receptor. This is the receptor at the heart of Graves disease. Graves patients develop autoantibodies that bind to and activate this receptor, both in the thyroid gland as well as behind the eye, leading to the changes of Grave's and thyroid eye disease. It's a receptor that undergoes a pretty significant conformational change. You can see that there's a very large extracellular domain. I'm showing you two different conformations, inactive conformation in blue, active conformation in magenta. SCP-204 binds in the transmembrane domain and prevents the activation of the receptor even when it has an antibody bound to it, which is exciting. And SCP-2004 is our development candidate. It's a potent oral small molecule. It has demonstrated inhibition of the receptor in the presence of Graves-derived antibodies. It's highly selective for this particular receptor. There are two closely related receptors, FSHR and LHR. These are reproductive hormone receptors. And as Graves is a disease of largely women of childbearing ages, we want to prevent the activation of those other receptors. I'm sorry, prevent the inhibition. of those of the receptors. And so we've got a very high degree of selectivity, over a thousand fold, and we've got robust PKPD demonstrated in healthy animals, mice, rats, dogs, and monkeys. We don't have time to share all that today, but what we expect to see in a healthy animal is, you can think of it a bit as the opposite of the PTH program. We see TSH levels going up and then at a certain threshold thyroid hormone levels starting to go down the compound has excellent pharmaceutical properties we were projecting a human half-life of about 20 to 40 days here we've completed GLP tox studies in rats and dogs and hope to be in the clinic with this this molecule in the first quarter of next year as well so I'm going to just show you a little bit of data this is this was presented at a the American Thyroid Association conference just last week it's a rat study where where we've dosed the rat with a human-derived, human-patient-deried antibody. This is a Graves patient antibody. And when you dose the rat on the graph in the upper right-hand corner with this antibody, 18 hours before dosing 204, you see thyroid T4 hormone levels going up. And then we're studying three different doses, one, three, and 10 milligrams per kilogram twice a day in a rat. We think it's a once-a-day drug in a human, but you can see that the middle two doses, the lower two doses normalize thyroid hormone levels, whereas the high dose suppresses it. So this is kind of what we would anticipate to see, but this gives an increasing suggestion that we may have dose optionality when we get into patients hopefully be able to either dose to thyroid hormone normalization or go to a full suppression, depending on what we want to do. last piece of data is in a mouse model this is where we've dosed that Graves disease antibody chronically now for six weeks actually we dose it for a total of eight weeks and by by week six we've got a Graves phenotype changes in the thyroid gland and behind the eye we're looking at thyroid histology photos where we we have significant changes in in the Graves mice that reversed with the drug so the histology changes the thyroid size also started to normalize and these and these graves mice also develop proptosis so this is effectively a mouse model of thyroid eye disease it's a new model that we developed in-house so you can see the middle photo there with clearly bulging eye and you can start to see some reversal of that as well so these are data that we're excited about and as I think I've already summarized the main preclinical findings. And like I said, we're hoping to be in the clinic in the near future. And so we can just kind of maybe stop and have our pipeline chart there. Great. So maybe just to follow up on the TSHR, it looks like you had an active control in that data set. So can you just maybe help everybody understand the importance of the K170? Yeah. So K170 is a TSH receptor autoantibody as well. This one's a blocking antibody, though. And so what it does is, and there now are antibodies that have been in clinical trials. K1 70 was at least in an early clinical trial and showed that it was able to reduce orbital proptosis in thyroid disease patients. So it's a good positive control for us. You can see that at our high dose, we're able to be in a similar zone to K170 or even a little bit better. Great. Maybe just to kind of take a step back, one of the things that I think is interesting about your choices of, you know, of particular disease states and opportunities is the ability to identify signals early with a novel oral approach. You know, why choose that and why choose these two particular disease States? Yeah, it's a great question. So we, it it's really a platform and a company drug discovery philosophy. We've tried to select targets for the most part where there is really good biological validation, things that we can expect. And every one of our programs that we've picked so far, we expect to learn something very significant in a phase one trial. The GPCR space is huge. There's so many things that could go after. In terms of the small molecule opportunity, one big opportunity space that we looked at, both these two programs represent, I think, sort of unmet opportunity spaces within the GPCR field. One is finding activators for, small molecule activators, for peptide GPCRS. That's been historically challenging, and so the PTH receptor is a good example of that. As part of our Novo collaboration, the inquiratin receptors, well known to everybody, are another example of where if you had a small molecule that could do what a peptide could do, that could have have great benefit, and in many cases, the peptides are sort of paving the way clinically, but we think we can replace it. The other TSHR is a different example, where we found an allosteric modulator. That's also been historically challenging for GPCR targets, and it's a case where, again, our platform is shining. We're able to find small molecules to do what, let's say, a blocking antibody would do. And one outlier, I think, on the pipeline list to some might be the willingness to go after osteoporosis, whereas you outlicense the Ingritin programs. Can you talk about sort of that as a capital-efficient decision for the company? Maybe I'll let Liz take this question. Yeah, so osteoporesis is actually a natural program for us to go efter, just given the long knowledge about PTH in that space. So, what's different in terms of hypoparathyroidism versus osteoporosis, in osteoporesis you need a short-acting compound, something that's going to be more pulsatile in nature. That's what teraparotitis told us as it relates to an approved drug in that space. And so, it was natural, given the wealth of information we have on PTH, to think about osteoprosis. But the field in osteobrosis actually has changed quite a bit as well. A new initiative called the SABR Initiative really kind of redefined how endpoints are there and such that we have the ability to really actually fully develop that now, such the bone mineral density is actually the final endpoint there. And that enables us to really actively really pursue this program really quickly. And I would say the final thing is there's a huge unmet need in osteoporosis. That's the other thing that really drives us as we think about choosing targets. Jeff talked about the biological validation. We think a lot about really where the unmet needs is, where a small molecule could fit really specifically into that space. In osteoporesis, there's huge unment need for anabolic agents that are oral agents for patients, or a lot of patients are untreated. And so we really see a great long-term opportunity, and you pair that with our understanding of PTH. It's actually, it's a really logical thing for us to be focusing on. And one other, you know, dynamic that I think is interesting in the market is continuing to gain more learning from, with the availability of oral incretins, the availability of oral immunologic agents. You know, an oral PTH product, one might think, well, actually, you really want to go, you know, everybody should be on an oral PTH drug across the board. But what is your own market research kind of showing you in terms of the reality of being able to unlock, you Know, patient or activate patients to really pursue treatment with an oral medication versus the current daily oral? So let's talk about hyperparathyroidism specifically. And so I think one of the things to think about particularly there is, certainly would be true with osteoporosis as well, is that these are lifelong therapies for hypoparathyroidism patients. Patients are diagnosed early in their life. They're on therapy for 40 years. And so being able to have an oral agent is really very important to them. Andso as we think about the current landscape right now, we do believe actually all hypoparythyroidism patient should be on PTH because it's a hormone. It's a replacement versus current standard of care being calcium and vitamin D. The current agents which are approved, the once-daily injectables, again, those are daily injections, are probably being really the uptake right now is primarily in the most severe patients, patients who can't get even control under current standard-of-care and may be really at risk of going to the emergency room a couple times a year because they're either hypercalcemic or hypocalcemic. However, there's a whole swath of patients that are, I would say, more moderate in nature. maybe their calc stones generally control most of the time but they still have a lot of other symptom ontology they have urinary calcium is not where it should be they're taking a huge pill burden relative to taking calcium they may have brain fog still and so this is where we think an oral agent really has the opportunity to unlock more patients that really expand the treatable patient population again in a disease where hormone replacement therapy really should be the standard beyond just what calcium and vitamin D can do from a replacement perspective. Great. And, you know, Jeff, can you talk about the importance of this longer half-life in particular? I think it's one thing that's been proved out by your path very effectively, but, you Know, what is the importance and what are you specifically looking for in the phase one data as we kind of progress towards that catalyst next year? Yeah. So these, these patients, because PTH is the kind of master control of calcium levels, we really want full-day coverage, and we want a very low peak to trough from day to day, and we set out to intentionally try to discover a compound with a very long half-life, and with PTH, or with 479 having a projected half-Life of three to four days, we think we can actually have pretty good stabilization. It's been proven out. Uropath has an effective half-life of about two and a half days, which is quite good at stabilizing that, and that is done quite well clinically. And so we wanted to be sort of at least in that ballpark, and I think three to four days is in the right range there. With regard to what we We hope to see, first, in healthy volunteers, we hope to see changes in PTH, in doses of PTH going down, probably about 50% or so, hopefully in that zone. And then serum calcium going up around about 0.5 mcs per deciliter. You can only take a healthy volunteer up so far ethically to avoid putting them at risk of hypercalcemia. So we will hopefully dose up a little bit higher, higher than 0.5 mgs per deciliter, but we'll see where we end up. Now, when we start to think ahead to going into a patient study, the most important thing for us in a first patient study or first phase two study in hyperparathyroidism patients It's determining what that starting dose should be, because hyperthyroidism is a disease where every patient will get titrated to their own optimal dose, and we need to figure out what that starting dosage should be and what the titration protocol should be. And we think we can do that with a reasonable number of patients, and maybe two to three starting doses. We'll have more to say about that when we finish this trial, but hopefully two or three restarting doses in a phase two, where we would hopefully start to see some control in hyperparathyroidism patients and then be able to identify the final dose for a phase three trial. Got it. And, you know, one of the characteristics of PTH and the trials that have been done so far is having flexibility in dosing. What is sort of the realistic dose range that, and without telling us the specific doses, But what would you say is a range that you feel confident? Yeah, we haven't said anything about actual doses, but we do think it's going to be quite a reasonable once-a-day pill size. Now, the number of doses is a really interesting question. So Yorvapath is currently approved, I think, at about eight different doses. So it is a, most pills don't have eight different dose sizes, but this could be an indication where we need several dose sizes. We will figure that out as we get into phase two, but we think it's going to be a very reasonable size. Okay. And just in terms of, you know, matching that, you know, sort of very flat profile, is it does it just kind of come down to identifying the half life and being able to model your molecule? And I guess the last piece is, is just how well behaved is the molecule to your knowledge? Yeah. So we know, we know a little bit from our, you know, phase one, sad study, that's what led us to say that the half-life was three to four days. It was between three and four days in every cohort that we tested. So it was actually not a huge amount of variability from person to person. Now, even if there was variability from person to person because it's a titration disease, each individual, individual variability will be sort of dialed out. We are along the way, our team is building and continues to build a quantitative systems pharmacology model. This is a very important aspect of this program. Every healthy subject, every patient, we're going to continue to improve that model, and that will allow us to predict exactly how to dose in the future. Got it. And, you know, in terms of a phase two, how should we think about that progressing, and is there any reason to do kind of a Phase 1b in patients themselves along the way? Yeah. I think we're going to just go straight to a phase two in patients. Just from a timing standpoint, if we finish up this phase one in Q1, we think it's kind of second half of the year to be in patients, one of the things I haven't mentioned is that we want to actually get our chronic toxicology studies out of the way before we start that phase two study. So we have started chronic safety studies, animal safety studies. And the reason for that is if we have a patient that is part of our Phase II trial and they're responding well to the drug, we want to be able to roll them over into an open-label extension study. Right. Okay. And typically the OLEs can go out as far as 52 or 108 weeks? Indefinitely. Oh, we can keep going. Definitely. Okay, great. Let's just talk a little bit about Graves itself. the dynamics of the challenges of bringing a program here. What were the trade-offs that you needed to kind of get to conviction to be able to advance this next year? Yeah. Maybe I'll talk about the molecule and then Liz can elaborate on the space and where we're going. In terms of the molecule itself, this was a drug discovery challenge. This took us longer than all of our other programs to get the right molecule. We had to dial in all those properties that I mentioned in terms of potency and selectivity and end up with great pharmaceutical properties. And we had several compound series earlier than that that ran into dead ends in terms of the human dose projections were too high. So we had to have good enough pharmaceutical properties that we thought we could have a once daily pill of a reasonable size. And, you know, we're excited about the molecule that we've got now. In terms of The Grave Space, I don't know if you want to elaborate there. Sure. One of the reasons we were excited about TSHR was really kind of the dual biology to work on both Graves' disease as well as thyroid eye disease. It is the one target because that's where you're generating the autoantibodies that really impacts both Grave's disease as wel as thyroid eyes. And within Graves disease itself, while antithyroid drugs are really kind of certainly the current standard of care, a lot of patients who are intolerant to them, they relapse on them. They may be on them for five years and just can't get off them because they can't get into remission. There are also many patients that have mild TED along the way, and current standard of care ATDs don't address that. When you get, obviously, into more severe TED, you need much more advanced therapies like TPEZA. So as we approach this space, we think from an opportunity perspective, there's certainly a lot of patients across the spectrum who are really in need of alternative options right now. And the reason why we're really excited about TSHR is, as I said earlier, is it really, from a mechanistic perspective, can hit both diseases. And again, our approach here versus many of the other ones out there is a once-a-day oral. And, again, we think that's going to be a compelling option for patients. Great. Maybe, Gil, just to wrap us up, the cash runway. Yeah, we just reported yesterday. So we reported over $565 million at the end of Q3. And that takes us through at least through mid-2029. So, we're in a very strong financial position. And that includes powering the entire pipeline that we've gone through today. And it excludes any milestones we get from Novo so we feel really good about where we are a lot of optionality on the capital side excellent exciting times and you know particularly exciting to see just how capital efficient you've been able to build a pipeline like this from scratch completely from scratch yeah so congrats thank you so much looking forward to a very actually quite busy 2027 ahead yeah thanks again for the interview thanks so much