All right, thanks everybody for joining us at Guggenheim's Third- Annual Healthcare Innovation Conference. I'm Seamus Fernandez, one of the Senior Biotech Analysts here at Guggenheim, and I'm really pleased to be joined by the management team from Septerna. Immediately to my left is Jeff Finer, to his left is Liz Bhatt, and to her left is Gil Labrucherie. I am really terrible.
Perfect.
Okay, close enough. CEO, Co-Founder, President, and COO, and CFO. Jeff's going to take us through 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 Guggenheim team for inviting us. I'm going to run through a few quick slides, and my clicker is not working here. Our discussion today will include some forward-looking statements, so please take that into consideration. I want to jump right into our pipeline. 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. Four programs are shown here. I'll start from the top. SEP-479 is a parathyroid hormone receptor agonist, small molecule, that is in a phase I trial right now, and we anticipate having that phase I read out in the first quarter of next year.
Newly announced, just last week, is SEP-204. 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 MRGPRX2 small molecule negative allosteric modulator called SEP-631. This one is through a phase I trial, so it's between phase I and phase II, and we are currently evaluating what mast cell indications to work on there. 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 agonist for osteoporosis, 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 have a number of earlier research stage programs, and we also have quite a substantial collaboration with Novo. This is a program that involves five targets, four concurrent programs, and is currently off to the races and moving along quite well. I want to quickly just give you guys some grounding on those first two programs. SEP-479, this is the hypoparathyroidism program. This is a very challenging receptor, one that our platform did crack multiple times. What you are looking at here is the PTH receptor in magenta, the PTH peptide in green, G protein in blue. We found multiple ways to activate this receptor with small molecules. It had been a historical drug discovery challenge. It is where our platform really showed its colors. We ended up with SEP-479, which is a compound that we are quite excited about.
I will show you a little bit of data in a monkey, and then we will spend most of the time talking about the phase I trial. We have 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 healthy volunteer study that is ongoing. 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. 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.
Once we reach a certain level, there is a threshold, we start to see serum calcium levels go up, as you start to see on the graph on the right. If we take the lessons from the PTH peptides that have been in the clinic and approved, including YORVIPATH, what we anticipate to see in a healthy volunteer, that should map to a hypoparathyroidism patient, is a decrease in endogenous PTH on the scale of about 50%, and then an increase in serum calcium on the scale of about 0.3-0.5 mg/dL. This phase I trial is ongoing. It is a standard single ascending dose, multiple ascending dose 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. We extended the duration of the multiple ascending dose portion to 14 days to try to approach steady state dose levels. 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 us say, 0.5 mg/dL. 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 Graves' disease 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. SEP-204 binds in the transmembrane domain and prevents the activation of the receptor even when it has an autoantibody bound to it, which is exciting. SEP-204 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. 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 other receptors.
We've got a very high degree of selectivity, over 1,000-fold, and we've got robust PK/PD demonstrated in healthy animals, mice, rats, dogs, and monkeys. Don't have time to share all that today. 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're projecting a human half-life of about 20- 40 days here. We've completed GLP tox studies in rats and dogs and hope to be in the clinic with this molecule in the first quarter of next year as well. I'm going to just show you a little bit of data. This was presented at the American Thyroid Association Conference just last week.
It's a rat study where we've dosed the rat with a human patient-derived antibody. This is a Graves' patient antibody. 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. Then we're studying three different doses, one, three, and 10 mg/kg twice a day in a rat. We think it's a once-a-day drug in a human. You can see that the middle two doses, the lower two doses, normalize thyroid hormone levels, whereas the high dose suppresses it. This is kind of what we would anticipate to see. 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 dosed it for a total of eight weeks, and 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 have significant changes in the Graves' mice that are reversed with the drug. The histology changes, the thyroid size also starts to normalize, and these Graves' mice also develop proptosis. This is effectively a mouse model of thyroid eye disease. It's a new model that we developed in-house.
You can see the middle photo there with clearly bulging eye, and you can start to see some reversal of that as well. These are data that we are excited about, and I think I have already summarized the main preclinical findings. Like I said, we are hoping to be in the clinic in the near future. We can just kind of maybe stop and have our pipeline chart there.
Great. Maybe just to follow up on the TSHR, it looks like you had an active control in that dataset. Can you just maybe help everybody understand the importance of the K1-70?
Yeah. K1-70 is a TSH receptor autoantibody as well. This one is a blocking antibody, though. 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 eye disease patients, so it is a good positive control for us. You can see that at our high dose, we are able to be in a similar zone to K1-70 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 particular disease states and opportunities is the ability to identify signals early with a novel oral approach. Why choose that, and why choose these two particular disease states?
Yeah, it's a great question. 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. Every one of our programs that we've picked so far, we expect to learn something very significant in a phase I trial. The GPCR space is huge. There's so many things that we could go after. In terms of the small molecule opportunity, one big opportunity space that we've 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 incretin receptors, well-known to everybody, are another example of that, where if you had a small molecule that could do what a peptide could do, that could have great benefit. 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.
Yeah. One outlier, I think, on the pipeline list to some might be the willingness to go after osteoporosis, whereas you out-licensed the incretin programs. Can you talk about sort of that as a capital-efficient decision for the company?
Yeah. Maybe I'll let Liz take this question.
Yeah. So osteoporosis is actually a natural program for us to go after, just given the long knowledge about PTH in that space. So, what's different in terms of hypoparathyroidism versus osteoporosis, in osteoporosis, you need a short-acting compound, something that's going to be more pulsatile in nature. That's what teriparatide has told us as it relates to an approved drug in that space. It was natural given the wealth of information we have on PTH to think about osteoporosis. But the field in osteoporosis actually has changed quite a bit as well. A new initiative called the SABRE Initiative really kind of redefined how endpoints are there, and such that we have the ability to really actually fully develop that now, such that bone mineral density is actually the final endpoint there. 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 biological validation. We think a lot about really where the unmet need is, where a small molecule could fit really specifically into that space. In osteoporosis, there's a huge unmet need for anabolic agents that are oral agents for patients, or a lot of patients who are untreated. 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 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. An oral PTH product, one might think, well, actually, you really want to go, 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 a patient or activate patients to really pursue treatment with an oral medication versus the current daily oral?
So, let's talk about hypoparathyroidism specifically. I think one of the things to think about particularly there is, and 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. So being able to have an oral agent is really very important to them. As we think about the current landscape right now, we do believe actually all hypoparathyroidism patients 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 who cannot 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 are either hypercalcemic or hypocalcemic. However, there is a whole swath of patients that are, I would say, more moderate in nature. Maybe their calcium's generally control most of the time, but they still have a lot of other symptomatology. They have urinary calcium is not where it should be. They are taking a huge pill burden relative to taking calcium. They may have brain fog still.
This is where we think an oral agent really has the opportunity to unlock more patients and 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. Jeff, can you talk about the importance of this longer half-life in particular? I think it is one thing that has been proved out by YORVIPATH very effectively, but what is the importance, and what are you specifically looking for in the phase I data as we kind of progress towards that catalyst next year?
Yeah. 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. We set out to intentionally try to discover a compound with a very long half-life. With PTH, or with SEP-479 having a projected half-life of three to four days, we think we can actually have pretty good stabilization. It has been proven out. YORVIPATH has an effective half-life of about 2.5 days, which is quite good at stabilizing that, and that has done quite well clinically. 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 hope to see, first in healthy volunteers, we hope to see changes in PTH, endogenous PTH going down probably about 50% or so, hopefully in that zone. Serum calcium going up around about 0.5 mg/dL. You can only take a healthy volunteer up so far ethically to avoid putting them into the at risk of hypercalcemia. We will hopefully dose up a little bit higher than 0.5 mg/dL, but we will see where we end up. When we start to think ahead to going into a patient study, the most important thing for us in a first patient study, first phase II study in hypoparathyroidism patients, is determining what that starting dose should be.
Because hypoparathyroidism is a disease where every patient will get titrated to their own optimal dose, and we need to figure out what that starting dose should be and what the titration protocol should be. We think we can do that with a reasonable number of patients in maybe two to three starting doses. We will have more to say about that when we finish this trial. Hopefully two or three starting doses in a phase II, where we would hopefully start to see some control in hypoparathyroidism patients, and then be able to identify the final dose for a phase III trial.
Got it. 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, 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. The number of doses is a really interesting question. YORVIPATH is currently approved, I think, in about eight different doses. 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 II, but we think it's going to be a very reasonable size.
Okay. Just in terms of matching that sort of very flat profile, does it just kind of come down to identifying the half-life and being able to model your molecule? I guess the last piece is just how well-behaved is the molecule to your knowledge?
Yeah. We know a little bit from our phase I SAD study, and that's what led us to say that the half-life is 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 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. In terms of a phase II, how should we think about that progressing, is there any reason to do kind of a phase I-B in patients themselves along the way?
Yeah. I think we're going to just go straight to a phase II in patients. Just from a timing standpoint, if we finish up this phase I 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 II study, so we have started chronic safety studies, animal safety studies. 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—
Indefinitely.
—even 52 or 108 weeks or—
Oh, we can keep going.
Definitely. Okay.
Keep going.
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 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 to 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. 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. We're excited about the molecule that we've got now. In terms of the Graves' 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 Graves' disease as well as thyroid eye. Within Graves' disease itself, while antithyroid drugs are really kind of the, certainly the current standard of care, there are 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 TEPEZZA.
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. The reason why we're really excited about TSHR is, as I said earlier, it really, from a mechanistic perspective, can hit both diseases. Again, our approach here versus many of the other ones out there is a once-a-day oral. 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 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 for having us.
Thanks so much.