All right, good morning, everyone. We're going to get started here with the next fireside discussion. My name is Derek Archila. I'm one of the Senior Biotech Analysts here at Wells Fargo. Very excited to have Septerna with us. From the company, we have Jeff Finer, CEO. We had a nice, really interesting update that you're going to share through some couple of slides here and walk us through, and then we'll get to the Q&A. I'll turn it over to you.
OK, great. Actually, I'll just stand up for a moment here. For those of you learning about Septerna for the first time, we're a company focused entirely on GPCRs. My brief presentation will include some forward-looking statements. Because we had an update this week with some significant data related to two of our programs, our parathyroid hormone receptor program, as well as our MRGPRX2 program, I wanted to kick things off with a few slides update. To set the context briefly, we've got a new way to do GPCR drug discovery that we call the Native Complex Platform. Very briefly, what that involves is taking receptors outside of cells, reconstituting them into fully functional systems. It's a brand new way of doing GPCR drug discovery. That has led to our ability to find new chemical matter, as well as to optimize it very quickly with structure-based drug design.
The portfolio is what we'll focus mostly on today. The parathyroid hormone receptor agonists, we've identified a new development candidate. We previously had a compound that was in the clinic that ran into some unexpected findings. I'll share that with you briefly as well. Our second program, MRGPRX2, is a mast cell-driven target. We've got a compound that just initiated in the clinic last month. We've got an earlier stage program focused on the thyroid stimulating hormone receptor and Graves' disease and thyroid eye disease. The fourth program is an incretin receptor agonist program as well. Over the last few months, we formed a major collaboration with Novo Nordisk. Briefly, I'm going to give you a brief update on the parathyroid hormone receptor. This is a receptor that's been a historically challenging drug discovery target. The receptor is shown here on the slide in magenta.
It's got a PTH peptide, which is a long helical peptide. It goes up onto an extracellular domain. This has been a target that the pharmaceutical industry has gone after for many years with really very little to no traction on small molecules. We found not one way to activate this receptor, but actually two independent ways, two different binding pockets. With the help of our Native Complex Platform, we've been able to optimize compounds very quickly. For each of these binding pockets, we got to very potent compounds that were working in animals in less than a year from starting medicinal chemistry. It's a real testament to our platform. This led to potent selective compounds. I'll show you a little bit of data on how we're able to normalize serum calcium levels in preclinical models. We've got profiles that we think would support once-daily dosing with our compounds.
First compound, and again, I'll have more to say about this again, SEP-786. This was the compound that was discontinued. More on that story in a moment. [SEP-479] is our next-generation compound. It is structurally completely unrelated to [SEP-786] and shows significantly improved pharmaceutical properties as well. With regard to SEP-786, the unexpected findings in these individuals were increases in unconjugated bilirubin. When people hear about unconjugated bilirubin, they immediately think liver injury. Fortunately for these healthy volunteers, they did not have liver injury at all. Liver enzymes were normal. Bilirubin actually comes from the blood cells, and there were no signs of breakdown of the blood cells or hemolysis. There were also no signs of backup in the bile duct system. Those are all positive signs. Unfortunately, we thought this was a point where we really couldn't proceed. We discontinued the trial back in February.
Unfortunately, also, this side effect was not predicted by the preclinical models for [SEP-786] before it went into the clinic, including 28-day [GLP-Toxicology] studies in both rats and dogs. On the more positive side, what did we learn from [SEP-786]? We learned that a small molecule can do basically what a peptide does in a human. We saw early signs of decreases in endogenous PTH. A healthy volunteer has an intact PTH set of parathyroid glands and an ability to dial up and down their parathyroid hormone release. What you expect to see in healthy volunteers is PTH going down. Once you hit a certain point, calcium will start to increase. We were on the road to that. We were seeing early signs of that in our phase one trial. We also saw a human half-life that we thought could support once or twice daily dosing.
In this indication what you want is you want really stable calcium control across patients. We did an investigation after the trial was discontinued, looking at the bilirubin metabolism pathway. Bilirubin is taken up into hepatocytes via a couple of transporters called OATP1B1 and [OATP1B3]. Once it's in hepatocytes, it's then conjugated with an enzyme called UGT1A1 and then exported into the bile. The conjugated bilirubin is exported into the bile with a third transporter. Our findings were actually crystal clear here. We found that SEP-786 is a potent UGT1A1 inhibitor. It directly inhibits that conjugation enzyme. Subsequently, after this trial was discontinued, we did additional studies in SEP-786 in monkeys. The purpose of this was to compare to the next-generation compounds that we were looking at and also to try to simulate a healthy volunteer study, but in a monkey. I'll share that with you.
To our surprise, in the monkey study, we also saw increases in unconjugated bilirubin. This is a circumstance where this compound, its effects on humans and non-human primates, is probably different than in rats and dogs. Getting to the next compound, SEP-479 is a compound that we just announced this week as our new development candidate. It's one we're quite excited about. What I'm going to show you here is our rat surgical model of hypoparathyroidism. What this model involves is taking out the rat's parathyroid glands. The animal then has hypoparathyroidism. They see the characteristic decrease of calcium. These animals get hypocalcemia. The idea is if we treat with our compound, could we normalize serum calcium levels? That's exactly what we're seeing. What you're looking at on this slide are two graphs. The one on the left is serum calcium. The one on the right is serum phosphate.
The gray dots represent the animals that have hypoparathyroidism but haven't been treated with our drug. Calcium is low, phosphate is high. The gray bands represent the normal physiologic ranges. That's where we want to be. You can see that over this 28-day study, where we're looking at detailed time courses on 4 / 28 days, we're able to get into that normal range on both calcium and phosphate. This is exciting. This is exactly what we want to see and simulates what we would hope to find in a hypoparathyroidism patient down the road. One thing to note on the bottom here is the dose. SEP-479 was effective in this model at a dose of 0.15 mg/kg once a day, whereas to get very comparable data with [SEP-786] required 3 mg/kg twice a day. It's about 40-fold lower dose.
We've got a compound that is hopefully going to have a very reasonable dose in humans. Also, from a PK/PD standpoint, this [SEP-479] has very optimal properties. Going back to SEP-786, it had good oral bioavailability across species, about 50% range. Half-lives range in rodents from about four hours all the way up to about eight hours in a monkey. That led to a predicted human half-life in the range of 9 - 27 hours. The actual human half-life that we observed in the phase one trial was about 18 hours. The prediction was good. If we do a similar set of predictions based on SEP-479, our bioavailability is higher, that's one of the reasons we can go to lower doses. The half-life is also longer.
This is predicting a human half-life somewhere in the 40 - 80 hour range. We will have to see how well that prediction holds out in the clinic down the road. Here's some new data that I wanted to share, just fresh hot off the press this week. This is a seven-day PK/PD study in monkeys. What we're looking at here is trying to simulate what a healthy volunteer would see. This is healthy monkeys. We do a seven-day dosing period, once a day oral dosing, and then a five-day recovery period. You can see from the right figure, which is looking at endogenous PTH levels, that we can get PTH to go way down, all the way down to about 80%+ with just a single oral dose of our drug. Calcium is a bit of a lagging indicator. It starts to go up over the first couple of days.
You can see calcium going up in a dose-dependent fashion. One question is, what is the relevant amount of calcium that we'd like to see? There have been a number of peptides that have been in human trials looking at both healthy volunteers as well as hypoparathyroidism patients. What we know from at least the peptide trials is that a dose that leads to about a 1 mg/dL increase in a healthy volunteer, plus or minus around, let's say, ±0.7 -± 1.5 or so, translates into the relevant dose range in hypoparathyroidism patients. In a monkey, to kind of straddle that same range, we're looking at the two lowest doses on this figure, so 0.5 - 1 mg/kg. This is exactly the type of data we would hope to see eventually in a healthy volunteer study. What's left with [SEP-479]?
First off, to kind of dispel any of the potential risk related to the [SEP-786] finding, no UGT1A1 inhibition was seen, no hyperbilirubinemia in all the studies, including that monkey study I just showed you. The 28-day [GLP-Toxicology] studies have already been completed in rats and dogs, well tolerated. We decided to go the extra mile and do an extra Sino study. We're doing a third species that's a bit unusual. The normal species are rats and dogs. We're doing a Sino study just to be extra cautious, heading into a phase one trial that we hope would track towards being in the clinic first half of next year. Now I just want to give you a very brief update on SEP-631. This is a mast cell target, MRGPRX2, going after an independent pathway.
To cut right to the chase, this is our phase one trial design, which we've announced quite recently. This is a randomized, placebo-controlled, single ascending dose and multiple ascending dose study. This drug is already in a tablet formulation. We plan to, in the multiple ascending dose portion of this study, do once-a-day dosing because we believe our PK profile will support that. We estimate about 150 or so healthy volunteers. When we design any of our programs, we like to pick programs where we can see something in phase one. For this particular program, we've decided to do an intradermal skin challenge. What that involves is injecting into the skin a drug that is known to stimulate the receptor and cause a wheal and flare response. This is a target where many of the indications are skin-based indications, including chronic spontaneous urticaria, atopic dermatitis, and others.
We think that a pharmacodynamic marker in phase one healthy volunteers will help us build confidence that the drug is doing exactly what we want it to do in skin. This skin challenge involves introducing this drug called icatibant, which is an approved drug. That drug is known to cause this response in healthy patients. The idea is to do a skin challenge before dosing the multiple ascending dose portion of the trial and then follow up with a skin challenge again nine days later after dosing. We hope to have data in the first half of next year. To wrap up briefly again with our pipeline, those are the two programs. Milestones for early 2026, first half of 2026, are getting [SEP-479] into the clinic, [SEP-631] hopefully being able to share some data.
We've got an earlier stage program that we don't have time to talk about today, our thyroid stimulating hormone receptor. Last but not least, we did form a deal with Novo Nordisk around our incretin receptor agonist. Hopefully, we've got a lot of time for some discussion.
Absolutely. Thanks, Jeff. I'm just going to leave it up there. That's perfect. Great updates there. Maybe let's start with [SEP-479] and I guess the [SEP-786] PTH program. One of the things you highlighted in the slides is kind of this next [GLP-Toxicology] study in SINO. I guess when you looked at 786 in that model, when did you actually start to see? Is it pretty early on that you see the [bilirubin] issue and any liver injury? Just so that you start running it with [SEP-479], is this something that you're going to be able to figure out pretty quickly?
Yeah, yeah. With SEP-786 in the SINO study, we saw it within a couple of days. It is very similar to what we actually saw in the patients. There were no signs of liver injury in that case either. It was just pure unconjugated bilirubin again.
Got it. OK. Have you started those studies or are they still in the planning phase?
They're just getting kicked off.
Just getting kicked off. Cool. I guess maybe kind of the broader picture with [SEP-479] and kind of the development plan. We've seen a couple of PTH programs kind of go through the regulatory steps. I guess how do you think about the phase one? You had kind of already set it up with [SEP- 786] prior. Just walk us through how you believe even in phase one, we should have pretty de-risking data and kind of know where we're headed for later stage trials.
Yeah, what's particularly appealing to us about this target is that there's a really good connection between preclinical data, healthy volunteer data, and eventual patient data for all the PTH peptides that have been in development. SEP-786 didn't quite make it all the way. It made it through the first two steps of that. What we hope to be able to see in our phase one study, which would be healthy volunteers, is data much like that SINO study that I just showed you, where we would hope to see decreases in endogenous PTH and increases in serum calcium. In a healthy volunteer, unfortunately, you can't go up. It's not ethical to go super high in calcium. We will push the limits as much as we can, obviously keeping the healthy volunteers safe. The plan would be to do that.
What we'd hope to do after that is to get into patients almost as soon as we could. This is an indication where, as you know, and many of you guys may know as well, when you get into hypoparathyroidism patients, the dose needs to be titrated on a patient-by-patient basis. What we'd like to be able to do going into eventually a later stage clinical trial is know exactly what the right starting dose would be and the right titration protocol. Our phase one study, we're going to hopefully see safety. We're hopefully going to learn a lot about the PK properties. We're going to hopefully learn about what the right starting dose would be to get into patients.
Hopefully, along the way there, we would do a smaller patient study to really try to lock in that titration protocol and the starting dose before going into a pivotal trial.
Gotcha. I mean, we should think phase one to small phase two to phase three is kind of the development.
That's how we're currently thinking about it.
Gotcha. OK. I guess when you think about the phase ones and comparing to some of the other peptides, is that 1 mg/dL ? Is that what we should be looking for for kind of that bar, let's say, if there is one in the phase one trial here?
I think so. If you look at Yorvipath, again, I would say today's gold standard. If you go back to their healthy volunteer data, their starting dose ended up with about 0.6 - 0.7 increase. That ended up being eventually the starting dose in patients. Many of those patients ended up having to go up to higher doses. I like to think of the relevant range between about 0.7 - 1.5. The hope would be that we can at least span some of that range in that initial phase one study.
Gotcha. I know you said this before, but in terms of [SEP- 479], you had looked at a variety of different kind of backup molecules. You had them already kind of ready to go even prior to the bilirubin with [SEP- 786]. I guess this is, as you noted, a completely different, it's not modeled off of [SEP- 786]. This is a completely different molecule. Maybe you can kind of dig into that a little bit more in terms of some of those key differences and ultimately what drove that kind of two paths for both of these molecules.
It is a completely different structural series. We have not seen any difference functionally in any of our cell-based assays or even in the rodent models between the two. Even though they're different binding pockets and we feel like completely unrelated from a structural standpoint, functionally, they appear to be doing the same thing to the receptor. From an on-target effect, we would expect the mechanisms to be the same. Hopefully, we don't end up with another off-target surprise. One of the features that we like about this compound is that we think the dose could be actually quite low relative to where SEP-786 was. Obviously, phase one will determine what the real doses are. Just by being able to be effective in animals at significantly lower doses also reduces the risk of yet another kind of random off-target effect.
Gotcha. Another feature of SEP-479 seems like a much longer half-life that now maybe q.d. dosing is far more possible with this molecule. Again, how important do you think that is to the PTH market?
I think that's going to be important. We've talked to a number of patients, a number of investigators. For hypoparathyroidism patients, they're actually used to taking, before the injectable PTH came around, the standard of care. This is what most hypoparathyroidism patients are on today: high-dose calcium supplements, where they take those calcium supplements several times a day. They also take high-dose vitamin D supplements. These patients are used to taking a ton of pills. We've talked to a number of patients. They would be absolutely thrilled with even a twice-a-day drug. We think either once or twice a day would be a win for us. With this SEP-479, we think we've got a much better shot at being once a day. Obviously, that would be a real win for patients. With hypoparathyroidism patients, what you want to do is stabilize serum calcium as tightly as possible.
That's one of the things we've learned from the injectable peptides, that these patients are super sensitized. They can actually almost sense their own calcium levels. They start to have tingling, and some of them can tell even that a little bit of brain fog is kicking in when they're either a little bit too high or too low. They're quite sensitive, and the tighter we can control it on a patient-by-patient basis, probably the better the patients will feel.
Gotcha. Maybe the overarching question again, this has been tried before for oral PTHs. There's been kind of failure in that area. What's kind of, again, novel about your platform that allows you to drug PTH the way and potentially successfully here versus some of the past attempts?
Yeah, I think it's really about the platform. A historical challenge in GPCR drug discovery has been to get small molecules that activate peptide GPCRs. It's been very challenging. We've done it multiple times now with several incretin receptors as well as PTH. I think it's been the drug discovery approach that's led us to novel ways of activating these receptors. There was previously a compound that went into the clinic, a small molecule from Chugai. That one made it into phase one. They never released the data. I don't know what happened to that. We've tested that compound. It's not a very potent compound relative to ours. We've got very potent compounds that are in the single-digit nanomolar range from a potency standpoint. As you can see, even in that SINO study, just even a single pretty low dose will immediately bottom out PTH.
Gotcha. In terms of timelines, how should we be thinking about [GLP-Toxicology]? Is that something that you'll actually communicate to the street and investors, and then the start of the phase one and how we should think about the timing?
I think we're currently looking at the first half of next year. We're not narrowing guidance quite yet in terms of a time window. My guess is that probably early next year, we'll be able to give a little finer point on the timeline.
Gotcha. Just kind of shift gears to your MRGPRX2 program. With [SEP- 631], where do you see the opportunity within mast cell disease as a whole before we drill down on the program? Just like why is this area interesting to you guys?
Yeah, so we think it's interesting in part because there are so many different mast cell-driven diseases. Just in terms of skin diseases, chronic spontaneous urticaria is getting a lot of attention these days. It's also turning into quite a competitive space as well. Atopic dermatitis is another skin condition. Prurigo nodularis is another. There are some non-skin conditions that we're excited about as well. We're continuing to look at that. Allergic asthma, and there's belief that some subsets of patients have mast cells as a major component of their disease. There are also some intriguing clues related to some pain conditions, including migraine as one that we're excited about. We think there's a swath of indications. We're thinking about this as effectively a portfolio in a product.
With this specific mechanism, we've seen some data from Evommune in CSU. We also saw some challenges with the insights program. How do you think your program's different, and what gets you confident that you guys will be able to exceed some of the things that we've seen with the other agents?
Yeah, so the other agents, unfortunately, we don't know exactly what their molecules are. They haven't published their structures. We have made our best guesses at some of their compounds based on their patents, and we've tried them side by side related to ours. We think we've got a unique mechanism. What's really interesting about our mechanism is we're able to completely turn off the MRGPRX2 receptor for a long time. When our compound binds to the receptor, it's actually on the receptor for hours, and it's got a profile that we call an insurmountable negative allosteric modulator. What that means is when SEP-631 binds to the MRGPRX2 receptor, it turns off the receptor, and it cannot be activated even if you throw excess amounts of an MRGPRX2 agonist at it.
In fact, every MRGPRX2 agonist that we've ever gotten our hands on, we're able to completely inhibit the activation of the receptor. We've got great pharmaceutical properties, pharmaceutical properties that we think should support once-daily dosing, very reasonable dose levels, and it looks very, very safe and generally well tolerated in all of our safety studies to date. We've got a profile that we like. Relative to the others, the SCN Insight program was discontinued. We don't know a lot about that because they didn't publish much information. Their original press release said that it was based on a preclinical finding even though they were already in phase two. The assumption is it was a chronic [toxicity] finding, but we don't know any more than anybody else does related to that program. We don't think it was mechanism-specific.
Obviously, Evommune is ahead of us in the clinic here, and we're hoping to learn from their experience.
Gotcha. I know you guys have thought about CSU as kind of maybe a lead indication. Is that more, again, given the competitive intensity there, one you would pursue? Is that one more as a tool to kind of understand where you kind of sit relative to some of the other agents in the competitive landscape?
Yeah, we're thinking about it as maybe one of multiple lead indications. We're still formulating our sort of later stage clinical strategy. The current thinking is we'll go after more than one condition in parallel in phase two. We haven't completed our strategy there. The hope would be that once we're in phase one, I'm sorry, once we're sharing the phase one data, sometime in the first half of next year, we'll be able to say more about our phase two strategy.
Gotcha. One of the features that you highlighted from that trial is this intradermal component. I guess how should we interpret that data? What should we be looking for in terms of just understanding the activity of [SEP- 631] based on that?
Yeah, we're thinking about it as a pharmacodynamic marker. If we're active in that model, it will tell us that our drug is getting to the skin, and it's getting to the skin at sufficient levels that will inhibit the activation of the receptor by a known X2 agonist. The challenge with this particular target will be how do we translate that into relevant clinical doses for the indications. That's something we're hoping to learn. We're hoping to at least bracket a relevant range of dosing so that when we go into phase two studies in those particular indications, we can be in a narrower range than we would otherwise.
What kind of distribution do you expect from this drug? Also, as you kind of highlighted a lot of different potential areas to take it, like asthma, are you confident that you can get it to the areas where you need to in terms of where these mast cells reside and they're activated?
Yeah, it's a good question. I mean, we know we're getting into the skin, at least in animals. We haven't specifically studied distribution to the lungs as far as I know yet. That's something that if we go into that indication, that's something that we would do in additional preclinical studies.
Gotcha. OK. In the last couple of minutes, I mean, those are kind of the lead programs. You have, given the platform, a lot of other areas, particularly the metabolic programs and your partnership with Novo Nordisk. Maybe just highlight that program and how that came about and ultimately your confidence level there for some of the programs that could emerge.
Yeah, so the incretin receptor program, now that we've got a partnership with Novo Nordisk, I can't say a whole lot about it. I can tell you what we said before the partnership. What we, and again, this is another testament to the platform, we discovered a novel binding pocket within these incretin receptors. There had been a couple of small molecule, well-known small molecule GLP-1 activators, most prominent of which now is orforglipron, assuming that's tracking towards approval. We discovered a binding pocket that was novel and had better conservation across the three incretin receptors, GLP-1 receptor, GIP receptor, and the glucagon receptor than either the orforglipron or the danuglipron scaffolds. We thought we might have a real shot at being able to, with a single small molecule, have multi-acting incretin receptor agonists.
With that, also, pre-deal, we were able to show that we had some very interesting data in animals. With that, we announced the Novo Nordisk deal back in May. The deal kicked off officially in July. We're off to the races now. The deal includes not only those three incretin receptors, but two additional named but undisclosed receptors. It's a total of five targets. What's great about that particular program is we're able to bring our expertise to play in GPCR drug discovery, yet have the ability to leverage Novo Nordisk's global leadership in the metabolic space for 100 years. We're excited about being able to pursue multiple different programs and have them really take hopefully multiple compounds into the clinic down the road. The deal included $195 million upfront. One important feature for the deal for us is that Novo Nordisk pays for all R&D costs going forward.
We've been able to take that off of our burn, yet expanded the program at the same time. It allows us to pursue multiple things in parallel.
Prior to the deal, how far were these from clinic? Where were they in terms of stage of development, just so we can kind of?
Yeah, still discovery stage. We never disclosed those timelines today either.
Gotcha. All right, great. I guess maybe last question, big picture, where else can you kind of take the platform? Ultimately, is there other types of Novo Nordisk deals or other collaborations on the platform that you'd be seeking? Is that a priority for you guys, or is it more kind of heads down on SEP-479 and SEP-631 at this point?
Yeah, so in terms of priorities, we're actually sitting in a very strong cash position, fortunately, again, relative to a lot of the companies in our environment. We're focused on sort of buckling down and executing as much as we can on those lead programs. At the same time, the GPCR target class is a very broad one. We think there's a huge amount of untapped opportunity space. We think our platform really opens up a number of previously undruggable GPCRs. We've disclosed other areas that we're interested in. One that we've talked about a little bit briefly that is still in the PTH receptor space is there's potentially opportunities in a different indication, osteoporosis. That's one that we're interested in as well. There's a whole slew of other targets. Interest areas for us include neurology, other cardiovascular diseases, respiratory diseases, and again, other inflammatory conditions.
We've got, I think, a pretty broad opportunity to build a deep pipeline over time. Obviously, at this point in time, we need to focus on creating real value with those lead programs.
Got it. Cool. I think, Jeff, we'll leave it there. Thank you so much.
OK, thanks.