Welcome once again to the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber, biotech analyst at TD Cowen, and it's a great pleasure to introduce Jeff Finer, CEO of Septerna. Septerna is really one of the preeminent GPCR drug discovery companies. We're very excited about the pipeline. We are finally seeing the highly anticipated MRGPRX2 phase I healthy volunteer data literally just over the weekend at AAAAI that shows differentiation from another drug in the market in this sense, but much more importantly, a really good pharmaceutical property, complete abrogation of the inflammatory cascade, and that's gonna move into a phase II CSU data later on this year. Equally to maybe perhaps even more importantly, the oral PTH agonist is shortly going into the clinic.
It's a drug that we've been very excited about. There's a pipeline even behind it working on TSH receptor biology. Obviously a fairly comprehensive preclinical right now collaboration with Novo relating to incretins. Jeff, great to see you. Thank you. We'll do a presentation and then a modified fireside chat.
All right. Thanks, Yaron, thanks to the Cowen team for the invitation, the opportunity to share our latest update, which as Yaron said, was just over the weekend. My presentation will include some forward-looking statements, so please take that into consideration. As Yaron said, Septerna has been a GPCR-focused company since the outset. We've discovered a new way to do GPCR drug discovery that we call the Native Complex Platform, that's designed to unlock a number of traditionally very difficult to drug GPCRs. I don't have time to go into the platform technology today, that platform has quickly yielded a portfolio. Our portfolio strategy from the outset has been to go after well-validated targets, ones with good biological validation and, in many cases, clinical validation.
Importantly, we've chosen targets where we can learn something in phase I, an early clinical readout. When I share the MRGPRX2 program data in a moment, it'll become very clear that the early clinical readouts are important to us. Each of the programs that we're going after represents a significant unmet need and a significant market opportunity, and we're sitting in a very well-capitalized position. We've got cash runway into at least 2029. We'll focus today on two programs. SEP-479, which is the parathyroid hormone agonist, for hyperparathyroidism, and SEP-631, which is an MRGPRX2 negative allosteric modulator. I'll have more to say about what that means in a moment, where we just announced exciting phase I results that I will share with you momentarily.
As Yaron mentioned, we've got a TSH receptor program behind that focused on Graves' disease. Last year, last summer, last spring, we announced a deal with Novo focused on incretin receptors plus a couple of other targets. That program's also going along quite well. All right, I'm gonna jump into sharing to start off with data on our SEP-631 program. For those of you who haven't thought about the mast cell space a whole lot, MRGPRX2 is an emerging target. It's a target that is located on mast cells and is activated by a whole host of endogenous agonists, neuropeptides, immune mediators. All those mediators activate MRGPRX2 through a non-IgE-dependent pathway.
There's a separate pathway that leads to ultimately mast cell degranulation and the release of a whole bunch of mast cell mediators that have effects on sensory neurons, causing pain and itch, as well as on nearby blood capillaries that have an effect on tissue inflammation and edema. These two pathways end up setting up a bit of a feedback loop, and the neurons and the immune cells subsequently release more mediators to activate the receptor. This positive feedback loop is one that we think we can cut off with a very potent MRGPRX2 inhibitor. A little bit on SEP-631. We announced yesterday for the first time some additional features of its mechanism. First off, it's a negative allosteric modulator. What's an allosteric modulator?
It's something that binds outside of the binding, the natural endogenous agonist binding pocket. This is a very potent compound. It's got sub-nanomolar binding affinity, a very slow off rate, with a half-life once the compound is on the receptor of a couple of hours. Importantly, SEP-631 locks X2 into a configuration where it can no longer be activated. What we're looking at right here are extracellular views of the receptor and transmembrane views of the receptor. In the top figure, that's the extracellular view. You can see labeled in teal, the agonist binding pocket. It's a very promiscuous pocket. That's what binds all those activators. We've colored one of the extracellular loops magenta just for as a reference.
The transmembrane view shown below has an agonist in the binding pocket. In this case, it's cortistatin-14. That's one of the endogenous agonists for this particular receptor. When 631 binds to X2, what you see is a really remarkable thing, which is that the extracellular loops, one of which is highlighted there, completely occlude the agonist binding pocket. So the agonist binding pocket can no longer be activated by any endogenous agonist. If you take that feature plus the very slow off rate and the high binding affinity, what we end up with is what we call an insurmountable negative allosteric modulator, meaning that it can't be outcompeted by excess amounts of endogenous agonist.
In terms of preclinical data, MRGPRX2 presents a preclinical challenge in that it's not well conserved across species. So here we had to make a knock-in mouse. We took the mouse's gene, replaced it with the human gene, and this is an animal model that we think is quite relevant to urticaria and also quite relevant to the phase I trial that I'll show you in a moment. We take that mouse, we dose it with our compound orally, and then we give the mouse a blue dye called Evans blue that tints the blood a little bit blue. The next thing we do is we do an intradermal skin injection with an X2 agonist.
I'll show you in a moment data for both cortistatin-14 as well as an agonist called icatibant, which is one that we ended up using in our phase I trial. At the site of that injection, the mouse develops a little blue hive, basically extravasation of the blue dye from the blood compartment into the skin. Theoretically, if you're able to completely knock down this receptor, that would prevent that hive formation. This is exactly what we see. We see in the case of cortistatin and icatibant basically complete knockdown of skin extravasation, and we think this was really a good translation from that insurmountable negative allosteric modulator now preclinically.
Now if we look at the big picture of the whole preclinical profile, we've got a very potent compound, a profile that we like, and as Yaron mentioned, very good pharmaceutical properties. We've got a PK profile that we thought preclinically could translate to a once-a-day drug, as well as other features that are interesting, including the fact that we're already in a tablet formulation. Now jumping into the phase I trial design and phase I data, we did phase I that had three parts. The first part was a single ascending dose study looking at doses ranging from 10 mg all the way up to 400 mg.
The second part was a multiple ascending dose portion of the trial, there with four doses, 10, 30, 90, and 200. Finally, in the third part, we did a food effect study. It was a crossover, fed and fasted, food effect study. Importantly, for every phase I trial, the most important thing you wanna know is safety and tolerability, PK as well. In the MAD portion of the trial, we did a skin challenge, much like in that animal model I just showed you. The skin challenge involved establishing a pre-dose baseline, then dosing again for nine days, it was a total of a 10-day dosing period, and doing a skin challenge again on day nine, when the drug was already at steady state.
I'll have more to say about that in a moment. Quickly to begin with the safety and PK profile, SEP-631 was very well-tolerated. There were no serious or severe adverse events. There were some mild events, but those mild events were completely comparable to placebo rates, which was good to see. The PK profile is exactly what we had hoped for. We've got a half-life of approximately 24 hours, which we think is optimal for once-daily dosing. Thankfully, we did not have a food effect. Because we don't have a food effect, we feel like we've got a drug that could be a once-daily oral tablet that can be taken whenever the patient wants, just for convenience purposes.
Now I'm gonna jump into the skin challenge data, this is quite exciting. As I mentioned earlier, icatibant is a drug that has an off-target effect that activates MRGPRX2 and induces skin wheals when it's injected. As I said, we did a skin challenge on before the study and again on day nine. The figure on the lower left-hand corner shows you a little bit about how we did that skin challenge. There were two important controls. One was saline. That's the negative control. Positive control is histamine. That causes a skin wheal no matter what. We did two doses of icatibant. One was 10 micrograms per ml as well as a higher dose of 100 micrograms per ml.
In terms of imaging and quantitating these skin wheals, we used a new technology that hasn't been used in a clinical trial before called an AllergyScope. This uses shortwave infrared imaging to in a very precise way quantitate the size of those skin wheals. Because it uses infrared light, it measures inflammation and not just the size of the wheal by itself. Here's the data. What we're looking at here are the two different doses. On the left is the 10 microgram per ml icatibant dose. On the right, 100 micrograms per ml. What we wanted to see is we wanted to see the knockdown of the icatibant wheal size from baseline all the way down, ideally to the saline baseline, that's exactly what we're seeing.
At the lower dose of icatibant, even at our lowest dose tested here at 10 mgs once a day, we see full knockdown all the way to the saline baseline. That's quite exciting. For the higher dose of icatibant, we also see a dose-dependent decrease where we go all the way down to the baseline on day nine or at the 90- 200 milligram doses. This is data that we thought was about as good as we could have even imagined. Looking at that data now retrospectively, if we think about the preclinical profile, this translated amazingly well to the phase I results, we think in some ways validates our Native Complex Platform.
In terms of target coverage, we talked about those features preclinically. That translated to an estimated receptor occupancy in the range of greater than 99% for some of those doses. The PK profile translated quite well to the 24-hour half-life. The insurmountable negative allosteric modulator profile translated to full inhibition of icatibant. On the safety side, we had a good safety profile preclinically and a well-tolerated molecule here as well. We think the combination of these features maps nicely to what we think has the potential to be a best-in-class profile, MRGPRX2 antagonist. Where are we going from here? Mast cells are present throughout the body. Many different conditions and many different diseases are thought to have some mast cell involvement.
One of the more common organs that are is important is the skin. Mast cells are thought to be involved in urticaria, both chronic spontaneous urticaria, as well as chronic inducible urticaria, as well as atopic dermatitis and prurigo. Mast cells are also located on mucosal surfaces, in the lung, where they're thought to be involved in asthma, in the GI tract, where they may be involved in IBD and irritable bowel syndrome, as well as in the urinary tract, and particularly in the bladder. The bladder is actually the highest level I'm sorry, the second highest level of MRGPRX2 activated mast cells in the body.
Obviously we can't do all of these at once, and as Jeroen mentioned, our strategy is to go into a phase II trial in chronic spontaneous urticaria as the 1st indication, and the plans are to initiate that trial sometime in the second half of the year. Beyond that, there's a number of other indications as listed over on the right, including a couple of the pain conditions that I hadn't mentioned before, migraine, as well as some rheumatology indications. What we're planning to do is we evaluate some of our prioritized indications. Those include atopic dermatitis, interstitial cystitis, migraine, and asthma for further studies. We'll hopefully have more to say about that at a future date.
Okay, I now want to spend a couple minutes, this will be a shorter update, on SEP-479. This is our program focused on hyperparathyroidism. For those of you who don't think about hyperparathyroidism every day, these are individuals who have lost their parathyroid glands, in most cases through surgery. That has a net effect of causing them to have their calcium levels go low because the parathyroid glands release a hormone called PTH, which is one of the master regulators of calcium in the body. It has its effects on a receptor called the Parathyroid hormone 1 receptor, PTH1R, that is located in the bone and the kidneys.
In when that receptor is activated by PTH, it leads to increases in increased mobilization of calcium from the bone as well as increased resorption from the kidney. There are also indirect effects through vitamin D on the intestine, all roads lead to increases in calcium. For those individuals who have lost their parathyroid glands, they have significant effects, consequences of low calcium. SEP-479 is our clinical candidate here. It's a very potent selective small molecule agonist. This has been a historically challenging target, we found a way to activate the target with a small molecule. We found pre-clinically it checks many of the boxes for us.
It has a comparable profile to PTH hormones in cell-based assays and animal models. It normalized serum calcium in a preclinical rat surgical model of hyperparathyroidism. As I'll show you on the next slide, we also did a monkey PK/PD study that shows some exciting data to emulate what a phase I healthy volunteer study might look like. It too has excellent pharmaceutical properties that we think could project to full-day calcium control in hyperparathyroidism patients with once-daily oral dosing. IND-enabling studies for this compound are pretty much wrapped up. This compound should be starting in the clinic in the next few months. I wanted to just. This is the very last data slide that I'll share.
This is SEP-479's seven-day monkey PK/PD study, where we dose these healthy animals with increasing doses of SEP-479. One thing that's important to know about this study, as well as our phase I healthy volunteer study, is that a healthy volunteer as well as a healthy monkey has an intact ability to dial up and down their PTH hormone secretion. A hyperparathyroidism patient has lost their glands and they, and they can't do that. In this case, the animals can. What you see is a very robust ability of the animal to turn down its endogenous PTH levels.
It's a seven-day study with a five-day recovery period, and you can see after day one, by day two, endogenous PTH levels, this is on the left figure, are already down about 80%, which is quite striking. After endogenous PTH has bottomed out, we can then increase calcium, increasing doses of the compound then have their effects on increasing calcium levels. Based on the data from peptides that were shown clinically to work in hyperparathyroidism, if we look back retrospectively as to what they did in healthy volunteer studies, the relevant amount of calcium increase, we think the.
that would be important to see in a healthy volunteer study is about 0.5 milligrams per deciliter, and that's kind of in the range of what we see at even the lowest dose here for this compound. In terms of SEP-479, it's got a very long projected human half-life in the range of about 40-80 hours. As I mentioned, the IND-enabling studies are wrapped up. We completed 28-day GLP tox studies, rats, dogs, as well as cynos. SEP-479 was again well-tolerated with the exception of on-target effects associated with hypercalcemia. If you take an animal and you put it in the hypercalcemic range for 28 days, you start to see some effects of hypercalcemia.
The compound manufacturing is all done, and as I said, we're getting geared up to start the Phase I trial in Australia. With that, I will kind of wrap things up. This is the overall pipeline that we have at the moment. In addition to those two programs that I just mentioned, we've got the TSH receptor program plus a handful of things behind that at earlier stages. Gonna open it up for discussion now.
Jeff, thanks for thanks for coming. Maybe on MRGPRX2, it sounds like that you'll start a phase II in the second half. Is that any sense there's gonna be a 24 week study?
Yeah. We're thinking about this mostly as a 12-week study, but one where we may do an open label extension.
Thank you.
Would you consider it would be head to head against placebo? Is there a dose finding component to that phase II as well?
Yeah. No. It would probably be a dose range plus placebo. We're thinking about it as three to four drug levels plus placebo.
An open long-term extension at that point.
Probably a long-term extension. The standard readout for a CSU trial is typically at about 12 weeks.
How much tox coverage do you have now in terms of chronic dosing?
Yeah, great question. Our original 28-day studies were enough to get us through the phase I study. We decided to do chronic tox studies before initiating phase II. Those chronic tox studies include six-month rat studies, nine-month dog studies, and those studies will be wrapped up. We should have that data mid-year in advance of actually starting this trial. That's important in that it will hopefully further de-risk the program, but also allow us to do that long-term extension.
Once you have the nine months, you're good to go. That's.
We're good to go. That's as long as anybody does in the animal studies.
Yeah. Carc studies are done in parallel.
Those are done, generally a little bit later.
Okay.
The X2 program, when you have diseases that are thought to be mediated by X2, when there are conditions that are thought to be mediated by X2, are they thought to be completely independent of IgE, or is there ever any overlap with the two, mediators of disease that contribute?
Yeah, it's a great question. I think the answer is that most people actually don't know. There are some diseases. CSU is a great example where there are some. It's probably both and probably a mixture. Some patients are probably more IgE mediated, others are probably more X2 mediated. We know that there's a number of patients that do not respond to the anti-IgE therapies if they've already failed high-dose antihistamines. Because X2 is the main other mechanism for degranulating mast cells, there's good indirect circumstantial evidence that X2 is pretty important for a subset of the population. The other indications are probably quite similar to that.
Do you believe that you're gonna need inhibition of both to get maximal efficacy?
I think it really depends on what the driver is for an individual patient. If it's got a clear allergic component, and there's IgE involved, that may or may not respond better to the anti-IgE therapies. If it doesn't respond there, the X2 pathway is gonna be good. There's also a chance, we believe, that targeting the X2 pathway could work in both IgE high as well as IgE low patients. I showed you when I showed you the diagram with those positive feedback loops with the mast cells.
even if you, and even if the initial insult is, an allergic mechanism through the high affinity IgE receptor, once there's degranulation, that sets off a feedback loop where there's actually more stimulation through the X2 pathway. It's possible that, an X2-targeted agent could dampen down, all activation, even if the initial trigger is through IgE.
The PTH program, you're doing that in Australia because it used to be a penal colony? I'm just kidding, obviously.
no, we're doing it just 'cause we can get going more quickly.
Thank you. One more question from me. The residence time of SEP-631 on the receptor is two hours, but you have a full day coverage in general. It's not covalent. When the orthosteric agonist comes off, the allosteric agonist comes off, does it go back on? Maybe explain how you get a full 24 coverage on the receptor.
There's actually kinda two different half-lives here. There's the half-life of the drug in the body. The half-life of the drug in the body is about, has a half-life of 24 hours. The half-life of a molecule when it's on a receptor is about two hours. Because we've got so much excess drug floating around, as soon as one molecule comes off, there'll be another one waiting to go on.
Can you remind us what you said on the binding site and where you actually bind on the receptor and how you cause a conformational change?
Yeah. We haven't disclosed the exact binding pocket. Let me just go back to that figure here with the receptor. One second. It's in the transmembrane domain. The compound's binding to a novel cryptic binding pocket that we discovered using our platform. Once the compound is in there, it causes this conformational change of the extracellular loops basically folding in and blocking the agonist binding pocket.
The agonist binding pocket, I'm sorry, the site that you're binding to, the cryptic domain, is it always free, or is it in dynamic state?
Yeah. It's in a dynamic state, it's an inducible pocket. If we look at the receptor just by itself, that pocket doesn't exist. Our compound somehow gets in and creates its own pocket, and that creation of that pocket then has an effect on this conformational change.
It's inducible when the receptor is active or inactive, or it doesn't really matter?
As far as we know, it doesn't matter, because the compound has such high binding affinity. It certainly will get in there, you know, when the receptor's inactive for sure. We've shown that even if we've got in some of our assays, even if we've got agonists on board, we're able to turn that off.
Is it a fairly conserved site, or, I mean, this is obviously not a disease with mutations, but is it fairly conserved and stable?
Yeah, we think so. We think so. There's not a whole lot of known heterogeneity in MRGPRX2 across individuals that's known.
Preclinically, it sounds like you've not seen any impact on liver function testing.
No, none.
in LFTs.
None.
In terms of potential drug-drug interactions, maybe just minus what you said on metabolism or clearance?
Yeah. We haven't said a whole lot on metabolism and clearance. It is metabolized in the liver. We haven't given the details on that, but we don't expect any significant drug-drug interactions.
Okay. maybe moving to PTH, how are you thinking about, you know, a phase I dose ranging study? What does that normally look like?
Yeah. We'll start with typically a pretty low dose, single ascending dose, just to kind of. What's important with the healthy volunteer is to not overshoot serum calcium levels too high, so we'll start low and sort of ramp our way up. As we start to go up on the single ascending dose, we'll then switch over and start doing multiple ascending doses based on the half-life that we see with the single ascending dose. Our thoughts initially are that the MAD portion of the trial will probably have dosing in the range of either seven- 10 days. It's really hard for a healthy volunteer to do much longer than that.
The idea is that hopefully as we get up in the dose range, we'll start to first see decreases in endogenous PTH levels. We'll probably see that before we start to see calcium increases, but the hope would be to subsequently get to a dose where we see calcium increases that are meaningful for patients.
A phase II is usually a 12-week study?
phase II is a little more complicated. phase II, each patient needs to be dosed, dose titrated. There's a starting dose typically, and then dosing for a couple of days to see what happens. You then try to titrate those individuals off of their calcium and vitamin D supplements. Depending on where you get with that, you may or may not change the dose level. There's dose increments that will probably change at some frequency. We haven't figured out exactly the right sequence of that. We'd probably titrate at every week or two to a different dose level to try to establish ideally independence of calcium and vitamin D supplements.
You know, ultimately in phase II, as you titrate, do you need to monitor? Do you need to monitor usually for a fixed duration of time?
Yeah. No, I mean, we will definitely have to monitor calcium levels for sure, with some frequency just to, as we establish this drug. You know, once we're fully established, that monitoring can decrease in frequency.
Any more questions?
Just looking at the Yorvipath's label, this titration schedule that they have, seems, you know, a little bit complicated. Then there's warnings and precautions associated with hypo- or hypercalcemia. Would you expect to, you know, maybe talk a little bit about what kind of titration schedule you would kind of predict if you have a sense and about warnings and precautions?
Yeah, great question there. I would think about it. Our titration schedule will probably be somewhat similar. Yorvipath's functional half-life's about every 60 hours. We'll have to see where our projected human half-life is kind of brackets that same range. Depends on where we end up. We think anything greater than about 20 hours will be fine with once daily dosing. The shorter that half-life is, probably the faster we can titrate. If we end up in the range that, the same range as Yorvipath, it'll be probably somewhat similar in terms of a titration scheme.
Our hope is that we'll be able to have tight control and ideally not get too many patients into either the hypercalcemia range or the hypocalcemia range. These are all things that we'll work out in phase II and phase III.