Septerna, Inc. ($SEPN)

The end of our first day of our Annual Healthcare Conference in a very toasty Las Vegas. I'm very pleased to have join us right now, Jeff Finer of Septerna, who will be providing us with the presentation. Jeff?

Okay. Yes. Thanks, Jason. Thanks for the invitation to present with you guys here. It's good to see a few people still in the room late in the day. I'm going to tell you about Septerna. For those of you who don't know us, we're a company focused entirely on GPCRs or G protein-coupled receptors, and we found a new way to do drug discovery for them. The presentation will include some forward-looking statements. But just a kind of quick overview of the company. We've got a platform that we call the Native Complex Platform that's allowed us to do drug discovery for GPCRs in a new way. It's allowed us to tackle previously difficult to drug GPCRs. And part of our portfolio strategy in general has been to go after well-validated targets with early clinical readouts. Every one of our programs, the ones we'll talk about today, has a meaningful Phase I readout that is important. We're well capitalized. We announced financial results just from the Q1 last yesterday, and we've got a cash runway into 2029. A couple of lead programs that we'll talk about today. We'll spend nearly the entire time talking about 2 of the programs. One is SEP-479, which is our parathyroid hormone receptor agonist for hypoparathyroidism. This is one that we recently announced the start of the Phase I trial, announced that start just a few weeks back. The second program, SEP-631, is going after a mast cell target called MRGPRX2. That one we announced very promising Phase I data just 2 months back, just in March, and I'll share that data with you today. And then I'll briefly introduce you to our thyroid stimulating hormone receptor program as well. This one is going after Graves' disease. And finally, last but not least, we have an incretin receptor agonist set of programs that we end up partnering with Novo. We announced a big deal with Novo last year, and that collaboration is off to the races. Okay. So jumping into our SEP-479 program. For those of you who don't think about hypoparathyroidism all the time, it's important to understand a little bit about parathyroid hormone physiology. So PTH is the master regulator of blood calcium levels. It's secreted by the parathyroid glands, and it has its effects on a receptor called PTH1R in the bone and the kidney. Those effects on the bone and kidney lead to increases in serum calcium, either through mobilization of calcium from bone, resorption of calcium on the kidney, and there's also effects on the GI tract as well. Patients with hypoparathyroidism have generally lost these parathyroid glands and an inability to regulate their blood calcium. So they end up with hypocalcemia and a whole bunch of consequences of that, including side effects. SEP-479 is our clinical candidate. We'll spend some time talking about today. It's a very potent selective oral small molecule. In this space, there's been a lot of peptide therapeutics, but this is, to our knowledge, the first effective oral small molecule. This is our second-generation compound, we have an earlier one that ran into an unexpected safety finding. But SEP-479 is our second-generation compound. This compound has shown activity that's very comparable to PTH peptides by all measures, cell-based assays, animal models. We've shown efficacy in a rat surgical model of hypoparathyroidism. I don't have time to share that with you today. But I will share with you a very interesting monkey PK/PD study, which we think is a good simulator of what a healthy volunteer study should look like. Compound has excellent pharmaceutical properties that we think project a once-daily dosing. And as I mentioned, the Phase I trial was just recently kicked off. Okay. So this is the monkey PK/PD study that I was alluding to. One thing to know about this physiology is that healthy volunteers are very different than hypoparathyroidism patients. And healthy monkeys are -- have the same situation as a healthy volunteer and that they have intact parathyroid glands. Those parathyroid glands, because the endocrine feedback system is so efficient, they can dial up and dial down PTH release from those glands very efficiently in response to any moves in serum calcium to try to hold serum calcium levels as tight as possible. And so what we do expect to see in a healthy volunteer as well as in a healthy monkey, the first consequence is the endogenous PTH secretion will go down. And what we're looking at here is a 7-day study with once-daily dosing followed by a 5-day recovery period. And what you can see on the left graph is that after just a single dose, the endogenous PTH levels are down about 80% or so. Once you've bottomed out PTH levels, your ability to turn down PTH, you start to get serum calcium increases in healthy volunteers as well. And we've learned some lessons from the PTH peptides that have been before us in clinical development, including that Novo pass from Ascendis, which is that if you look back retrospectively at the doses that work in healthy -- I'm sorry, in hypoparathyroidism patients and then see what those same doses would have done in healthy volunteers, you get a target range of calcium that you'd like to see increase in the healthy volunteer to predict a starting dose in hypoparathyroidism patients. And that amount of calcium increase is probably on about the scale of about 0.3 milligrams to 0.5 milligrams per deciliter. And so we're seeing that in this monkey study, which is promising. The rest of the preclinical development for this compound went very, very smoothly. As I mentioned, it's a potent oral small molecule. PK studies, we did across multiple species mice, rats, dogs and monkeys. And it led to a projected human half-life in the range of about 40 to 80 hours, which, again, we think is -- should be compatible with once-daily human dosing. We think anything above 20 hours would be good for once-daily dosing. And then on the safety side, we did 3 GLP tox studies rats, dogs and cynos for this particular compound. And all we saw was on-target effects, on-target effects of hypercalcemia, no other significant side effects. So we were excited about this, decided to move it into the Phase I trial. Here's a quick overview of this Phase I trial design. We're doing a randomized placebo-controlled single ascending dose and multiple ascending dose study. We're doing a food effect study as well. The number of cohorts is a variable here. We're doing -- we're going to dose escalate. We're going to be looking primarily at a few things. Safety and tolerability, obviously, always comes with Phase I trial as does PK. But we're going to be looking at those markers that I just mentioned in that monkey study, endogenous PTH going down and calcium going up. In terms of the translation to human trials, I mentioned this already. Based on the peptide experience, we sort of know what we want to look for. And the objectives of this study are to figure out ultimately what that starting dose should be in hypoparathyroidism patients. With that, we anticipate results from this study either late this year or early next year, again, it depends on the number of cohorts that we end up doing. Okay. So quickly moving on to our second program. This is SEP-631, going after a mast cell target called MRGPRX2, I'll call it X2 for short. Mast cells increasingly important targets of a number of diseases, a number of drugs at this point in time. Mast cells live in proximity to 2 important systems in tissues. One are sensory neurons, where they control pain and itch. And then also they're near tissue capillaries and mast cell degranulation can lead to release of immune cells from those blood vessels as well as edema. And these lead to positive feedback loops of activation. So a little bit on SEP-631. This is a very potent compound. It has a mechanism that we call a negative allosteric modulator. And negative allosteric modulator is something that binds outside of the exogenous binding site of the exogenous ligands and turns off the receptor. And we've got an insurmountable one here. We released some recent data on the potency. So we've got a very potent compound, high binding affinity, Ki in the 500 picomolar range, a very slow off rate when the compound is on the target. It turns the target. It's on the target for hours. And importantly, we've been able to show that we're able to lock the receptor in a very inactive state. So what we're looking at here is the receptor. From the extracellular view, you can see the very large binding pocket in teal. We've colored one of the extra loops in magenta, so we can just follow it. If you look at the transmembrane view, you can see that there's an endogenous ligand that fits in there, that's cortistatin-14. When 631 binds to X2, a very remarkable thing happens, which is the extracellular loop pulled over and basically completely block the binding pocket. So this is a unique mechanism where if you take this ability to turn off the receptor combined with a very slow off rate, we're pretty much turning the receptor off. That showed good effects in animal studies led to this Phase I study. Phase I was a single ascending dose, multiple ascending dose study plus a food effect. But importantly, in the multiple ascending dose portion of the trial, we did a skin challenge test and we think is actually quite relevant to this condition. Importantly, on the safety side, safety of this compound was very well tolerated, pretty much indistinguishable from placebo, which was great. PK properties were also very promising. It's got a 24-hour half-life, which we think will sustain once daily dosing. And then there was no food effect. So we should have an oral pill that could be taken any time of the day, which would be great from a convenience standpoint. The data we're particularly excited about is the icatibant skin challenge data. So I'll spend a moment telling you about that. Icatibant is a drug that's dosed subcutaneously. It's got an off-target effect on this receptor that leads to mast cell degranulation and a skin reaction. We did 2 doses of icatibant, 10 microgram per ml and 100 microgram per ml as well as a negative control, which is saline and a positive control, which is histamine. And what we wanted to see, if you inject anything into your skin, you get a skin reaction even if it's just saline. We wanted to see how much we could dampen down the response from icatibant to the saline level. And this was the data that we shared at the AAAAI meeting a couple of months back, which showed that at the low dose of icatibant, we're able to take this response all the way down to saline even with our lowest dose tested, which was 10 milligrams once a day, which is quite exciting. And at the high dose of icatibant, which represents a higher bar, we saw a nice dose -- a dose-dependent squelching of the icatibant skin response all the way down to baseline as well at the highest doses. So we're excited about what we saw here. We think we've got an effective compound, and this data shows that we're effective in humans in the skin. So where are we going with this compound? There are a ton of mast cell indications. Seemingly every day, there's new publication with roles of mast cells in different disease stage. There's many. There's many -- most common place that everybody goes with this target and mast cells first is chronic spontaneous urticaria. We're thinking along the same lines of doing that as well. So we're planning to do a Phase II study in chronic spontaneous urticaria. We're planning to do a chronic inducible urticaria study along the way with that as well. And we're also exploring a whole variety of other indications, many of which are listed there on the right-hand slide -- right-hand part of the slide, including atopic dermatitis, interstitial cystitis, migraine and asthma as well. So we're thinking about cost-effective ways to do signal finding studies in other trials. Just really briefly, with regard to our TSH receptor program, this is one that we're going after Graves' disease. Graves' disease is becoming a hotter area of investigation these days. One thing that makes Graves' disease quite challenging is that every patient develops their own autoantibodies that activate this TSH receptor in both the thyroid gland as well as in the orbital fibroblast behind the eyes. That's what leads to both thyroid eye disease and the Graves' phenotype. And again, one challenge is every patient has their own antibodies and they're polyclonal in many cases. So we need an approach to basically turn off all the antibodies if we can. And again, once again, we're using a negative allosteric modulator in this particular case as well. In terms of the status of this program, we believe we've got line of sight to a development candidate and hope to have more to say about that later in the year. And with that, I will just kind of quickly wrap up with a snapshot of the pipeline. Things that we're looking for later this year are the Phase I data for SEP-479 in the PTH program, either late this year or early next year and for SEP-631 getting into Phase II later this year. So I'll stop there and we probably have time for a question or 2.

Questions from the audience? I guess when you take a step back and you think of the platform itself, I mean, obviously, G-coupled protein receptors have been a focus for many drug developers. I guess what gives you sort of conviction that kind of the approach here is going to prove much more, I guess, fruitful, especially just given worries about off-target effects?

Yes. It's a great question. Maybe I'll just kind of quickly say just a little bit about our platform and a little bit what's different about it. So I've got a slide here that shows this. With this native complex platform, we found a way to actually get these receptors outside of cells. That's very important. Nobody had actually ever done that before and kept them functional. They cross the cell membrane 7 times. They will quickly denature if you take them out. So we found a way to reconstitute them with all of their natural binding partners, including the G proteins, ligands, all in an artificial lipid bilayer. This has allowed us to do structural biology at an unprecedented pace. We've solved more than 150 high-resolution structures for each of our programs to date with this platform. We found novel binding pockets that the world didn't know about. Many times, they've been cryptic inducible pockets as well. We've also got technologies to allow us to screen millions of compounds and use the combination of technologies to optimize quite quickly. So we think we've got a competitive advantage at the early part of drug discovery to find novel binding pockets. And we've got the evidence. Finding small molecule agonists for peptide GPCRs has been a big breakthrough for us and also finding allosteric modulators is something that the whole world struggle with.

Dr. Finer, thank you so much.

Okay. Thanks.