Septerna Stifel 2026 Healthcare Conference 2026

Okay. Thanks, Alex. Thanks to the Stifel team for inviting us. Septerna, for those of you who don't know us, is a company focused entirely on GPCRs, or G protein-coupled receptors. We were founded about five, six years ago and developed a new way to do drug discovery for GPCRs. My presentation and our comments today will include some forward-looking statements, so please take those into considerations. Starting off with our pipeline, that platform that I mentioned at the outset has led to a very exciting pipeline. Our lead program is SEP-479. This is a PTH1R agonist for hypoparathyroidism. We have an ongoing phase I trial, I'll tell you a little bit about that more in a moment, with a data readout anticipated in Q1 of next year. Second program, which we just announced last week, a new molecule, a new development candidate called SEP-204.

This is a TSH receptor negative allosteric modulator. An allosteric modulator is something that binds outside of the binding pocket of the normal endogenous ligand. I'll go over that program a bit as well. We had some exciting preclinical data that we shared at the American Thyroid Association meeting last week, and anticipate this one to be in phase I, also in the first quarter. So those are two milestones for the first quarter. Behind that, we've got a mast cell-oriented program called MRGPRX2. We won't spend much time on that one today. And the newest entrant to our pipeline is a second PTH receptor program for osteoporosis. This is different than the lead program in that we have to have a short-acting compound to be anabolic for bone formation, whereas for 479, it's a long-acting compound. Beyond that, we've got a collaboration with Novo.

We did announce in our earnings on Monday that Novo had selected the first candidate from the collaboration. I'm going to just spend a little bit of time on two programs, the hypoparathyroidism program and the Graves' disease program. So 479 is going after this receptor. I'm showing you the PTH receptor in magenta. The PTH peptide is a long helical peptide in green, if you can see that. We discovered multiple ways to activate this receptor with small molecules. It has been a historically challenging small molecule target, but our platform shined here. We optimized multiple compounds, and 479 is our current clinical candidate. It is, as I said, well underway in a phase I trial. It's got excellent pharmaceutical properties.

We announced a couple months back that we've got a very long half-life, a half-life of about three to four days, and we're looking forward to some data in the near future. In order to kind of frame the data expectations, I thought it would be helpful to share some monkey data. This is a healthy monkey data, monkey experiment, seven-day dosing, five-day recovery period. You can think about this analogous to a healthy volunteer phase I study. What's different about healthy volunteers, healthy monkeys versus hypoparathyroidism patients is that they have intact parathyroid glands, and the endocrine system is actually quite efficient. It allows the PTH secretion to be turned up and down very, very efficiently. Given that efficiency, when the drug is dosed, we see significant decreases in endogenous PTH secretion, down about 80% here, and then after that, we see calcium increases.

If we think about where we want to head with a drug, our drug, there are some lessons from the PTH peptides that came before us. A relevant starting dose for Yorvipath, as an example, it's the leading injectable peptide. If you look retrospectively at what that did in its phase I healthy volunteer trials, it decreased endogenous PTH about 50% and increased serum calcium about 0.5 mEq/dL. We think that's a great drug, and we're holding that as our benchmark as well. We're aiming for a drug that has that. In hypoparathyroidism patients, it's a disease of dose titration, and so we want to have some headroom to go above that. So the range that we're looking at is 0.5 to 1 mEq/dL.

Right. Okay. Yeah, exactly. Yeah, 0.3 to 0.5 would be a good starting dose potentially, but in some patients, they'll have to dose higher.

So we want to be able to go past those doses in our phase I trial. So the phase I trial is ongoing, and again, we expect a readout in Q1. Single ascending dose, multiple ascending dose. We're also doing a food effect study. We don't anticipate a food effect, but we always do them in our phase I trials. I mentioned the half-life already. Given the long half-life, we extended the duration of the multiple ascending dose trial to 14 days of dosing once a day. As I mentioned, the signals that we're looking for are in the ranges that we just discussed. So hopefully we'll have those results in Q1.

I want to briefly introduce you to the second program, the TSH receptor program for Graves' disease and thyroid eye disease. This is a receptor that is behind both of these diseases. Both diseases are autoimmune conditions where the patients develop autoantibodies that bind to the TSH receptor and activate it. You can see in this diagram that I have that the receptor undergoes quite a substantial conformational change from the inactive state in blue to the active state in magenta. SEP-204 binds in the transmembrane domain of the region, a receptor in this region, and prevents the activation of the receptor even with an autoantibody bound. 204 has excellent pharmaceutical properties. It is highly selective. One of the features that is important is selectivity over closely related receptors. FSH receptor and LH receptor are the two most closely related ones.

They happen to be reproductive hormone receptors, and Graves' is commonly a disease of women of childbearing ages, and we do not want to inhibit those receptors. We spent a lot of effort in dialing in a high level of selectivity for our compound for the TSH receptor over those receptors. I will share some of the animal data, mice and rat data today, but we have also got some data in dogs and monkeys as well. Compound has excellent pharmaceutical properties. We are projecting this also to be a once-daily oral pill. Just to kind of jump into one experiment here, this is a rat study, where we have got a normal rat, but we have dosed this rat with a Graves' disease patient-derived antibody, called M22, and that antibody causes an immediate increase in thyroid hormone levels.

In the plot in the upper right, you can see that after M22 is dosed, about 18 hours later, we start dosing 204. But by the time we start, thyroid hormone levels have already started to go up. In the untreated population, which is represented by the black dots, thyroid hormone stays high. Two doses, one mg per kilogram and three mg per kilogram, basically take the thyroid hormone levels into a normalizing range, whereas the 10 mg per kilogram suppresses that. What this brings up is a very intriguing possibility that we may have dose optionality. Not only would oral be a differentiating feature for us, but dose optionality could be one as well, where we are able to potentially dose into a range of thyroid hormone normalization without the need for thyroid hormone replacement. But of course, we will have to work that out in the clinic.

Last piece of data is in the mouse. This is now a chronic study where we have dosed that same Graves' disease patient antibody over and over again for eight weeks. During the last two weeks of the study, we introduced 204. You can see that these mice end up with quite a prominent Graves' phenotype. I am showing you some thyroid histology. You can see the healthy control. That is what normal looks like. The Graves' mice is the middle photo. You can see the thyroid histology is quite substantially changed. Then over just the last couple of weeks, we are starting to normalize and return the thyroid histology to normal, and the thyroid size is also returning. On the eye side, the middle photo is a good example of a mouse with thyroid eye disease.

You can see a very prominent bulging of the eye there, and we are also starting to see some reversal of that as well. Very exciting. This compound, as I mentioned, has a long half-life. We have now completed 28-day GLP tox studies in rats and dogs, and all of the effects were consistent with exaggerated on-target pharmacology, namely hypothyroidism.