Septerna, Inc. Common Stock Wells Fargo 21st Annual Healthcare Conference

Yeah, thanks, Derek, and appreciation to the Wells Fargo team for inviting us.

Yeah, great. I've got a pipeline slide that I can just share briefly here. Septerna is a company working on G protein-coupled receptors, and we've discovered a new way of doing drug discovery for GPCRs, which based on the few years that we've been doing this, has proven that we can actually unlock a number of difficult to drug GPCRs. This includes GPCRs that have peptides as their endogenous ligands, as well as we've got a new way of finding allosteric modulators. This has led to the portfolio that you see here on this slide, which includes our lead program in hypoparathyroidism. This is a PTH receptor agonist, which I'm sure we'll spend some time talking about. We've got a second program targeting MRGPRX2, which is a targeted mast cell diseases. Both of those are clinical stage programs. We've got behind that quite a robust discovery portfolio.

The next program that we hope to be able to share information on is our thyroid-stimulating hormone receptor negative allosteric modulator, which is targeting Graves' disease and thyroid eye disease. Just recently we announced a fourth program added to our portfolio focused on osteoporosis. This is another PTH receptor program. There are actually several more programs under the surface here that we haven't talked about. In addition to that, we have a deal with Novo Nordisk, targeting a whole variety of cardiometabolic targets.

Yeah. We're tracking towards being able to share the entire phase I data set, that's the SAD and the MAD, in Q1 of next year. That trial is moving along nicely. We did disclose recently an extended half-life for that molecule. We were pleasantly surprised to see that the half-life of the drug is approximately 3 to 4 days, which we think will actually do a really good job of controlling day-to-day fluctuations on serum calcium levels. But in terms of the full readout, obviously like all phase I trials, we're looking for safety and tolerability, that's number one. PK, we've already disclosed a little bit about the PK profile, but we'll disclose the full PK profile as well. For the SAD and the MAD, the two biomarkers that we're looking most closely at are endogenous PTH suppression and calcium increases.

Maybe it's worth a moment to just share that, for those of you who don't think about this every day, normal patients, normal healthy individuals are different than hypoparathyroidism patients in a very fundamental way, in that healthy volunteers like all of us would be, we have intact parathyroid glands, and that allows us to control the parathyroid hormone levels. The parathyroid hormone's the master regulator of calcium in the body. The endocrine loop is so efficient, it allows calcium to be controlled very steadily by dialing up or down PTH. So in a healthy volunteer, we're looking for PTH suppression, and in fact, we anticipate PTH suppression well before we start to see increases in calcium. So those will be the main biomarkers that we're looking for, and we hope that in our full SAD and MAD data set, we're able to share that.

Yeah, fortunately, we've had the PTH peptides pave the trail for us here. If you look back at the effective doses in hypoparathyroidism patients for a drug like YORVIPATH as an example, and look back at what that drug did in its phase I healthy volunteer study, there are some clear learnings in terms of the magnitude of effects that we hope to see with both PTH and calcium increases to identify a dose that may translate into hypoparathyroidism patients. Just to give you some numbers here, what we're looking for in PTH suppression is a decrease of about 50% or so. At that point, that's when calcium increases generally start to kick in, and we'd be looking for increases in serum calcium in the range of about 0.3-0.5 milligrams per deciliter.

That dose should, based on precedent with PTH peptides, translate actually very well to a starting dose for hypoparathyroidism patients. Another thing to remind everybody of here is that hypoparathyroidism patients on an individual-by-individual basis need to be titrated into the right drug levels. That starting dose is an important point because it does, in the case of YORVIPATH, it does control a decent percentage of the population, and others need to probably only go up a little bit from that baseline.

Yeah. The goals of that first phase II study in patients are pretty simple. Obviously, to show that we have pharmacology, but also to figure out what the starting dose is and that titration protocol. Fortunately, again, with our half-life being actually not that far off from YORVIPATH's apparent half-life. YORVIPATH is a sustained release form of PTH. While the PTH peptide itself is short-lived, their sustained release system mimics a half-life of about 2.5 days. We think with a half-life of 3-4 days, even if it is a bit longer than that, we should be able to leverage their learnings on how to titrate patients.

We will be thinking about ways to streamline that potentially a bit further to see if we can improve titration there.