Septerna 3rd Annual Guggenheim Healthcare Innovation Conference

All right, thanks everybody for joining us at Guggenheim's 3rd Annual Healthcare Innovation Conference. I'm Seamus Fernandez, one of the Senior Biotech Analysts here at Guggenheim, and I'm really pleased to be joined by the management team from Septerna. Immediately to my left is Jeff Finer, to his left is Liz Bhatt, and to her left is Gil Labrucherie. I am really terrible. Perfect.

Okay, close enough. CEO, Co-Founder, President, and COO, and CFO. Jeff's going to take us through just sort of a backgrounder, quick backgrounder on Septerna, but definitely one of the stories that we're particularly excited about here at Guggenheim.

Yeah, thanks, Seamus, and thanks to the Guggenheim team for inviting us. I'm going to run through a few quick slides, and my clicker is not working here. Our discussion today will include some forward-looking statements, so please take that into consideration. I want to jump right into our pipeline. Septerna, from the outset, has been a company focused entirely on GPCRs, or G protein-coupled receptors, and we found a new way to do drug discovery for GPCRs, and we don't have time today to go into our platform, but it's quickly yielded a portfolio that we're quite excited about. Four programs are shown here. I'll start from the top. SEP-479 is a parathyroid hormone receptor agonist, small molecule, that is in a phase I trial right now, and we anticipate having that phase I readout in the first quarter of next year.

Newly announced, just last week, is SEP-204. This is a thyroid-stimulating hormone receptor, negative allosteric modulator. It antagonizes the receptor. It's a small molecule as well for Graves' disease and thyroid eye disease. I'll have more to say about both of those programs. We also have an MRGPRX2 small molecule negative allosteric modulator called SEP-631. This one is through a phase I trial, so it's between phase I and phase II, and we are currently evaluating what mast cell indications to work on there. Also recently announced is a fourth early but discovery stage program in osteoporosis. This is a second approach to the parathyroid hormone receptor, where we've got also an agonist, but we need to have a short-acting agonist for osteoporosis, whereas, as we'll spend, I'm sure, a bunch of time talking about, for hyperparathyroidism, we want a long-acting small molecule agonist.

Below the deck there, we have a number of earlier research stage programs, and we also have quite a substantial collaboration with Novo Nordisk. This is a program that involves five targets, four concurrent programs, and is currently off to the races and moving along quite well. I want to quickly just give you guys some grounding on those first two programs. SEP-479, this is the hypoparathyroidism program. This is a very challenging receptor, one that our platform did crack multiple times. What you are looking at here is the PTH1R in magenta, the PTH peptide in green, G protein in blue. We found multiple ways to activate this receptor with small molecules. It had been a historical drug discovery challenge. It is where our platform really showed its colors. We ended up with SEP-479, which is a compound that we are quite excited about.

I will show you a little bit of data in a monkey, and then we will spend most of the time talking about the phase I trial. We have a compound with great pharmaceutical properties, as well as a half-life now that is in the range of about three to four days. This is a healthy volunteer study that is ongoing. Quickly, to show you a little bit of data, preclinical data, this is a monkey study, seven-day healthy monkey study, which is meant to simulate what we would hope to see in a healthy volunteer patient. Healthy patients, healthy subjects, as well as healthy monkeys, have intact parathyroid glands, and since the endocrine feedback loop is so efficient, the first thing we anticipate seeing is a decrease in endogenous PTH secretion, based on the endocrine feedback. That happens actually very quickly.

Once we reach a certain level, there is a threshold, we start to see serum calcium levels go up, as you start to see on the graph on the right. If we take the lessons from the PTH peptides that have been in the clinic and approved, including YORVIPATH, what we anticipate to see in a healthy volunteer, that should map to a hypoparathyroidism patient, is a decrease in endogenous PTH on the scale of about 50%, and then an increase in serum calcium on the scale of about 0.3-0.5 mg/dL. This phase I trial is ongoing. It is a standard single ascending dose, multiple ascending dose design. It is happening in Australia. Safety, tolerability is first and foremost. These are the important things we look at. PK, I just mentioned, and then the two key biomarkers, endogenous PTH and calcium.

We showed that this compound has a, in the SAD portion of the trial, a half-life of about three to four days. We extended the duration of the multiple ascending dose portion to 14 days to try to approach steady state dose levels. As I mentioned, what we will be looking for are changes on that scale of about PTH going down about 50% and calcium going up about, let us say, 0.5. We anticipate these results in Q1. Second program I want to just kind of kick off with and introduce you to is our new program focused on Graves' disease, going after the thyroid-stimulating hormone receptor. This is the receptor at the heart of Graves' disease. Graves' patients develop autoantibodies that bind to and activate this receptor, both in the thyroid gland as well as behind the eye.

leading to the changes of Graves' disease and thyroid eye disease. It's a receptor that undergoes a pretty significant conformational change. You can see that there's a very large extracellular domain. I'm showing you two different conformations, inactive conformation in blue, active conformation in magenta. SEP-204 binds in the transmembrane domain and prevents the activation of the receptor even when it has an autoantibody bound to it, which is exciting. SEP-204 is our development candidate. It's a potent oral small molecule. It has demonstrated inhibition of the receptor in the presence of Graves-derived antibodies. It's highly selective for this particular receptor. There are two closely related receptors, FSHR and LHR. These are reproductive hormone receptors. As Graves' is a disease of largely women of childbearing ages, we want to prevent the activation of those other receptors, I'm sorry, prevent the inhibition of those other receptors.

We've got a very high degree of selectivity, over 1,000-fold, and we've got robust PK/PD demonstrated in healthy animals, mice, rats, dogs, and monkeys. Don't have time to share all that today. What we expect to see in a healthy animal is, you can think of it a bit as the opposite of the PTH program. We see TSH levels going up, and then at a certain threshold, thyroid hormone levels starting to go down. The compound has excellent pharmaceutical properties. We're projecting a human half-life of about 20 to 40 days here. We've completed GLP tox studies in rats and dogs and hope to be in the clinic with this molecule in the first quarter of next year as well. I'm going to just show you a little bit of data. This was presented at the American Thyroid Association Conference just last week.

It's a rat study where we've dosed the rat with a human patient-derived antibody. This is a Graves' patient antibody. When you dose the rat, on the graph in the upper right-hand corner, with this antibody, 18 hours before dosing 204, you see thyroid T4 hormone levels going up. Then we're studying three different doses, one, three, and 10 mg/kg twice a day in a rat. We think it's a once-a-day drug in a human. You can see that the middle two doses, the lower two doses, normalize thyroid hormone levels, whereas the high dose suppresses it. This is kind of what we would anticipate to see. This gives an increasing suggestion that we may have dose optionality when we get into patients.

Hopefully be able to either dose to thyroid hormone normalization or go to a full suppression, depending on what we want to do. Last piece of data is in a mouse model. This is where we've dosed that Graves' disease antibody chronically now for six weeks. Actually, we dosed it for a total of eight weeks, and by week six, we've got a Graves' phenotype. Changes in the thyroid gland and behind the eye. We're looking at thyroid histology photos where we have significant changes in the Graves' mice that are reversed with the drug. The histology changes, the thyroid size also starts to normalize, and these Graves' mice also develop proptosis. This is effectively a mouse model of thyroid eye disease. It's a new model that we developed in-house.

You can see the middle photo there with clearly bulging eye, and you can start to see some reversal of that as well. These are data that we are excited about, and I think I have already summarized the main preclinical findings. Like I said, we are hoping to be in the clinic in the near future. We can just kind of maybe stop and have our pipeline chart there.

Great. Maybe just to follow up on the TSHR, it looks like you had an active control in that dataset. Can you just maybe help everybody understand the importance of the K1-70?