Okay, we'll get started. Good afternoon. I'm Eric Joseph, Senior Biotech Analyst with JPMorgan, and our next presenting company is Septerna. Presenting on behalf of the company is CEO Jeff Finer. There's a Q&A after the presentation. Just if you have a question, raise your hand. We'll bring a mic over to you, and if you're tuning in via the webcast, you can also submit questions via the portal, so with that, Jeff, thanks for joining us.
Okay. Thanks, Eric. I'm joined up here today by Liz Bhatt, our Chief Operating Officer, and Jay Kim, our Chief Medical Officer, who will participate in the Q&A after the presentation. I need to let everybody know that I will be making forward-looking statements today, so take that into account. Septerna, for those of you who are learning about us for the first time, is a company that's entirely focused on a class of cell receptors called G-protein coupled receptors, or GPCRs. And we've developed with our GPCRs a very new platform for GPCR drug discovery that we call the Native Complex Platform. I'll go over and review this platform with you guys. But one of the key features of it is that we're able to do very rapid and iterative structure-based drug design, so I'll focus on that.
From our portfolio standpoint, we've intentionally focused on highly validated targets, ones with good biological, and in many cases, clinical validation, that have just proven to be challenging from a drug discovery standpoint. Each of our programs also has an early clinical readout, usually a phase one biomarker, so we will know in phase one if our programs are on track, and each represents an area of significant unmet need and a large market opportunity. We completed our IPO in October, and that has left us with a good cash runway well into 2027. Today, we'll review four programs. SEP786 is a PTH receptor agonist for hypoparathyroidism. This is currently in a phase one trial, and we're anticipating being in a position to share results from that phase one trial with you mid-year.
Our second program, SEP631, goes after a mast cell target called MRGPRX2, and we're developing a negative allosteric modulator, or NAM. You'll hear me use that term NAM a couple of times. We believe there's a lot of opportunity in mast cell diseases, so we'll go over that with you as well. This is a program that's in IND enabling studies and should be in the clinic later this year if all continues to go well. Two earlier stage programs, thyroid stimulating hormone receptor, NAM, negative allosteric modulator. This is another oral small molecule for Graves' disease and thyroid eye disease, which we think has disease-modifying potential. And last but not least, we've got an incretin receptor agonist program. What we're doing here is actually quite different than what you've heard from other companies.
We've identified a novel binding pocket, and that novel binding pocket, we believe, gives us prospects for being able to get activity against multiple receptors from the same small molecule. To step back and give you guys a little bit of perspective, the GPCR target class has been one of the most productive in all of drug discovery history. This has led to hundreds of approved drugs, and there are actually hundreds of GPCRs represented by the branches on this tree. There's about 400 GPCRs here. Everywhere where you see a dot on this tree diagram is where there are approved drugs, and the larger the dot, the more approved drugs there are. So you can see that there's a concentration of the larger dots on the upper branch of the tree.
The concentration of GPCR drug discovery success has been something that not everybody has appreciated quite as much. More than 70% of all those 500 approved drugs target just six small subfamilies of GPCRs. There's a lot of other GPCRs out there that have just proven to be difficult to drug, and our goal as a company is to unlock those difficult to drug GPCRs with our Native Complex Platform. I'll introduce you briefly to the Native Complex Platform now. When we first started thinking about forming Septerna about six years ago, one thing that was quite obvious was that there had been a lot of new drug discovery technologies, but very few were being used for GPCRs.
And there was a significant limitation in applying those modern drug discovery technologies in that in order to use many of them, it required an ability to isolate the protein, in this case, the receptor, outside of a cellular environment. And that's where the Native Complex Platform comes in. So what do I mean by Native Complex? A Native Complex is a GPCR that's been taken out of a cell and reconstituted in a fully functional form with all of its naturally interacting partners, including the G-protein on the inner surface of the cell, the ligand on the outside of the receptor, and all reconstituted in an artificial lipid bilayer that mimics the cell membrane. So the receptor is entirely surrounded in all dimensions by its natural binding partners. And in this form, the receptor maintains all of its natural structure, function, and dynamics, and that's quite important.
What can we do with these Native Complexes? We can do a few things, one of which is to solve high-resolution 3D structures. Those high-resolution structures allow our chemists to know the exact binding pose of a compound. This has enabled us to identify novel binding pockets in receptors that were previously unknown. It's also allowed us to identify new ways of modulating these receptors in previously unexplained ways. In addition to finding structures, we've used these Native Complexes to screen literally billions of compounds. And we have two complementary approaches to do that. One is a computational approach, represented by the image on the right, where we dock virtually libraries of billions of compounds into pockets on our structures. There's a completely complementary biophysical approach to this, represented by the image on the left, which is using DNA-encoded libraries. So these Native Complexes are modular.
We can mix and match the pieces, mix in different G-proteins, different ligands. And by doing that multiple different ways with these DNA-encoded libraries, we've been able to date find compounds with pretty much any mechanism of action that we wanted. And these two things come together: the ability to find new chemical matter for our targets, as well as the ability to get structures in a very rapid and iterative structure-based design and optimization process. For each of our programs to date, and all four that I'll tell you about today, we found from the time we started medicinal chemistry to the time we had active compounds in animals was less than a year. So in terms of the structural biology, this is one area where we've really continued to do quite well. I wanted to show you a little bit more about that.
We're using a technology called cryo-electron microscopy, and with that, we can directly image the entire Native Complex, both the receptor and the G-protein. Once we have a structure for the first time, as often it's a little challenging with the first one, but once we get the first one, for each subsequent compound that our chemists make, we're able to get a structure as fast as a week or two. And this is really an unprecedented pace to be able to do this, and it's incredibly enabling. It allows our chemists to see the exact binding pose of the compound to high resolution. That can feed back on their design ideas to make a better and better compound. So we can run a very fast, rapid, and iterative structure-based design cycle. To date, we've solved over 100 structures with ligands bound. Several of those are shown in this diagram.
Each of the columns on this plot is a different GPCR, and each of the horizontal bars within each plot is a new high-resolution structure with a different ligand. They're color-coded by the type of mechanism of action of that ligand. And as you can see, it's actually a process that can be used for a variety of different mechanisms. If you look at the four taller bars, these represent lead optimization campaigns, and we will frequently solve between 10 and 20 plus structures. Okay, now pivoting to our pipeline. I mentioned these targets at the outset. And as I mentioned, the PTH program is in phase one. Again, we're hoping to have data later mid-year. MRGPRX2, IND enabling studies, again, data, hopefully not data, but going into the clinic this year. I wanted to point out two things. The second column is our therapeutic areas.
We have intentionally built the company as one where we will just go after the best ideas independent of therapeutic area. Currently, our programs are in three areas: endocrinology, immunology, inflammation, and metabolic diseases. There's more targets in the GPCRs for each of those. Listed below are several other therapeutic areas of interest for us that we've got some early stage efforts on, and the other thing I wanted to point out in the first column is the modes of action, because they really represent two of the challenges historically for GPCR drug discovery. So the first one, the PTH program, as well as the fourth one, the incretin receptor agonist, these are both small molecule agonists for peptide GPCRs. That's been a historic challenge for GPCR drug discovery. The middle two represent allosteric modulators, and in this case, negative allosteric modulators. So what is an allosteric modulator?
An allosteric modulator is a compound that basically binds in a different site than the endogenous ligand, and in that way, it can actually act as a tuner. It can actually either dial up the activity of the receptor or dial it down. In this case, in a negative allosteric modulator, we dial it down, and again, very few allosteric modulators have been approved, but our platform is hopefully one that can open this up in a large way. All right, so I'm going to pivot to SEP786, which is our lead program. In order to give you a little bit of introduction, I wanted to talk a little bit about hypoparathyroidism, very significant unmet need. In order to understand it, you have to get a feel for some of the physiology.
The parathyroid glands are located within the thyroid gland in the neck, and they release a hormone called parathyroid hormone, or PTH. PTH is the master regulator of blood calcium levels. It works through the PTH receptor that's located in the bone and the kidney. In the bone, it causes increases in calcium release. In the kidney, it causes increases in resorption of calcium from the urine so that it doesn't go out. In the kidney, it also increases the formation of vitamin D, which has indirect effects on the gut to increase absorption. All those metrics allow calcium levels to go up. For patients that have hypoparathyroidism, they've actually lost their parathyroid glands in most cases, usually by surgery, often by a thyroid surgery.
And when they lose those parathyroid glands, they lose the ability to make this hormone, and they can no longer control their calcium levels, and they end up going low. The effect of that is that these patients end up developing a number of challenging symptoms. I've got a few listed here: muscle cramps, tingling, brain fog. We've talked to patients. Many of them can't think straight. But it can also cause life-threatening complications because calcium is important in a number of other systems. It can lead to cardiac arrhythmias. It can lead to seizures. Long-term standard of care for hypoparathyroidism has been calcium supplements and vitamin D. That may sound relatively straightforward on the surface, but these are mega doses of calcium. These patients take several calcium pills every few hours, and so there's a lot of burden to that.
In addition to that, the calcium supplements related to the kidney function that I mentioned before lead to excessive amounts of calcium going into the kidneys, which can lead to kidney calcifications, kidney stones, and ultimately kidney failure in some cases. So more recently, as many of you guys know, there's been injectable PTH therapies that have been approved. These are hormone replacement therapies, but all of these will require lifelong injections, which isn't great for the patients. So our strategy has been to develop oral PTH receptor agonists to functionally replace PTH. So how did we find it? We found this with our Native Complex Platform. I want to introduce you to the PTH receptor, which is in blue there. The G-protein's in yellow. The PTH peptide may be a little hard to see, but it's in green. It's a long helical peptide.
It starts in the transmembrane domain and goes up onto the extracellular surface. We used our platform to probe a Native Complex that looks much like this. And this allowed us to find multiple chemical starting points. And this was quite rewarding because this is a target that a number of pharma companies have worked on literally for decades without any tractability. So it's a good use case for a historically difficult drug target. From there, we used our Native Complex-based structure-based design loop to rapidly optimize these. And we had multiple series that we took all the way to the point of activity in animal models, again, in less than a year. And out from there came 786. And 786 is a potent selective oral small molecule. As I'll show you on the next slide, it normalizes serum calcium in a preclinical model.
We've done PKPD modeling, which projects to full-day calcium control in patients with either once-a-day or twice-a-day dosing. And it's currently in a phase one trial in healthy volunteers. The animal model data that I wanted to share involves this rat surgical model of hypoparathyroidism. We surgically remove the parathyroid glands. These animals develop hypocalcemia. And then the idea is if we dose our drug, could we normalize serum calcium? The first thing we wanted to figure out is whether or not we could actually mimic an injectable PTH peptide with an oral small molecule. And that data is shown here. This is just a single-dose study. We're looking at serum calcium levels. The gray band across the plot indicates the normal calcium level. And the black curve is long-acting PTH, so that's a subcutaneously dosed peptide. The colored curves are our compound, SEP786, at three different doses.
You can see at the high dose, we're actually completely mimicking the profile, and the time course of calcium increases as the injectable peptide. What we want to do clinically, however, is we want to be in that normal calcium range all day long for patients. What we did was we took the low dose there in purple and then did a 28-day study. This is a 28-day study where we dosed that 3 milligrams per kilogram twice a day. If you look in at detailed time courses on any one of the days, we chose four days throughout that 28-day period, we're able to maintain serum calcium within that normal range for that entire timeframe. Again, this was quite exciting. Additional preclinical studies we did were PK studies across a whole variety of different species.
That led to human PK predictions that would be consistent with either once-a-day or twice-a-day dosing. We also did 28-day GLP-toxicology studies in rats and dogs. The compound was well tolerated. The only effect that we did see when we went up to very, very high levels were signs of exaggerated on-target pharmacology. So if you take these animals up to very high levels of serum calcium, they start to have calcification. We would never go up to that level in a human. So phase one trial's underway. As I mentioned, it's in healthy volunteers. It's a standard single ascending dose, multiple ascending dose design. We're looking in the MAD portion at both once-a-day and twice-a-day dosing. Primary endpoints are safety and tolerability. And in addition to that, we're looking at PK, calcium, and other biomarkers. Okay, moving on to our second program, SEP631 for mast cell diseases.
So a little bit on MRGPRX2. It's an emerging target for mast cell diseases. The canonical pathway for mast cell activation, mast cells are obviously, as you guys know, involved in the allergic response, involves IgE and allergens binding to a high-affinity IgE receptor on the surface of a mast cell. That leads to degranulation of the mast cells and the release of a whole variety of inflammatory mediators, including histamine and a bunch of others listed there. About a decade or so ago, there was a new receptor identified called MRGPRX2, which is on this receptor and represents a different pathway. It responds to several different endogenous agonists. These are peptides and other things in your body that activate this receptor, and they too can actually lead to mast cell degranulation. When they cause the degranulation, they actually cause degranulation in a slightly different way.
You get release of different granules. We've studied that with overlapping mediators. The effect of that mast cell degranulation can lead to a bunch of symptoms listed at the bottom, but our interest here is that there are a lot of mast cell-driven diseases. I've listed just a couple here: chronic spontaneous urticaria or CSU, atopic dermatitis, allergic asthma. There's a whole bunch of others. In terms of CSU, this is where the mast cell space is getting a lot of focus. Patients develop these itchy, painful hives. These are chronic symptoms that can be debilitating to be itching all night. People can't sleep. There's significant effects of that. First-line therapy is antihistamines. That works for a decent number of patients, but about 37% are refractory.
Second-line therapy for those refractory patients is an anti-IgE therapy, usually Xolair, but the large majority of those are also refractory in that second-line therapy. So that's evidence that there's an additional pathway in play here. So our strategy has been to develop these negative allosteric modulators that I described before. So SEP631 is a potent oral small molecule. It blocks activation by all endogenous agonists. We've done several. It also has an insurmountable negative allosteric modulator profile. And what do I mean by that? Insurmountable means that once the compound is onto the receptor, the receptor can't be activated at all by even excess amounts of an endogenous agonist. It also has a very long half-life. Once the compound is on the receptor, it's on there for hours. So we've taken this compound into preclinical models.
One of the challenges for this particular receptor is it's not well conserved across species. So we had to make a knock-in mouse. So we removed the mouse's natural gene, replaced it with the human gene. And this model system we have here is one that we think is quite relevant to urticaria and other skin conditions. So we first give the animal an oral dose of our compound, and then we dose the animal through an IV with a blue dye. That blue dye goes into the bloodstream. And the third thing we do to the animal is we give it an intradermal skin challenge. In this case, with an MRGPRX2 agonist, Cortistatin-14, at the site of that injection, we get extravasation of that blue dye from the blood compartment into the skin compartment. So it's like giving this mouse effectively a little blue hive.
Ideally, if you were able to inhibit MRGPRX2, you would not get that extravasation. That's exactly what's shown in the data on the right. The tall blue bar there represents the significant amount of extravasation you get normally. The Y-axis there is fold-over vehicle. One is basically the zero extravasation line. You can see with three milligrams per kilogram of SEP631, we're completely shutting this down. We're getting no extravasation. That's quite exciting. Additional data that we have that I don't have time to share with you is that we did some studies with primary human mast cells as well, and we showed that we can completely inhibit activation and degranulation of those mast cells as well.
So with SEP631, we think we've got a compound with a differentiated profile, very high potency, single-digit nanomolar or picomolar by some metrics, broad inhibition, great oral bioavailability, great PK that we think projects to once-a-day dosing in humans. I showed you some PD data. And from a safety standpoint, this compound's actually looked very, very clean. We've done 14-day non-GLP-tox studies in rats and dogs, very favorable safety profile there. And the compound is currently in IND enabling studies. And as I said earlier, we hope to be in the clinic later this year. Okay, moving on to two shorter stories now. The thyroid-stimulating hormone receptor, negative allosteric modulator for Graves' disease and thyroid eye disease. So Graves' disease and thyroid eye disease share a common etiology. Individuals develop autoantibodies that bind to the TSH receptor. The TSH receptor is in the thyroid gland.
That's how you end up increasing your thyroid hormone levels, so these individuals end up with hyperthyroidism. The TSH receptor also happens to be on a different set of cells, orbital fibroblasts behind the eyes, and in that setting, when that receptor is stimulated, you get an expansion of the fat behind the eyes, and that fat leads to the classic proptosis that thyroid eye disease patients are experiencing. Historically, treatment for Graves' disease has involved anti-thyroid drugs, radioactive iodine to ablate the thyroid, or surgically removing the thyroid. If you treat Graves' disease with any of these methods, patients can still go on to having thyroid eye disease because those antibodies are still running around. On the flip side of that, if you treat thyroid eye disease with either historically surgery or more recently Tepezza, you're actually not treating the Graves' part of the disease either.
Tepezza is an anti-IGF receptor antibody. It's shown great data, as many of you know, in decreasing proptosis, but it requires multiple IV infusions over several months. And more recently, it's been associated with some significant side effects, including hearing loss. So the drug discovery challenge for both of these conditions is that every patient develops their own autoantibody. And in many cases, they're actually polyclonal. Within a given patient, there's several different antibodies. And so the challenge is, how are we possibly going to find something that inhibits the activity of all of those? So what we set out to do was very similar to the last program, come up with a negative allosteric modulator that would have this universal approach to inhibit all patient antibodies. And that's exactly what we found. We found some selective TSH receptor negative allosteric modulators.
They blocked activation by all patient-derived antibodies that we've been able to get our hands on. And they also have insurmountable profiles, much like what I mentioned in the last program. Preclinically, we got our hands on some Graves' disease polyclonal serum samples, also on some primary orbital fibroblasts isolated from patients who had thyroid eye disease surgery, and it fully inhibited the activation of those patient serum samples on those cells. So we're enthusiastic about the universal mechanism. From an animal model standpoint, we had to invent a model. There actually wasn't a great Graves' disease model in mice. And what we did was we found a way to take a patient-derived antibody. We found one that cross-reacts with the mouse's receptor, and then we treated the mouse over and over and over again for six weeks with that antibody.
It developed all the hallmarks of Graves' disease: increased thyroid hormone levels, the thyroid got enlarged, and the eyes began to bulge. I'll show you that in a moment. In the setting of continuing to dose with that activating antibody, we asked, could we inhibit that effect with our compound and reverse these effects? First, on the thyroid side of the equation, the left plot shows that the Graves' animals, which are shown by the magenta bar, have thyroid T4 hormone levels about three times normal. Within about a week of dosing of our compound, we've been able to bring that all the way back down. The next plot over shows that the thyroid size, these thyroids get enlarged. It's almost double in mass if you actually take and weigh the thyroid glands.
Just within one week of dosing, we're able to get that substantially on its way to reversal as well and then this is kind of a first-of-its-kind picture of mice with thyroid eye disease represented by the two middle photos. You can see the characteristic bulging of the eyes and then on the lower two photos, you can see that we're able to start to reverse some of that as well so very exciting progress there. We're continuing to optimize our compound there. We don't have a lead compound quite yet. All right, and the last program I want to introduce you to very briefly is our incretin receptor agonist and I mainly want to make the point that we're doing something quite different than what everybody else is doing.
I don't need to tell you guys that the incretin receptor peptides have been transformative in clinical care over the last couple of years. Our strategy has been to focus on oral small molecules and to develop next-generation incretin receptor oral small molecules. And the key to this is that with our platform, we identified a novel binding pocket. And this novel binding pocket is one that has similarity across three different incretin receptors: GLP-1 receptor, GIP receptor, and the glucagon receptor. That's what GCGR is. That's the glucagon receptor. And that has much better sequence similarity across our pocket relative to the small molecule GLP-1 compounds that are currently in clinical development. So the plot on the right, or the figure on the right, shows that the donnaglipron and the orforglipron scaffolds, these are the two most common GLP-1 small molecule scaffolds.
It's about 40%-60% sequence similarity across the three receptors. With our binding site, if you look in the vicinity of the binding pocket, it's about 80%-90%. So we think we have got a real shot at being able to get multi-incretin receptor agonists, and we have. We have found a number of compounds that have multiple different profiles. We're currently pursuing three different profiles: a mono GIP receptor agonist, a dual GIP receptor glucagon receptor agonist. Each of those first two could be theoretically combined with GLP-1 therapies, either peptides or small molecules. And we've also started to get some traction now on a triple, meaning that we've got an oral small molecule that can actually hit all three receptors and activate them all simultaneously. So I wanted to just share one piece of data here. This is for a mono GIP receptor agonist.
What you can see is this is a weight loss study in a diet-induced obese mouse. And we've tested our compound plus and minus semaglutide, which is the kind of gold standard GLP-1 peptide. So the magenta curve shows that we get a little bit of weight loss with our compound. The light blue curve is sema. You can see significant weight loss there. The green curve is tirzepatide, tirzepatide is the dual GLP-1 GIP peptide. And potentially the most interesting curve is the purple one. The purple one is our compound dosed orally on top of semaglutide dosed subcutaneously. And from that profile, you can see that we're completely mimicking the profile of tirzepatide. So we're getting exactly the additive activity. And so this has given us a lot of confidence that we are having the type of pharmacology that we want.
All right, so just to wrap up now, I just want to say a few words about the company, our leadership team, in addition to Liz and Jay, who are up here today. Gil Labrucherie just joined us as CFO. We announced his arrival last week. And then we have, across the board, other leaders. Everybody on this top line has at least two decades of experience. And so we've got a lot of confidence in our leadership team, and we've got a great board and set of scientific founders and advisors. So just to kind of wrap things up, I just want to come to conclude on a few points. One, again, most importantly, is that our PTH receptor program, SEP786, is going to have data, hopefully, mid-year that we can share. That's exciting. We also have multiple products behind that.
Each one of these programs, if you look at each one of them individually, each is a potentially multi-billion-dollar market opportunity. Our Native Complex Platform has really been the secret that's enabled us to create this type of pipeline at this speed. And we think it can allow us to further expand our pipeline in the future. And as I mentioned at the outset, we're well capitalized at this point in time. So with that, we can take some questions.
Oh, excuse me. We're great. We do have some time for questions. So maybe I'll just start off with a question on SEP786 and hypoparathyroidism, just with data from healthy volunteers reading out in the middle of the year. Maybe Jeff, perhaps you can set the stage a little bit there for sort of the, I guess, the sort of quantum of data that you hope to present and just the utility that seeing change in, or the amount of calcium change that you may be able to see in healthy volunteers to the extent that might actually de-risk the path forward in patients.
Okay, yeah. Yeah, in terms of the data that we plan to share mid-year, it's going to be healthy volunteer data. It's going to be the single ascending dose and multiple ascending dose data there. In addition to the safety and tolerability, which are the number one things, we're going to be looking at calcium. We're going to be looking at PK. We're going to be looking at other biomarkers. There's another important biomarker that we're heavily focused on is endogenous PTH levels.
And just to maybe add a little story there, one thing that we have to our advantage is that there are peptides that have paved the trail ahead of us, and we've been able to learn from their data what they have, and I think between calcium and PTH, what's clear is that a healthy volunteer is actually different than a patient. A healthy volunteer actually has PTH levels that it can modulate. It can dial them up and dial them down. And so I think as we look forward to that data, I would say the combination of calcium and endogenous PTH are actually going to be pretty important markers for us. Jay, I don't know if you have anything to add to that.
No, that's great.
Maybe just say a little bit more than that. What's your expectation around how PTH levels will change basically in a healthy volunteer patient? You expect them to kind of go down?
Yeah, at a high level, yes, SEP786 is being designed as the first-in-class oral small molecule replacement for parathyroid hormone. So as Jeff was saying, that in the phase 1 first-in-human study in healthy volunteers, our expectation is to see that single and multiple doses of SEP786 will result in sustained increases in serum calcium. And if you have the corresponding reciprocal reductions in endogenous PTH, that should be sufficient to declare clinical proof of concept that SEP786 can replete parathyroid hormone function.
Got it. Okay. Right. So seeing both signals just substantiates target engagement as opposed to serum calcium increases for some other reason.
Yeah, exactly. So, a healthy volunteer actually can't push its calcium levels up as aggressively because the feedback loops cause the PTH levels to go down.
Okay. Got it. Okay, great.
Looked like there was another question in the audience.
Regarding this, hypoparathyroidism generally comes from some sort of surgical.
Hypoparathyroidism generally comes from parathyroidectomy. Is there any interest in for hypoparathyroidism? Is there any interest in treating hypoparathyroidism and getting in on that side of the disease before patients need a parathyroidectomy?
Usually it's a surgery not related to taking out the parathyroid glands. It's often a thyroid effect that leads to the surgery. The most common is thyroid cancer, where somebody will take out the whole thyroid gland or Graves' disease, another example that we've talked about. Our compound should really only work in the direction of basically increasing the parathyroid function. On the hyperparathyroid function, we need a different molecule. We need an inhibitor instead.
What do you think about making that?
We think it's interesting. I mean, it's something that we're starting to look into.
You made reference, obviously, to the injectable PTH agonist, right, and just sort of the burden for patients there with chronic injections. Obviously, having it in oral modality is more amenable. Obviously, it is a convenience advantage for patients. I guess, what other perhaps differentiators do you think about in a targeted product profile, I guess, with 786? And with those in mind, can you talk a little bit sort of how that intent might be built into a subsequent trial, a phase two trial?
Yeah. Liz, do you want to comment on the?
Yeah, I can comment a little bit initially on the commercial opportunity. As Jeff mentioned, hypoparathyroidism patients right now with current standard of care take very high doses of calcium and vitamin D, and that's just really challenging for me. Speak to patients, it really is a burden for them. There are injectable peptides coming. Those are primarily going to be daily injections, and this is really as a chronic therapy, so we've heard loud and clear from patients that an oral option is really highly desired for them
And so we do believe that this provides an option actually for all hypoparathyroidism patients, not just those who are going to be severe, but those who potentially could be mild to moderate as well and really come off current standard of care. Or they're going to learn a lot more about the program as we go through clinical development and the opportunity to treat some of the additional symptoms that go along with the disease, like brain fog, etc., as we learn more about the compound through clinical development.
Okay. Oh, yes, I have a question here. Just, I guess one question is, how close are you going to be to achieving your expectations on a therapeutic dose? And I guess, how do you think about the mitigation of off-target toxicity?
Yeah, so in terms of off-target toxicity, we've done a lot preclinically to try to do that. We've tested a whole variety of different receptors and everything we can find. We haven't found any off-target effects so far. In terms of getting a dose, Jay, do you want to talk about our strategy there?
Yes, I think so. There's been ample precedent in developing therapeutics that replete parathyroid hormone function, and based on the healthy volunteer data in serum calcium response and endogenous PTH reductions, that we should be able to extrapolate will be a reasonable starting dose in the patient population, but not only that, the goal is to have a starting dose that most patients will be able to stay on chronically without requirement for up-titrations, and I think you've seen with Yorvipath and also with other peptide therapeutics that there should be a reasonable dose level that most patients can achieve normal calcemia and independence from supplemental calcium and vitamin D, and that will be our goal as well.
I don't know if you noted it. How long is the MAD portion of the phase one healthy volunteer study?
Yeah, it's five days currently. That's our plan. We have the flexibility to lengthen that. But the reason we chose five days was because we think we will be at steady-state drug level at that point in time.
Okay. Yeah, just kind of a forward developmental question. Just walk us through the various, the additional perhaps dose-finding studies in a patient population and then what ultimately sort of a pivotal study might look like in terms of size and timeline, that kind of thing.
Yeah, so it's pretty early to speculate on that at this point in time. We're going to think a lot more about what those trials look like. We're hoping to, when we announce our phase one trial results mid-year, that we'll be able to at least share what the next trial looks like.
Okay. Got it. And maybe just one question on the MRGPRX2 asset, SEP631. Obviously, there was a setback with a competitor compound not being moved forward. But that seems to be very molecule-specific. To some extent, the target sort of is yet to be sort of de-risked. So with the phase one study that you expect to launch later this year, I guess, how, apart from sort of clinical endpoints from a biomarker side, is there a profile that you would look to to support kind of proof of concept that de-risked the target?
Yep. Jay, do you want to comment on that one?
Sure. As you've said, there has been a setback for Incyte's asset that appears to be drug-specific and not a class effect. At a high level, going into the clinic, as Jeff has stated, we've done some extensive non-GLP toxicity studies. From that, we are anticipating that our IND-enabling GLP tox studies will be able to support our first-in-human studies with an ample non-clinical safety margin. We are anticipating that we should have great margins in support of our human studies. In terms of what we're going to use in terms of biomarkers and proof of concept, I think we have not disclosed that at this time. As Jeff said, we are planning to start our phase one study this year.
Okay, got it. Okay, great. Well, I think let's leave it there for time. So thanks everybody for tuning into the session. And thanks, Jeff and team, for the presentation and the Q&A. Thanks.